Magellan Rx Report Spring 2020
Rare Liver Disease Update: Nonalcoholic Steatohepatitis
Managing Obesity: Weight-Management Programs and Gaps in Strategies
Multiple Sclerosis: Therapy Recommendations and Treatment Advances
Gene Therapy: Changing Market Landscape and Pipeline
Magellan Rx Report MEDICAL AND PHARMACY BENEFIT MANAGEMENT Spring 2020
Autoimmune Diseases: Emerging Therapies and Management Strategies
IN THIS ISSUE | Spring 2020
Managed Care Newsstand
Rare Liver Disease Update:
Introducing MRx Navigate:
Emerging Therapies and Management Strategies
Therapy Recommendations and Treatment Advances
Whole Patient Care Meets Digital Innovation
Published By Magellan Rx Management 15950 N. 76th St. Scottsdale, AZ 85260
Contributors Caroline Carney, M.D., M.Sc., FAPM, CPHQ
Tel: 401-344-1000 Fax: 401-619-5215
SVP, Market General Manager, MRx Specialty
magellanrx.com Editor Lindsay Speicher, J.D.
Project Manager, Magellan Method email@example.com 401-344-1105
Advertising, Sales and Distribution Carole Kallas firstname.lastname@example.org 401-344-1132
Changing Market Landscape and Pipeline
Employer Weight-Management Programs and Gaps in Strategies
CMO, Magellan Rx Management
Steve Cutts, Pharm.D.
Haita Makanji, Pharm.D.
VP, Clinical Strategy and Innovation, Specialty
SVP, Sales and Business Development, Specialty
Yousaf Ali M.D., FACR
Chief, Division of Rheumatology, Mount Sinai West; Associate Professor of Medicine, Icahn School of Medicine at Mount Sinai
Steven L. D’Amato, B.S.Pharm.
Executive Director, New England Cancer Specialists
Joseph Mikhael M.D., M.Ed., FRCPC, FACP
Chief Medical Officer, International Myeloma Foundation
Natalie Tate, Pharm.D., MBA, BCPS Vice President, Pharmacy Management, BlueCross BlueShield of Tennessee
Steve Marciniak, R.Ph.
VP, Business Development, Magellan Method
Director II, Medical Benefit Drug Management, BlueCross BlueShield of Michigan
Stacy Inman, Pharm.D.
Saira A. Jan, M.S., Pharm.D.
Senior Clinical Project Manager
Director of Pharmacy Strategy and Clinical Integration, Horizon BlueCross BlueShield of New Jersey
Brian Kinsella, Esq. The content of Magellan RxTM Report — including text, graphics, images, and information obtained from third parties, licensors, and other material (“content”) — is for informational purposes only. The content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Magellan RxTM Report does not verify any claims or other information appearing in any of the advertisements contained in the publication and cannot take responsibility for any losses or other damages incurred by readers in reliance on such content. Developed by D Custom.
Senior Legal Counsel
VP, External Communications
Director, External Communications
Editorial Advisory Board Mona M. Chitre, Pharm.D., CGP
Chief Pharmacy Officer & VP Clinical Analytics, Strategy & Innovation, Excellus BlueCross BlueShield
Dennis Bourdette M.D., FAAN, FANA
Chair and Roy and Eulalia Swank Family Research Professor, Department of Neurology, Oregon Health & Science University
A NOTE FROM OUR CMO
Dear Managed Care Colleagues, Welcome to our spring 2020 issue of the Magellan Rx Report! 2020 is off to an exciting and fast-paced start. Already this year, 11 novel drugs have been approved by the U.S. Food and Drug Administration (FDA), with many more to come. Magellan Rx Management is committed to keeping our clients and partners informed by reporting upto-date managed care trends and offering valuable insight into anticipated drugs in our MRx Pipeline.
Other timely topics include the shifting landscape of gene therapy (page 30) and a new medical management program, MRx Navigate (page 26). No issue of the Magellan Rx Report would be complete without our Managed Care Newsstand highlighting current hot topics (page 4). To learn more about Magellan Rx Management and our support of the payer initiatives of the future, please feel free to contact us at MagellanRxReport@magellanhealth.com. As always, we value any feedback you may have. I hope you enjoy the Report! Sincerely,
This issue’s cover story (page 6) focuses on the current state of treatment, FDA approvals, and the pipeline for autoimmune diseases and associated implications for managed care. A second feature (page 18) discusses current treatment guidelines and therapy recommendations, advances in treatment, and pipeline therapies for multiple sclerosis.
Caroline Carney, M.D., M.Sc., FAPM, CPHQ In the first installment of a new MRx Report series, this issue also explores the importance of obesity management and gaps in employer-sponsored weight management programs (page 45). The series will dive into the structure of an effective weight-management program and conclude with the results of an implemented, real-world, employer-sponsored weightmanagement program.
Chief Medical Officer Magellan Rx Management
SUBSCRIBE TODAY! Stay on top of managed care trends and become a Magellan Rx™ Report subscriber. Email us at MagellanRxReport@magellanhealth.com to subscribe today. Magellan Rx™ Report provides pharmacy and medical management solutions for managed care executives and clinicians. We hope you enjoy the issue; thank you for reading.
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MANAGED CARE NEWSSTAND FDA Proposes Rule to Allow Importation of Prescription Drugs The U.S. Food and Drug Administration (FDA) issued a proposed rule in December seeking comments on a proposal to amend Section 804 of the Food, Drug, and Cosmetic Act that would allow the importation of prescription drugs from Canada. President Trump has expressed support for the notion as a way to reduce drug costs. States including Florida, Colorado, Maine, and Vermont have expressed interest in the proposal. PhRMA, the trade association representing the drugmanufacturing industry, has expressed concern, calling the proposal a political move rather than a pragmatic policy solution. There are no estimates as to the possible savings under the rule, since it is unclear how many states might participate. The FDA framed it as a proof-in-concept proposal that could be expanded if successful. The rule-making process is expected to take some time.
House of Representatives Passes Legislation to Require Government Negotiations of High-Cost Drugs The U.S. House of Representatives passed legislation in December that would require the federal government to negotiate payment rates for up to 250 of the highest-priced drugs in the U.S. that face little or no competition. Negotiations would be based on an international pricing index that averaged the prices of drugs from six developed countries (France, Canada, Germany, UK, Japan, and Australia), with prices capped at 120% of the international
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In February, the Centers for Medicare & Medicaid Services issued its proposed rule and Advance Notice Part II for changes to the Medicare Advantage and Part D programs. pricing index. The Congressional Budget Office (CBO) estimated that the bill would save more than $450 billion over 10 years. The bill, HR3, passed 230192 with two Republicans in support and no Democrats in opposition. The White House stated it would veto the bill if it reached the president’s desk. The Senate majority leader stated that the bill would not be brought up in the Senate. Senate leaders continue to push for their own drug-pricing legislation. The Senate Finance Committee passed drug-pricing legislation in July that would limit Medicare drug-price increases to the inflation rate; CBO estimated 10year savings at $100 billion. However, the bill has yet to reach the Senate floor. Many Republican senators oppose the bill, calling it government interference in the marketplace. Senate majority leader Mitch McConnell stated in February that the bill faced “internal divisions” among Republicans and would not likely move to a floor vote until those divisions could be overcome. The committee bill
passed 19-9 with all Democrats voting in favor of the bill and nine Republicans on the Republican-led committee voting against it.
CMS Releases Advance Notice and Proposed Rule for Medicare Advantage and Part D Programs In February, the Centers for Medicare & Medicaid Services (CMS) issued its proposed rule and Advance Notice Part II for changes to the Medicare Advantage (MA) and Part D programs. The proposed changes are expected to increase payments in the MA program by 0.93% and in the Part D program by 2.85%. The proposed rule intends to do the following: • Codify the SUPPORT Act, a recent law dealing with opioids that requires Part D plans to implement drugmanagement programs by 2022. • Amend network adequacy requirements. • Prevent contracting with look-alike Dual-Eligible Special Needs Plans. • Allow individuals with end-stage renal disease to enroll in MA plans beginning in 2021, removing the prohibition that has been in place before the passage of the 21st Century Cures Act. • Allow for a second “preferred” specialty tier with lower cost-sharing obligations. • Call for real-time drug-pricing cost comparisons beginning in 2022.
CREATES Act Included in Final End-of-Year Spending Bill Passed by Congress President Trump reached an agreement with Congress in December on an end-ofyear spending bill for 2020. The federal government had been operating on a temporary spending bill since Oct. 1, the
start of the federal fiscal year. Included in the package of tax and spending bills was legislation titled the Creating and Restoring Equal Access to Equivalent Samples (CREATES) Act of 2019. This bill, first introduced in 2016, prevents brandname drug manufacturers from refusing to sell samples to generic manufacturers in order to block the introduction of generic alternatives and allows generic companies to sue drug manufacturers for access to these samples. The legislation will help speed the introduction of generic drugs to the marketplace and carries estimated savings of $3.8 billion to Medicare and Medicaid programs over 10 years.
FCC Approves 988 as Future Suicide Prevention Hotline Number In December, the Federal Communications Commission (FCC) unanimously approved the creation of a three-digit suicideprevention hotline — 988 — similar to the current 911 emergency call system. Congress passed legislation in 2018 directing the FCC to examine the feasibility of establishing a nationwide hotline similar to 911. The FCC approval begins the process to establish the hotline, which will take an estimated 18 months. It will cost approximately $500 million in the first year of operation, with costs dropping to under $200 million in year two. Approximately 2.2 million people called the current 10-digit suicide prevention lifeline in 2018. Approximately 47,000 people died of suicide in 2017, an increase of over 33% since 1999. Suicide rates have increased from 10.5 per 100,000 to 14 per 100,000 over the past two decades.
CMS Allows for States to Shift to Block Grant Funding for Medicaid In late January, the CMS announced optional demonstration authority for states to shift their Medicaid program to a block grant financing model, which the CMS referred to as the Healthy Adult Opportunity (HAO) program. While the CMS cannot impose block grants on states, it invites states to opt into a block grant or per capita cap funding model as a demonstration project, also known as a waiver under Section 1115 of the Social Security Act. The demonstration would provide states with unprecedented flexibility to tailor their state Medicaid programs. Under the guidance, states could pursue an aggregate cap or a per capita cap financing model for populations not eligible under their state plan. Under both financing approaches, states could design benefit packages (including drug formularies), cost-sharing requirements, and delivery care models within broad parameters. As part of the program, and to ensure accountability, the CMS would impose various monitoring, evaluation, and reporting requirements on states. At this point, it is not clear if any state will pursue block grant demonstration with the federal government.
Language to Ban Spread Pricing in PBM Contracts Included in Surprise Medical Billing Legislation In December, committee leaders in the Senate HELP Committee and House Energy and Commerce Committee announced an agreement on surprise medical billing legislation that would limit costs to consumers who seek care at an in-network facility but are charged out-of-network costs by providers who are not in-network within that facility. The legislation includes provisions that would:
• Ban spread pricing, or the shifting of the variability of risk from plans to pharmacy benefit managers (PBMs), in both commercial and government markets, and instead require that all contracts have passthrough pricing, meaning risk is borne by the plan sponsor and not the PBM. • Require that all rebates and discounts be passed through to plan sponsors. • Require regular reporting to plan sponsors of all costs, fees, discounts, and rebates associated with PBM contracts. The House Ways and Means Committee marked up surprise medical billing legislation in February that differs significantly from the other committees’ bills. Given that the significant policy discrepancies reflect the differences in insurers’ and hospital and provider groups’ views on how to address surprise medical billing, it is not clear if the legislation will pass this year.
SCOTUS to Hear PBM/ERISA Case: Rutledge v. PCMA On Jan. 10, 2020, the U.S. Supreme Court announced that it will hear Rutledge v. Pharmaceutical Care Management Association (PCMA). In 2015, Arkansas enacted a MAC Transparency law that imposed new regulations on PBMs and their relationships with pharmacies. The PCMA filed suit challenging the Arkansas statute preempted by the Employee Retirement Income Security Act of 1974 (ERISA) and Medicare Part D plans. The Supreme Court will hear the case in April; a decision is expected by the end of June. ERISA has long enabled employers to provide consistent, nationwide healthcare benefits due to its preemption of state laws.
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Autoimmune Diseases: Emerging Therapies and Management Strategies With millions of patients in need of effective treatments, there are several strategies around formulary management that managed care organizations can consider for managing the growing use and cost of biologics. A primary function of the body’s immune system is to protect against foreign microorganisms, such as viruses or bacteria, to prevent infection and disease.1, 2 Under normal conditions, the immune system identifies these foreign invaders and produces antibodies or sensitized lymphocytes to target and destroy unhealthy cells.1 However, in individuals with an autoimmune disease, the immune system becomes unable to differentiate between normal cells and unhealthy cells and therefore targets and attacks healthy organs and tissues; the exact causes of this phenomenon are not fully understood.2
Saira A. Jan, M.S., Pharm.D. Director, Enterprise Pharmacy Horizon BlueCross BlueShield of New Jersey
According to the American Autoimmune Related Diseases Association (AARDA), more than 100 autoimmune diseases have been identified to date.1 Furthermore, a 2016 report from PhRMA on medicines in development for autoimmune diseases highlights the fact that autoimmune disease affects more than 23.5 million Americans, with more than 75% of those individuals being women.2 Progress in understanding potential developmental factors of autoimmune disease continues; current research suggests a genetic component and a higher incidence in women. Although the cause is unclear, environmental factors such as foods, chemicals, and physical trauma can also trigger the immune system to target and attack normal, healthy cells.1, 2 Here, we focus on rheumatoid arthritis, psoriasis, and inflammatory bowel disease — including both Crohn’s disease and ulcerative colitis — which are among the most common autoimmune diseases in the U.S., collectively affecting approximately 10 million individuals.3 These chronic conditions, all characterized by immune-mediated inflammation of unknown cause, are without cure. Affected individuals experience significant morbidity, reduced survival, and lower health-related quality of life compared to their healthy peers.3
Current State of Treatment Generally, the primary goal of treatment in autoimmune disease is to control the patient’s symptoms by controlling the autoimmune reaction that caused the disorder.4 In many cases, proper drug
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Table 1. FDA-Approved Targeted Immune Modulators*7-26 Psoriasis
Adalimumab (Humira®, AbbVie)
Certolizumab pegol (Cimzia , UCB)
Etanercept (Enbrel®, Amgen)
Golimumab (Simponi®, Simponi Aria®, Janssen)
Infliximab (Remicade®, Janssen)
Brodalumab (Siliq™, Bausch Health [formerly Valeant]) IL-17R inhibitor
Ixekizumab (Taltz , Eli Lilly) IL-17A inhibitor
Guselkumab (Tremfya®, Janssen) IL-23 inhibitor
Risankizumab (Skyrizi™, AbbVie) IL-23 inhibitor
Sarilumab (Kevzara®, Sanofi/Regeneron) IL-6 inhibitor
Secukinumab (Cosentyx , Novartis) IL-17A inhibitor
Tildrakizumab-asmn (Ilumya™, Merck) IL-23 inhibitor
Tocilizumab (Actemra®, Genentech) IL-6 inhibitor
Ustekinumab (Stelara®, Janssen) IL-12/23 inhibitor
Baricitinib (Olumiant®, Eli Lilly)
Tofacitinib (Xeljanz®, Pfizer)
Upadacitinib (RinvoqTM, AbbVie)
Targeted Immune Modulator TNFα Inhibitors
CD20-Directed Cytolytic B-Cell Antibody Rituximab (Rituxan®, Genentech/Biogen) IL Inhibitors
Integrin Receptor Antagonist Vedolizumab (Entyvio®, Takeda) JAK Inhibitors
T-Cell Costimulation Modulator Abatacept (Orencia®, Bristol-Myers Squibb) *Products may have additional indications not listed here. Abbreviations: IL=interleukin, JAK=Janus kinase, R=receptor, TNF=tumor necrosis factor
therapy may lead to symptom remission. Some commonly used medications include anti-inflammatory agents such as corticosteroids, as well as nonsteroidal immunosuppressant agents such as sirolimus, methotrexate, and cyclophosphamide.4 More recently, disease-modifying drugs such as etanercept, adalimumab, and infliximab have been used to stop inflammation and slow the damage in certain autoimmune diseases, including rheumatoid arthritis.4 In even more recent advances, we see organ-specific therapies such as vedolizumab (Entyvio®), which is unique in that
it is a gut-selective, anti-inflammatory treatment for inflammatory bowel diseases; evidence suggests targeted, organ-specific therapies may help patients avoid the adverse safety profiles associated with systemic therapeutics.5 Using a variety of mechanisms, these targeted immune modulators (TIMs) inhibit signaling pathways, auto-reactive processes, or excessive protein production to impact the inflammatory cascade in diseases such as rheumatoid arthritis.6 Many TIMs currently available in the U.S. have multiple indications (Table 1).7-26
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AUTOIMMUNE DISEASES | Continued
Biosimilars in Autoimmune Treatment In addition to the currently available branded TIM products, the FDA has approved several biosimilars since 2016, with the ultimate goal of improving access to care and potentially lowering drug costs (Table 2).27 Although there are no interchangeable products approved, biosimilars may be approved for the same indications as the reference product.27 There are currently 13 FDA-approved biosimilar TIMs; however, due to ongoing patent litigation, there are only three biosimilar TIMs on the market.27-40 The widespread uptake of biosimilars in the U.S. market presents many more challenges than patent litigation. Duplicating the manufacturing processes required for such complex biological products is difficult, and the clinical trial requirement for approval of a biosimilar is significantly more complex than for a small-molecule generic.41-43 The fact that biosimilars may not be used interchangeably for the reference product without
additional clinical trials may also hinder uptake and impact the perceptions of biosimilars for patients and prescribers alike. Patients may be comfortable with the process of receiving a generic small-molecule drug but may be confused or concerned by a biosimilar that has a different brand name than the product with which they are familiar.41-43 Similarly, prescribers may have more brand recognition of the originator product and may more readily prescribe the originator product rather than look up brand names of new biosimilars with which they may not be familiar.41
Recent FDA Approvals While the development of biosimilars continues to be an important focus, several newly approved TIMs may offer advancements in the treatment of autoimmune disease.
Table 2. FDA-Approved Biosimilar Targeted Immune Modulators27 Approval Date
Not yet available29
Anticipated January 202330
Anticipated July 202332
Will not launch in U.S.33
Anticipated September 202334
TBD, pending patent litigation36
Anticipated January 202037
Anticipated June 202338
Biosimilar Name Inflectra® (infliximab-dyyb) Erelzi® (etanercept-szzs) Amjevita™ (adalimumab-atto) Renflexis® (infliximab-abda) Cyltezo™ (adalimumab-adbm) Ixifi™ (infliximab-qbtx) Hyrimoz™ (adalimumab-adaz)
*Products may have additional indications not listed here.
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Skyrizi™ (risankizumab-rzaa) Skyrizi™ (risankizumab-rzaa) is an interleukin-23 (IL-23) inhibitor that received FDA approval in April 2019 for the treatment of moderate to severe plaque psoriasis in adults who are candidates for systemic therapy or phototherapy.16, 44 Risankizumab-rzaa is administered at a dose of 150 mg delivered in two subcutaneous injections every 12 weeks following two initial doses at weeks 0 and 4.44 The approval of risankizumab-rzaa was supported by the results from the global phase three program, which evaluated the safety and efficacy of risankizumab-rzaa in adults with moderate to severe plaque psoriasis across four randomized, controlled trials that included either placebo or active-comparator groups (ultIMMa-1, ultIMMa-2, IMMhance, and IMMvent).16, 44 The co-primary efficacy endpoints across all studies were a 90% improvement in the Psoriasis Area and Severity Index (PASI 90) and static Physician Global Assessment (sPGA) score of clear or almost clear (sPGA=0 or 1) at 16 weeks compared to placebo.16, 44 UltIMMA-1 Results:16, 44 » 75% of patients on risankizumab-rzaa achieved PASI 90 at 16 weeks, compared with 5% of placebo patients (p<0.001). » 36% of patients on risankizumab-rzaa achieved PASI 100 at 16 weeks, compared with 0% of placebo patients (p<0.001). » 82% of patients on risankizumab-rzaa achieved PASI 90 and 56% achieved PASI 100 at 52 weeks (p<0.001). » 88% of patients on risankizumab-rzaa who achieved PASI 90 at week 16 maintained the response at week 52, according to an integrated analysis of the two studies. UltIMMA-2 Results:16, 44 » 75% of patients on risankizumab-rzaa achieved PASI 90 at 16 weeks, compared to 2% of placebo patients (p<0.001). » 51% of patients on risankizumab-rzaa achieved PASI 100 at 16 weeks, compared with 2% of placebo patients (p<0.001). » 81% of patients on risankizumab-rzaa achieved PASI 90 and 60% achieved PASI 100 at 52 weeks (p<0.001). » 80% of patients on risankizumab-rzaa who achieved PASI 90 at week 16 maintained the response at week 52, according to an integrated analysis of the two studies. There are currently three IL-23 inhibitors on the market, including Skyrizi™ (risankizumab-rzaa), Tremfya® (guselkumab), and Ilumya™ (tildrakizumab-asmn).15, 16, 19 While a lack of head-to-head clinical trials precludes direct comparisons between products, 73% of patients treated with guselkumab in clinical trials achieved PASI 90 at week 16, and 61% to 64% of patients treated with tildrakizumab-asmn in
clinical trials achieved a 75% improvement in PASI (PASI 75) at week 12.16, 19, 45, 46
Rinvoq™ (upadacitinib) In August 2019, the FDA approved RinvoqTM (upadacitinib), an oral Janus kinase (JAK) inhibitor, for the treatment of moderate to severe rheumatoid arthritis in adults who have had an inadequate response or intolerance to methotrexate.25, 47 The FDA approval of upadacitinib was supported by data from the phase three registrational SELECT program, which is one of the largest clinical programs in rheumatoid arthritis, with 4,400 patients enrolled across the five studies.47 The studies evaluated the safety and efficacy of upadacitinib across a variety of patient populations, including those who failed or were intolerant to biologic DMARDs and those who were naïve to or had an inadequate response to methotrexate, although it is not indicated for methotrexate-naïve patients at this time. The SELECT program also evaluated whether patients treated with upadacitinib achieved clinical remission, defined as no disease activity and symptoms, even without methotrexate.47 All primary and ranked secondary endpoints were met across all SELECT phase three studies.25, 47 SELECT Results: » SELECT-EARLY: 52% of patients who were methotrexate-naïve and treated with upadacitinib achieved a 50% improvement in American College of Rheumatology score (ACR50), compared with 28% of patients treated with methotrexate alone at week 12. » SELECT-MONOTHERAPY: 68% of patients who had an inadequate response to methotrexate and were treated with upadacitinib achieved ACR20, compared with 41% of patients treated with methotrexate alone at week 14. » SELECT-COMPARE: Similar results were found in patients treated with upadacitinib compared with those treated with placebo plus methotrexate. 30% of patients achieved clinical remission at week 12 with upadacitinib plus methotrexate and 41% achieved clinical remission at weeks 24 and 26. » SELECT-NEXT and SELECT-BEYOND: 64% of patients who had an inadequate response to DMARD and 65% of patients who had an inadequate response to the biologic, respectively, went on to achieve ACR20 with upadacitinib treatment. There are currently three JAK inhibitors on the market, including Rinvoq™ (upadacitinib), Olumiant™ (baricitinib), and Xeljanz® (tofacitinib).23-25 While a lack of head-to-head clinical trials and
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AUTOIMMUNE DISEASES | Continued
The National Institutes of Health have estimated the annual direct healthcare costs for autoimmune disease at approximately $100 billion. Since this estimate was reported nearly five years ago, movement and advances in the autoimmune space have likely led to an increase in direct healthcare costs. slight differences between patient populations in the clinical trials precludes direct comparison between products, 61.8% of patients in the ORAL Scan trial who were treated with tofacitinib 10 mg and had an inadequate response to methotrexate achieved ACR20 at six months.48 In the RA-BUILD study that included patients who were biologic-naïve and had an inadequate response to at least one conventional DMARD, 62% of patients treated with baricitinib 4 mg daily achieved ACR20 response at week 12.49
Autoimmune Disease Pipeline Despite the number of agents approved for psoriasis, rheumatoid arthritis, Crohn’s disease, and ulcerative colitis, a significant unmet need remains across a number of other autoimmune diseases.1, 2 According to a 2016 PhRMA report on medicines in development for autoimmune diseases, more than 300 medicines and vaccines are in development for a variety of autoimmune diseases, including 76 for autoimmune forms of arthritis, 58 for inflammatory bowel disease, 39 for lupus, 34 for Type 1 diabetes, and 32 for multiple sclerosis.2
Anifrolumab Anifrolumab is an investigational, fully human, monoclonal antibody currently being studied for the treatment of systemic lupus erythematosus (SLE).50 Anifrolumab exerts its effect by binding to subunit 1 of the type I interferon receptor, blocking the activity of all type I interferons, including IFN-α, IFN-β, and IFN-Ω.50 Type I
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interferons are implicated in the inflammatory pathways, and between 60% and 80% of adults with SLE have an increased type I interferon gene signature, which correlates with disease activity.50 The safety and efficacy of anifrolumab in SLE are being evaluated in the pivotal TULIP clinical program, which consists of two phase three trials, TULIP 1 and TULIP 2.50 Both trials enrolled patients with moderately to severely active autoantibody-positive SLE who were receiving standard of care treatment.50 In September 2018, topline data from TULIP-1 was announced, indicating that the primary endpoint was not met, failing to achieve a statistically significant reduction in disease activity in patients with SLE, as measured by the SLE Responder Index 4 at 12 months.51 In TULIP-2 (N=373), patients were randomized to a fixed-dose intravenous infusion of anifrolumab 300 mg or placebo every four weeks for 48 weeks.52 The primary endpoint was the British Isles Lupus Assessment Group (BILAG)-based Composite Lupus Assessment (BICLA) response at week 52. BICLA response requires reduction in any moderate to severe baseline disease activity and no worsening in nine organ systems in the BILAG index, no worsening on the SLE Disease Activity Index, no increase of 0.3 points or more in the score on the Physician Global Assessment of disease activity, no discontinuation of the trial intervention, and no use of medications restricted by the protocol.52 At week 52, 47.8% of patients treated with anifrolumab achieved a BICLA response, compared with 31.5% in the placebo group (95% confidence interval 6.3 to 26.3, p=0.001).52 BICLA responses were similar among patients with high and low interferon gene signatures.52 Based on the favorable results from the TULIP-2 trial, the manufacturer intends to file for FDA approval in the second half of 2020.53 If approved, anifrolumab would be the second medication specifically approved for SLE, following Benlysta (belimumab).51
Larazotide Larazotide, an investigational agent in a new class of drugs referred to as tight junction regulators, is currently being studied for the treatment of celiac disease.54 In patients without celiac disease, tight junctions, which are located in the bowel, remain closed. In patients with celiac disease, gluten causes tight junctions to remain open, causing inflammation that results in intestinal damage.54 When taken prior to a meal, larazotide may help keep tight junctions closed, diminishing the inflammatory response caused by gluten.54 In a phase two study of larazotide in patients with celiac disease who were maintained on a gluten-free diet, patients experienced fewer symptoms with larazotide than with placebo.55 In August 2019, the manufacturer announced that the first patient had been dosed in the first phase three clinical trial for patients
with celiac disease.56 CeD LA 3001 is a phase three multicenter, double-blind, placebo-controlled, randomized, parallel-group trial that is expected to enroll 600 patients. Similar to the phase two trial, the primary objective is to evaluate larazotide as an adjunct therapy for patients who still experience symptoms despite being on a gluten-free diet.56
Managed Care Implications Autoimmune diseases carry a significant economic burden in the U.S. The National Institutes of Health have reported the most current estimate for the annual direct healthcare costs for autoimmune disease at approximately $100 billion.57 Since this estimate was reported nearly five years ago, movement and advances in the autoimmune space have likely led to an increase in direct healthcare costs, meaning updated cost estimates are necessary to more clearly reflect the current market. In comparison, direct costs for cancer are approximately $57 billion and for heart disease and stroke are $200 billion.57 The cost attributed to autoimmune diseases is, in part, being driven by the cost of the biologics being used.3 In 2015, three of the top six best-selling prescription drugs were biologics indicated for the treatment of autoimmune disorders, and 20% of all specialty drug spending was for autoimmune disorder drugs.3 According to the Magellan Rx Management 2018 Medical Pharmacy Trend Report, biologic drugs accounted for a double-digit increase in both commercial and Medicare per member per month (PMPM) costs (21% and 13%, respectively).58 Biologics in the autoimmune category are also forecasted to increase and have the highest potential for category growth; the Trend Report forecasts PMPM autoimmune drug costs to increase 90% (from $1.40 to $2.66) from 2017 to 2022.58 In the case of patients who have been stable on therapy and are either in remission or have demonstrated low disease activity, there may be an opportunity for providers to attempt downwards dose titration for certain members, depending on the diagnosis and the biologic being prescribed. Multiple studies support the conclusion that many stable members can have their doses tapered successfully while maintaining clinical response.59, 60, 61 Doses can be adjusted either via a lower dose per administration or extension of each dosing interval, depending on the drug and on patient and provider preferences.60, 62 Such an approach is supported in rheumatoid arthritis treatment guidelines published by the American College of Rheumatology. If members do not qualify for this approach because their disease activity remains moderate or severe despite optimization of a biologic, this could create an opening for conversations focused on promoting consistent use of functional assessments to evaluate disease progression. Given the multitude of products available, these
members may benefit from targeted case management to evaluate whether there is an opportunity to discontinue therapy in favor of an alternative. Similarly, completion of functional assessments could be built into initial and renewal criteria to evaluate treatment efficacy. Not only would this help to address a gap in practice, but objective data obtained via completion of an assessment could also be helpful in evaluating the efficacy of a current treatment and, if appropriate, getting the member on the right treatment sooner rather than later. With millions of patients in need of effective treatments, there are several strategies around formulary management that managed care organizations can consider for managing the growing use and cost of biologics. Because treatment options for autoimmune diseases will likely fall on both the medical and pharmacy benefits, a holistic formulary management strategy incorporating both categories can help identify all areas of opportunity. Site-of-service programs may be an approach for medical benefit drugs. Because these medications are administered by clinicians and billed under the medical benefit, identifying cost-effective sites for members to receive their doses could offer payers potential savings while still delivering quality care to members. Some payers are also turning to indication-based formulary management strategies. Indication-based formulary design allows health plans to tailor their formulary and negotiate coverage of drugs based on specific indications.63 For example, a drug could be on the plan formulary for one indication but not on the plan formulary for another. In August 2018, the Centers for Medicare & Medicaid Services announced that an indication-based formulary design would be permissible for Part D plan sponsors beginning in contract year 2020.63 While other health plans and pharmacy benefit managers have already begun exploring indication-based management strategies, the announcement from the CMS may help to accelerate this shift in mindset for payers, manufacturers, and members.64 There may be an opportunity for managed care organizations to encourage the use of biosimilars currently on the market; step therapy requirements can influence prescribing habits and drive members toward the less-expensive treatment. Specifically, criteria can be leveraged to place a step therapy requirement for providers to first prescribe a biosimilar for treatment-naĂŻve members when the biosimilar is approved for the same indication as the reference biologic. With the number of autoimmune disease drugs on the market with overlapping indications, coupling indication-based management strategies with benefit structure changes that incentivize the member and/or provider to use preferred, more-cost-effective products may allow payers to prefer the most effective drug for each specific indication based on clinical data â€” and may allow for more strategic contract negotiations with manufacturers.
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AUTOIMMUNE DISEASES | Continued
“Autoimmune Disease List.” American Autoimmune Related Diseases Association, Inc., 2018, https://www.aarda.org/ diseaselist/.
“Medicines in Development for Autoimmune Diseases 2016 Report.” PhRMA, Sept. 12, 2016, https://www.phrma.org/en/ Report/Medicines-in-Development-for-Autoimmune-Diseases2016-Report.
McCain, Jack. “The Disease Burden of the Most Common Autoimmune Diseases.” Managed Care, July 19, 2016, https:// www.managedcaremag.com/archives/2016/7/disease-burdenmost-common-autoimmune-diseases.
“Autoimmune Disease.” U.S. Pharmacist, June 16, 2016, https:// www.uspharmacist.com/article/autoimmune-disease.
Wyant, Tim et al. “An Overview of the Mechanism of Action of the Monoclonal Antibody Vedolizumab.” Journal of Crohn’s and Colitis, Dec. 2016, https://www.ncbi.nlm.nih.gov/pubmed/27252400.
“Targeted Immune Modulators for Rheumatoid Arthritis: Effectiveness & Value Evidence Report.” Institute for Clinical and Economic Review, April 7, 2017, https://icer-review.org/ wp-content/uploads/2016/08/NE_CEPAC_RA_Evidence_Report_ FINAL_040717.pdf.
Humira® [package insert]. North Chicago, IL: AbbVie; 2019.
Cimzia® [package insert]. Smyrna, GA: UCB; 2019.
Enbrel® [package insert]. Thousand Oaks, CA: Amgen; 2018.
10. Simponi® [package insert]. Horsham, PA: Janssen Pharmaceutica; 2019. 11. Remicade® [package insert]. Horsham, PA: Janssen Pharmaceutica; 2018. 12. Rituxan® [package insert]. South San Francisco, CA: Genentech; 2019. 13. Siliq™ [package insert]. Bridgewater, NJ: Bausch Health; 2017. 14. Taltz® [package insert]. Indianapolis, IN: Eli Lilly; 2019. 15. Tremfya® [package insert]. Horsham, PA: Janssen Pharmaceutica; 2019. 16. Skyrizi™ [package insert]. North Chicago, IL: AbbVie; 2019. 17. Kevzara® [package insert]. Bridgewater, NJ: Sanofi/Regeneron; 2018. 18. Actemra® [package insert]. South San Francisco, CA: Genentech, Inc; 2019. 19. Ilumya™ [package insert]. Whitehouse Station, NJ: Merck & Co; 2018. 20. Cosentyx® [package insert]. East Hanover, NJ: Novartis; 2018. 21. Stelara® [package insert]. Horsham, PA: Janssen Pharmaceutica; 2019. 22. Entyvio® [package insert]. Deerfield, IL: Takeda; 2019. 23. Olumiant® [package insert]. Indianapolis, IN: Eli Lilly; 2019. 24. Xeljanz® [package insert]. New York, NY: Pfizer; 2019.
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25. Rinvoq™ [package insert]. North Chicago, IL: AbbVie; 2019. 26. Orencia® [package insert]. Princeton, NJ: Bristol-Myers Squibb; 2019. 27. “Biosimilar Product Information.” U.S. Food and Drug Administration, Nov. 15, 2019, https://www.fda.gov/drugs/biosimilars/biosimilarproduct-information. 28. “Pfizer announces the U.S. availability of biosimilar Inflectra® (infliximab-dyyb).” Oct. 17, 2016, https://www.pfizer.com/news/ press-release/press-release-detail/pfizer_announces_the_u_s_ availability_of_biosimilar_inflectra_infliximab_dyyb. 29. “Sandoz will appeal District Court of New Jersey ruling in biosimilar Erelzi® (etanercept-szzs) US patent case.” GlobeNewswire, Aug. 9, 2019, https://www.globenewswire.com/newsrelease/2019/08/09/1900111/0/en/Sandoz-will-appeal-DistrictCourt-of-New-Jersey-ruling-in-biosimilar-Erelzi-etanercept-szzs-USpatent-case.html. 30. “Product Profile: Adalimumab-atto (Amjevita).” BR&R Biosimilars Review & Report, 2019, https://biosimilarsrr.com/product-profileamjevita-2-2-2/. 31. Gifford, C. Nichole. “Samsung Bioepis and Merck Launch Renflexis® in the US.” Rothwell Figg, 2018, https://www.biosimilarsip. com/2017/08/09/samsung-bioepis-merck-launch-renflexis-u-s/. 32. “Boehringer Ingelheim announces resolution of Cyltezo® patent litigation.” Boehringer Ingelheim, May 14, 2019, https://www. boehringer-ingelheim.us/press-release/boehringer-ingelheimannounces-resolution-cyltezo-patent-litigation. 33. Stanton, Dan. “Pfizer: ‘No plans to launch second approved Remicade biosimilar in US’.” BioPharma Reporter, Dec. 14, 2017, updated Nov. 16, 2018, https://www.biopharma-reporter.com/Article/2017/12/14/ Pfizer-No-plans-to-launch-second-infliximab-biosimilar-in-US. 34. “FDA Approves Sandoz’s Biosimilar Adalimumab, Hyrimoz.” The Center for Biosimilars, Oct. 31, 2018, https://www. centerforbiosimilars.com/news/fda-approves-sandozs-biosimilaradalimumab-hyrimoz. 35. Davio, Kelly. “First Rituximab Biosimilar, Truxima, Launches in the United States.” The Center for Biosimilars, Nov. 7, 2019, https://www. centerforbiosimilars.com/news/first-rituximab-biosimilar-truximalaunches-in-the-united-states. 36. Holt, Benjamin R. “Another Biosimilar Receives FDA Approval and Is Confronted with Litigation.” Rothwell Figg, 2019, https://www. biosimilarsip.com/2019/05/28/another-biosimilar-receives-fdaapproval-and-is-confronted-with-litigation/. 37. Davio, Kelly. “Pfizer Announces Launch Dates for 2 More Anticancer Biosimilars: Ruxience and Trazimera.” The Center for Biosimilars, Oct. 29, 2019, https://www.centerforbiosimilars.com/news/ pfizer-announces-launch-dates-for-2-more-anticancer-biosimilarsruxience-and-trazimera. 38. “FDA Approves Samsung Bioepis’ HADLIMA™ (adalimumab-bwwd).” BioSpace, July 24, 2019, https://www.biospace.com/article/releases/ fda-approves-samsung-bioepis-hadlima-adalimumab-bwwd-/.
References (cont.) 39. “FDA approves Pfizer’s biosimilar, ABRILADA™ (adalimumabafzb) for multiple inflammatory conditions.” Pfizer, Nov. 18, 2019, https://www.pfizer.com/news/press-release/press-release-detail/ fda_approves_pfizer_s_biosimilar_abrilada_adalimumab_afzb_for_ multiple_inflammatory_conditions. 40. Davio, Kelly. “FDA approves Amgen’s Infliximab Biosimilar, Avsola.” The Center for Biosimilars, Dec. 6, 2019, https://www. centerforbiosimilars.com/news/fda-approves-amgens-infliximabbiosimilar-avsola. 41. Wentworth, Simon. “Are we on the verge of a biosimilars breakthrough in the USA?” The Pharma Letter, Aug. 22, 2017, https://www.thepharmaletter.com/article/are-we-about-to-see-abiosimilars-breakthrough-in-the-usa. 42. “How do Drugs and Biologics Differ?” Bio, 2018, https://www.bio. org/articles/how-do-drugs-and-biologics-differ. 43. “Comparison of Biosimilars and Generic Drugs.” First Report Managed Care, Oct. 16, 2013, https://www. managedhealthcareconnect.com/articles/comparison-biosimilarsand-generic-drugs. 44. “AbbVie Expands Immunology Portfolio in the U.S. with FDA Approval of SKYRIZI™ (risankizumab-rzaa) for Moderate to Severe Plaque Psoriasis.” April 23, 2019, https://news.abbvie.com/news/ press-releases/abbvie-expands-immunology-portfolio-in-us-withfda-approval-skyrizi-risankizumab-rzaa-for-moderate-to-severeplaque-psoriasis.htm. 45. TREMFYA® (guselkumab). “Efficacy.” https://www.tremfyahcp.com/ efficacy/clinical-study-voyage-1. 46. ILUMYA® (tildrakizumab). “Results at week 12 are just the beginning as demonstrated in reSURFACE 1 and 2.” https://www.ilumyapro. com/results/. 47. “AbbVie Receives FDA Approval of RINVOQ™ (upadacitinib), an Oral JAK Inhibitor For The Treatment of Moderate to Severe Rheumatoid Arthritis.” Aug. 16, 2019, https://news.abbvie.com/news/pressreleases/abbvie-receives-fda-approval-rinvoq-upadacitinib-anoral-jak-inhibitor-for-treatment-moderate-to-severe-rheumatoidarthritis.htm.
52. Morand, Eric F. et al. “Trial of Anifrolumab in Active Systemic Lupus Erythematosus.” The New England Journal of Medicine, Dec. 18, 2019, https://www.nejm.org/doi/full/10.1056/NEJMoa1912196. 53. Taylor, Nick Paul. “AstraZeneca plans 2020 filing for anifrolumab in lupus.” FierceBiotech, Nov. 12, 2019, https://www.fiercebiotech. com/biotech/astrazeneca-plans-2020-filing-for-anifrolumab-lupus. 54. “First Patient Dosed in First Ever Phase 3 Clinical Trial for Celiac Disease.” Celiac Disease Foundation, Aug. 15, 2019, https://celiac. org/about-the-foundation/featured-news/2019/08/first-patientdosed-in-first-ever-phase-3-clinical-trial-for-celiac-disease/. 55. Leffler, D.A. et al. “Larazotide acetate for persistent symptoms of celiac disease despite a gluten-free diet: a randomized controlled trial.” Gastroenterology, June 2015, https://www.ncbi.nlm.nih.gov/ pubmed/25683116. 56. “Innovate Biopharmaceuticals, Inc. Announces First Patient Dosed in the First Phase 3 Clinical Trial for Patients with Celiac Disease.” Innovate Biopharmaceuticals. GlobeNewsWire, Aug. 13, 2019, https://www.globenewswire.com/newsrelease/2019/08/13/1901121/0/en/Innovate-BiopharmaceuticalsInc-Announces-First-Patient-Dosed-in-the-First-Phase-3-ClinicalTrial-for-Patients-with-Celiac-Disease.html. 57. “Autoimmune Disease Statistics.” American Autoimmune Related Diseases Association Inc., 2019, https://www.aarda.org/newsinformation/statistics/. 58. “Medical Pharmacy Trend Report 2018 Ninth Edition.” Magellan Rx Management, 2018, https://www1.magellanrx.com/ documents/2019/03/medical-pharmacy-trend-report_2018.pdf/. 59. Singh, Jasvinder A. et al. “2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis.” American College of Rheumatology. Arthritis & Rheumatology, January 2016, https://www.ncbi.nlm.nih.gov/pubmed/26545940. 60. Verhoef, L.M. et al. “Down-titration and discontinuation strategies of tumor necrosis factor-blocking agents for rheumatoid arthritis in patients with low disease activity.” Cochrane Database of Systematic Reviews, May 24, 2019, https://www.ncbi.nlm.nih.gov/ pubmed/31125448.
48. “At a glance: The ORAL trials of tofacitinib for the treatment of RA.” Medicine Matters rheumatology, April 8, 2017, upated April 2019, https://rheumatology.medicinematters.com/rheumatoid-arthritis-/ tofacitinib/oral-trials-of-tofacitinib/13335124.
61. van den Bemt, B.J. et al. “Sustained effect after lowering high‐dose infliximab in patients with rheumatoid arthritis: a prospective dose titration study.” Annals of the Rheumatic Diseases, December 2008, https://www.ncbi.nlm.nih.gov/pubmed/18245109.
49. “At a glance: Trials evaluating baricitinib in RA.” Medicine Matters rheumatology, Dec. 9, 2017, updated January 2019, https:// rheumatology.medicinematters.com/rheumatoid-arthritis-/jakinhibitors/at-a-glance--trials-evaluating-baricitinib-in-ra/14224702.
62. van der Maas, A. et al. “Down titration and discontinuation of infliximab in rheumatoid arthritis patients with stable low disease activity and stable treatment: an observational cohort study.” Annals of the Rheumatic Diseases, November, 2012, https://www. ncbi.nlm.nih.gov/pubmed/22504561.
50. “Anifrolumab Phase III trial meets primary endpoint in systemic lupus erythematosus.” AstraZeneca, Aug. 29, 2019, https://www. astrazeneca.com/media-centre/press-releases/2019/anifrolumabphase-iii-trial-meets-primary-endpoint-in-systemic-lupuserythematosus-29082019.html. 51. “AstraZeneca’s Lupus Drug Misses Primary Endpoint in Study.” Zacks Equity Research. Yahoo! Finance, Sept. 3, 2018, https://finance.yahoo. com/news/astrazeneca-apos-lupus-drug-misses-134001878.html.
63. “Indicated-Based Formulary Design Beginning in Contract Year (CY) 2020.” Centers for Medicare & Medicaid Services, Aug. 29, 2018, https://www.cms.gov/newsroom/fact-sheets/indication-basedformulary-design-beginning-contract-year-cy-2020. 64. Spjut, Russ J. “Effects of indication-Based Formulary Design.” First Report Managed Care, Sept. 27, 2018, https://www. managedhealthcareconnect.com/blog/effects-indication-basedformulary-design.
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Multiple Sclerosis: Therapy Recommendations and Treatment Advances The MS treatment landscape has been centered around disease-modifying therapies (DMTs), with more novel agents, biosimilars, bioequivalents, and generics coming to further saturate the market. Multiple sclerosis (MS) is a chronic autoimmune inflammatory demyelinating disease of the central nervous system (CNS) with a largely unknown etiology.1 The clinical course begins with an immune-mediated attack on the CNS that leads to demyelination via destruction of oligodendrocytes, then degeneration of axons.1 Activation of both T-lymphocytes and B-lymphocytes are believed to be involved in the inflammation and damage that occurs within the CNS. Research suggests that the risk of developing MS is determined by genetic as well as environmental components,1 which may include low vitamin D levels, a history of Epstein-Barr virus, ultraviolet light exposure, and cigarette smoking.1 Currently, an estimated nearly one million people in the U.S. live with MS. Women are three times more likely than men to receive a diagnosis of MS.2 Sue Wilhelm, B.S.Pharm., BCPS Director of Pharmacy Security Health Plan
Patients diagnosed with MS are classified into two core phenotypes: relapsing-remitting and progressive disease. Patients are then further classified into four clinical subtypes: • Clinically isolated syndrome (CIS). A CIS is the first clinical episode suggestive of an MS diagnosis.3 Patients with a CIS may or may not be diagnosed with MS at a later point in time.3 • Relapsing-remitting MS (RRMS). Accounting for approximately 85% of initial MS diagnoses, RRMS is the most common disease course and is defined by periods of attacks or relapses followed by periods of recovery or remission.3 • Primary progressive MS (PPMS). Approximately 15% of MS patients are diagnosed with PPMS, characterized by progression or worsening of neurologic function from the disease onset without periods of relapse and remission.3 • Secondary progressive MS (SPMS). SPMS is a progressive course with worsening neurologic function that follows an initially relapsing-remitting course.3 Most patients diagnosed with RRMS will progress to SPMS.
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Treatment Guidelines The following are the MS treatment guidelines set forth by the American Academy of Neurology (AAN) with recommendations for starting, switching, and stopping DMT.4 Table 1. Therapy Recommendations Starting DMT Recommendations
Clinicians should counsel patients with newly diagnosed MS about specific treatment options with DMT at a dedicated treatment visit.
Clinicians must ascertain and incorporate/review preferences with patients with MS in terms of safety, route of administration, lifestyle, cost, efficacy, common adverse effects (AEs), and tolerability in the choice of DMT.
Clinicians must engage patients with MS in an ongoing dialogue regarding treatment decisions throughout the disease course.
Clinicians should counsel patients with MS that DMTs are prescribed to reduce relapses and new MRI lesion activity. DMTs are not prescribed for symptom improvement in patients with MS.
Clinicians must counsel patients with MS on DMTs to notify the clinicians of new or worsening symptoms.
Clinicians should evaluate readiness or reluctance to initiate DMT and counsel on its importance in patients with MS who are candidates to initiate DMT.
Clinicians should counsel patients with MS initiating DMTs about comorbid disease, adverse health behaviors, and potential interactions of the DMT with concomitant medications.
Clinicians should evaluate barriers to adherence to DMT in patients with MS.
Clinicians should counsel patients with MS initiating DMTs on the importance of adherence.
Clinicians should discuss the benefits and risks of DMTs for patients with a single clinical demyelinating event with two or more brain lesions that have imaging characteristics consistent with MS.
After discussing the risks and benefits, clinicians should prescribe DMT to patients with a single clinical demyelinating event and two or more brain lesions characteristic of MS who decide they want this therapy.
Clinicians may recommend serial imaging at least annually for the first five years and close follow-up rather than initiating DMT in patients with CIS or relapsing forms of MS who are not on DMT, have not had relapses in the preceding two years, and do not have active new MRI lesion activity on recent imaging.
Clinicians should offer DMTs to patients with relapsing forms of MS with recent clinical relapses or MRI activity.
Clinicians should monitor patients with MS on DMTs for medication adherence, AEs, tolerability, safety, and effectiveness of the therapy.
Clinicians should follow up with patients with MS on DMTs either annually or according to medication-specific REMS.
Clinicians should monitor the reproductive plans and counsel regarding reproductive risks and use of birth control during DMT use in women of childbearing potential who have MS.
Clinicians should counsel men with MS on their reproductive plans regarding treatment implications before initiating treatment with teriflunomide or cyclophosphamide.
Because of the high frequency of severe AEs, clinicians should not prescribe mitoxantrone to patients with MS unless the potential therapeutic benefits greatly outweigh the risks.
Clinicians should prescribe alemtuzumab, fingolimod, or natalizumab for patients with highly active MS.
Clinicians may direct patients with MS who are candidates for DMTs to support programs.
Clinicians may recommend azathioprine or cladribine for patients with relapsing forms of MS who do not have access to approved DMTs.
Clinicians may initiate natalizumab treatment in patients with MS with positive anti-JCV antibody indexes above 0.9 only when there is a reasonable chance of benefit compared with the low but serious risk of progressive multifocal leukoencephalopathy (PML).
Clinicians should offer ocrelizumab to patients with PPMS who are likely to benefit from this therapy unless there are risks of treatment that outweigh the benefits.
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MULTIPLE SCLEROSIS | Continued
Table 1. Therapy Recommendations (cont.) Switching DMT Recommendations
Clinicians should monitor MRI disease activity in patients with MS using DMT from the clinical onset of disease to detect the accumulation of new lesions in order to inform treatment decisions.
Clinicians should recognize that relapses or new MRI-detected lesions may develop in patients with MS after initiation of a DMT and before the treatment becomes effective.
Clinicians should discuss switching patients with MS from one DMT to another if they have been using one long enough for the treatment to take full effect and are adherent to their therapy but experience one or more relapses, two or more unequivocally new MRI-detected lesions, or increased disability on examination over a one-year period.
Clinicians should evaluate the degree of disease activity, adherence, AE profiles, and mechanism of action of DMTs when switching patients with MS with breakthrough disease activity during DMT use to another DMT.
Clinicians should discuss a change to noninjectable or less-frequently injectable DMTs with patients with MS on injectable DMTs who report intolerable discomfort with the injections or injection fatigue.
Clinicians should ask patients with MS who are using a DMT about medication AEs and attempt to manage these AEs as appropriate.
Clinicians should monitor laboratory abnormalities found on requisite laboratory surveillance (as outlined in the medication’s package insert) in patients with MS who are using a DMT.
Clinicians should discuss switching DMT or reducing dosage or frequency (where there are data on different doses — e.g., interferons, teriflunomide, azathioprine) when patients with MS exhibit persistent laboratory abnormalities.
Clinicians should counsel patients with MS considering natalizumab, fingolimod, rituximab, ocrelizumab, and dimethyl fumarate about the PML risk associated with these agents.
Clinicians should discuss switching to a DMT with a lower PML risk with patients with MS taking natalizumab who are or become JCV antibody-positive, especially those with anti-JCV antibody indexes above 0.9 while on therapy.
Clinicians should counsel patients with MS starting or using new DMTs without long-term safety data that they have an undefined risk of malignancy and infection.
If a patient with MS develops a malignancy while using a DMT — especially azathioprine, methotrexate, mycophenolate, cyclophosphamide, fingolimod, teriflunomide, alemtuzumab, or dimethyl fumarate — clinicians should promptly discuss switching to an alternate DMT.
Patients with MS with serious infections potentially linked to their DMT should switch DMTs (does not pertain to PML management in patients with MS using DMT).
Clinicians should check for natalizumab antibodies in patients with MS who have infusion reactions before subsequent infusions or experience breakthrough disease activity with natalizumab use.
Clinicians should switch patients with MS who have persistent natalizumab antibodies to a different DMT.
Physicians must counsel patients with MS discontinuing natalizumab that there is an increased risk of MS relapse or MRI-detected disease activity within six months of discontinuation.
Patients with MS choosing to switch from natalizumab to fingolimod should initiate treatment within eight to 12 weeks after discontinuing natalizumab (for reasons other than pregnancy or pregnancy planning) to diminish the return of disease activity.
Clinicians should counsel women to stop their DMT before conception for planned pregnancies unless the risk of MS activity during pregnancy outweighs the risk associated with the specific DMT during pregnancy.
Clinicians should discontinue DMTs during pregnancy if accidental exposure occurs, unless the risk of MS activity during pregnancy outweighs the risk associated with the specific DMT during pregnancy.
Clinicians should not initiate DMTs during pregnancy unless the risk of MS activity during pregnancy outweighs the risk associated with the specific DMT during pregnancy.
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Table 1. Therapy Recommendations (cont.) Stopping DMT Recommendations
Clinicians should counsel patients with RRMS who are stable on DMT and want to discontinue DMT on the need for ongoing followup and periodic reevaluation of the decision.
Clinicians should advocate that patients with MS who are stable on DMT (that is, no relapses, no disability progression, stable imaging) should continue their current DMT unless the patient and physician decide a trial off therapy is warranted.
Clinicians should assess the likelihood of future relapse in patients with SPMS by assessing patient age, disease duration, relapse history, and MRI-detected activity (e.g., frequency, severity, time since most recent relapse or gadolinium-enhanced lesion).
Clinicians may advise discontinuation of DMT in patients with SPMS who do not have ongoing relapses (or gadolinium-enhanced lesions on MRI activity) and have not been ambulatory (EDSS 7 or greater) for at least two years.
*Definitions for evidence levels can be found within the American Academy of Neurology Guidelines for Disease-Modifying Therapies for Adults with Multiple Sclerosis.
Treatment Advances The number of DMTs for MS has increased rapidly over the past several years, with a total of 15 medications currently available. New agents released within the past few years include ocrelizumab (Ocrevus®), siponimod (Mayzent®), and diroximel fumarate (Vumerity™).
The number of DMTs for MS has increased rapidly over the past several years, with a total of 15 medications currently available. Ocrelizumab
47% lower in OPERA II 2 (0.16 versus 0.29; p<0.001).8 » In prespecified pooled analyses, the proportion of patients with confirmed disability progression was significantly lower with ocrelizumab than with interferon beta-1a — 9.1% versus 13.6% respectively (p<0.001) at 12 weeks and 6.9% versus 10.5% respectively (p=0.003) at 24 weeks.8 » The mean number of gadolinium-enhancing lesions was 94% lower in OPERA I with ocrelizumab (p<0.001) and 95% lower in OPERA II (p<0.001) than with interferon beta-1a.8 » The percentage of patients with serious infections was 1.3% of those treated with ocrelizumab and 2.9% of patients treated with interferon beta-1a. » In the ocrelizumab treatment group, 0.5% of the patients developed a neoplasm, compared with 0.2% of patients in the interferon beta-1a group.8 The safety and efficacy of ocrelizumab as the first DMT indicated for the treatment of PPMS were established in the ORATORIO trial.9 ORATORIO Results:
Ocrelizumab was approved in 2017 based on the results from the OPERA I and II trials for patients with relapsing forms of MS.8 These identically designed trials were randomized, double-blind, doubledummy, active comparator-controlled clinical trials.8 Included patients had experienced at least one relapse within the prior year, or two relapses within the prior two years, and had an Expanded Disability Status Scale (EDSS) score of 0 to 5.5.8 Patients with PPMS were excluded.8 Patients were randomized 1:1 to receive either ocrelizumab 600 mg every 24 weeks or interferon beta-1a 44 mcg three times weekly.8 OPERA I and II Results: » The annualized relapse rate (ARR) was 46% lower with ocrelizumab compared to interferon beta-1a (0.16 versus 0.29; p<0.001), and
» At 12 weeks, 32.9% of patients on ocrelizumab (p=0.03) had confirmed disability progression, compared with 39.3% of placebo patients. » At 24 weeks, 29.6% of patients on ocrelizumab had confirmed disability progression, compared with 35.7% of placebo patients (p=0.04). » At 120 weeks, performance on the timed 25-foot walk worsened 38.9% in patients on ocrelizumab and 55.1% in placebo patients (p=0.04). » Patients on ocrelizumab had a 3.4% decrease in total brain lesion volume on T2-weighted MRI, while placebo patients had a 7.4% increase (p<0.001). » Patients on ocrelizumab had a brain-volume loss of 0.9%, compared with 1.09% in placebo patients (p=0.02).
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MULTIPLE SCLEROSIS | Continued
» Infusion-related reactions, upper respiratory tract infections, and oral herpes infections occurred more frequently in patients on ocrelizumab than in placebo patients. » Neoplasms occurred in 2.3% of patients on ocrelizumab and 0.8% of placebo patients. » The difference in the rates of serious adverse events and serious infections between groups was not clinically significant.
Siponimod Siponimod (Mayzent®) was approved in March 2019, joining fingolimod (Gilenya®) in the class of sphingosine-1-phosphate receptor (S1P) modulators. Siponimod was designed to be more selective than fingolimod and may have fewer risks.10 Siponimod is also proven to be effective in patients with active SPMS.10 Compared to fingolimod, which requires first-dose monitoring for all patients, siponimod requires first-dose monitoring only in patients with pre-existing heart conditions.10 The safety and efficacy of siponimod were established in patients with SPMS in the EXPAND trial.11 This trial was a randomized, double-blind, parallel-group, placebocontrolled, time-to-event study in patients with SPMS.11 Included patients were 18 to 60 years old, had evidence of disability progression in the previous two years, no relapse in the three months prior to study entry, and an EDSS score of 3.0 to 6.5 at the time of study entry. 11 Patients were randomized 2:1 to receive siponimod 2 mg once daily following an initial dose titration or placebo for up to 3 years or until the occurrence of a predetermined number of confirmed disability progression events. 11 The primary endpoint was the time to 3-month continued disability progression (CDP), which was defined as a ≥1-point increase in EDSS, or a ≥0.5-point increase for baseline EDSS ≥5.5, sustained for three months. 11 EXPAND Results: » 26% of patients on siponimod had confirmed disease progression, compared with 32% of placebo patients (p=0.013). » The ARR with siponimod was 0.071 versus 0.16 with placebo (relative reduction of 55%; p<0.01). » While a significant difference in disability progression was found in patients with active SPMS, or those with a relapse in the prior two years, the effect on patients with nonactive SPMS was not statistically significant. » 82% of patients on siponimod and 78% of placebo patients completed the study. » AEs occurred in 89% of patients on siponimod and 82% of placebo patients.
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» Serious AEs occurred in 18% of patients on siponimod and 15% of placebo patients. » Lymphopenia, increased liver transaminase concentration, bradycardia and bradyarrhythmia at treatment initiation, macular edema, hypertension, varicella zoster reactivation, and convulsions occurred more frequently in the siponimod treatment group. » Cardiac first-dose effects were managed by the initial dose titration.
Diroximel fumarate Diroximel fumarate was approved in November 2019 via the 505(b)(2) pathway, meaning that at least a portion of the data supporting its approval was derived from a reference product (dimethyl fumarate).12 Diroximel fumarate shares the same active metabolite as Tecfidera® (dimethyl fumarate), with potentially fewer side effects.13 Bioavailability studies comparing dimethyl fumarate to diroximel fumarate in patients with relapsing forms of MS and healthy subjects were used to establish the efficacy of diroximel fumarate.12 The safety of diroximel fumarate is currently being evaluated in the EVOLVE-MS-1 trial, which is an ongoing open-label, phase three, long-term safety study.14 The ongoing EVOLVE-MS-2 trial is assessing the GI tolerability of diroximel fumarate versus dimethyl fumarate.15
Multiple Sclerosis Pipeline Monomethyl Fumarate Monomethyl fumarate (Bafiertam™) is an immunomodulator and the active metabolite of dimethyl fumarate.16 Monomethyl fumarate received tentative approval via the 505(b)(2) pathway as a bioequivalent of dimethyl fumarate (Tecfidera®).16 A portion of the data supporting its approval was derived from the
prodrug, dimethyl fumarate.16 A trial is currently ongoing to assess the GI tolerability of monomethyl fumarate compared to dimethyl fumarate.17 Market entry is expected in June 2020, pending the patent expiration of Tecfidera®.16
Ozanimod Ozanimod, a selective S1P modulator, acts by blocking lymphocytes from exiting the lymph nodes, decreasing the number of lymphocytes in the peripheral blood.18 Ozanimod is highly selective for the S1P 1 and 5 subtypes.18 The safety and efficacy were established in the phase three SUNBEAM and RADIANCE trials.18, 19 The SUNBEAM trial and the RADIANCE trial studied the efficacy of ozanimod versus interferon beta-1a over 12 months and 24 months respectively.18, 19
mon adverse events.21 Market entry is expected in late 2020.23
Ofatumumab Ofatumumab, an anti-CD20 antibody, is currently marketed under the trade name Arzerra® for the treatment of chronic lymphocytic leukemia (CLL).24 Ofatumumab acts by binding to the CD20 antigen on B-cells leading to B-cell lysis.24 The safety and efficacy of ofatumumab is currently being evaluated in the phase three ASCLEPIOS I and II studies, which are identically designed, flexible duration (up to 30 months), double-blind, randomized, multicenter studies evaluating ofatumumab 20 mg monthly versus teriflunomide 14 mg once daily in adults with relapsing MS.24 ASCLEPIOS I and II Results:
SUNBEAM and RADIANCE Results: » In the SUNBEAM trial, adjusted ARR were 0.35 with interferon beta-1a, 0.18 with ozanimod 1 mg, and 0.24 with ozanimod 0.5 mg. There were no clinically significant reports of bradycardia or second-degree or third-degree atrioventricular block related to the first dose of ozanimod.19 » In the RADIANCE trial, adjusted ARR were 0.28 with interferon beta-1a, 0.17 with ozanimod 1 mg, and 0.22 with ozanimod 0.5 mg.18 » In both trials, fewer patients treated with ozanimod discontinued treatment due to adverse events than did those treated with interferon beta-1a.18, 19 » There were no reports of bradycardia or second-degree or third-degree atrioventricular block related to ozanimod in either trial.18, 19 » Approval is currently pending, and market entry is expected March 25, 2020.20
Ponesimod Ponesimod is another S1P modulator.21 It was studied in patients with relapsing forms of MS in the Oral Ponesimod Versus Teriflunomide In Relapsing Multiple Sclerosis (OPTIMUM) trial, a phase three multicenter, randomized, double-blind, parallel-group, active-controlled, superiority study.22 The study was completed May 16, 2019, and early data showed statistically significant reduction of the ARR by 30.5% at week 108 with ponesimod versus teriflunomide (ARR=0.202 for ponesimod 20 mg versus 0.290 for teriflunomide 14 mg, p=0.0003).21, 22 Nasopharyngitis, headache, upper respiratory tract infections, and an increase in alanine amino transferase (ALT) were the most com-
» The ARR was 0.11 for patients on ofatumumab, compared with 0.22 for patients on teriflunomide (relative reduction 50.5%, p<0.001). » The ARR was 0.10 for patients on ofatumumab, compared with 0.25 for patients on teriflunomide (relative reduction 58.5%, p<0.001.) » Significant suppression of new inflammatory activity with ofatumumab compared to teriflunomide was demonstrated by a suppression of gadolinium (Gd)-enhancing T1 lesions. » In prespecified pooled analyses, ofatumumab demonstrated relative risk reductions of 34.4% (p=0.002) and 32.5% (p=0.012) in 3- and 6-month confirmed disease progression, respectively, compared with teriflunomide.24 » Market entry is expected in late 2020.23
Ublituximab Ublituximab is an anti-CD20 antibody. Phase two trials showed annualized relapse rate of 0.07, with 93% of patients relapse-free at week 48.25 T1 Gd-enhancing lesions were eliminated by ublituximab at week 24 and complete elimination was maintained at week 48.25 Ublituximab was well-tolerated overall, and rapid infusion as low as one hour was also well-tolerated.25 The ULTIMATE 1 and 2 trials are currently two ongoing phase three, randomized, multicenter, double-blinded, active-controlled trials comparing ublituximab to teriflunomide in patients with relapsing MS.25 Market entry is expected in 2021.23
Natalizumab (Tysabri®) Polpharma is currently recruiting participants for a phase three trial to establish efficacy and similarity of safety with biosimilar
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MULTIPLE SCLEROSIS | Continued
PB006 compared to Tysabri® in patients with relapsing-remitting MS.26, 27 The estimated study completion date is August 2021.27 Market entry is to be determined.
Dimethyl fumarate Several generic manufacturers have submitted ANDAs for generic dimethyl fumarate.28 Market entry is expected in June 2020 pending the patient expiration of Tecfidera®.29
Effectiveness and Value of Disease Modifying Therapies The Institute for Clinical and Economic Review (ICER) published a final evidence report in 2017, “Disease-Modifying Therapies for Relapsing-Remitting and Primary-Progressive Multiple Sclerosis: Effectiveness and Value,” as well as “Siponimod for the Treatment of Secondary Progressive Multiple Sclerosis: Effectiveness and Value” in 2019.30, 31 These reports outline the clinical effectiveness of each therapy as well as the cost effectiveness and value.30, 31 The 2017 report determined that the most effective DMTs for reduction of relapses were alemtuzumab, natalizumab, and ocrelizumab.30 The next-most effective therapies were fingolimod, rituximab, and dimethyl fumarate. The least effective therapies were interferons, glatiramer acetate, and teriflunomide.30 The report also determined that for treating RRMS, there was moderate certainty of small to substantial net health benefit for alemtuzumab, natalizumab, and ocrelizumab, and moderate certainty of comparable or better net health benefit for fingolimod and dimethyl fumarate, compared with the interferons and glatiramer acetate. For the treatment of PPMS, the report concluded that, compared with best supportive care, there is moderate certainty of small to substantial net health benefit for ocrelizumab.30 Although the newer therapies are more effective, they also have greater risks of life-threatening infections and serious AEs compared with interferons and glatiramer acetate.30 ICER calculated the incremental cost-effectiveness ratio using the cost per additional qualityadjusted life year (QALY) for each DMT compared with best supportive care and determined that alemtuzumab had good value with a cost per QALY of $38,000.30 The other DMTs were above the range of reasonable value, $100,000-$150,000, meaning that these therapies have poor long-term value for money.30 The report recommended that launch prices of new DMTs be better aligned with the value they provide to the patients.30 The 2019 report concluded with high certainty that siponimod provides at least a small net benefit in patients with active SPMS, compared to placebo. However, economic analyses concluded
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that siponimod exceeds the commonly cited thresholds of costeffectiveness.31 The report recommended that the manufacturer lower the current price of siponimod in order to better align with the value that this therapy provides to patients.31
Managed Care Implications The MS treatment guidelines recommend initiation of DMT early in the disease course of MS patients to delay the progression. As a result, the treatment landscape is becoming increasingly centered around these DMTs. As many novel agents, biosimilars, bioequivalents, and generics come to the market, and the therapeutic class becomes more saturated, formulary management and selection of preferred agents are likely to become the focus for payers.
“About MS.” National Multiple Sclerosis Society, https://www. nationalmssociety.org/For-Professionals/Clinical-Care/About-MS.
Wallin, Mitchell T. et al. “The prevalence of MS in the United States: A population-based estimate using health claims data.” Neurology, March 5, 2019, https://www.ncbi.nlm.nih.gov/pubmed/30770430/.
Lublin, Fred D. et al. “Defining the clinical course of multiple sclerosis: the 2013 revisions.” Neurology, July 15, 2014, https:// www.ncbi.nlm.nih.gov/pubmed/24871874.
Rae-Grant, Alex et al. “Practice guideline recommendations summary: Disease-modifying therapies for adults with multiple sclerosis: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology.” Neurology, April 24, 2018, https://www.aan.com/ Guidelines/Home/ByStatusOrType?status=all.
“Relapse Management.” National Multiple Sclerosis Society, https:// www.nationalmssociety.org/For-Professionals/Clinical-Care/ Managing-MS/Relapse-Management.
Cortese, Irene et al. “Evidence-based guideline update: Plasmapheresis in neurologic disorders: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology.” Neurology, Jan. 18, 2011, https://www. ncbi.nlm.nih.gov/pubmed/21242498.
Ocrevus® [package insert]. South San Francisco, CA; Genentech; November 2019.
Hauser, Stephen L. et al. “Ocrelizumab versus Interferon Beta1a in Relapsing Multiple Sclerosis.” New England Journal of Medicine, Jan. 19, 2017, https://www.nejm.org/doi/full/10.1056/ NEJMoa1601277.
Montalban, Xavier et al. “Ocrelizumab versus Placebo in Primary Progressive Multiple Sclerosis.” New England Journal of Medicine, Jan. 19, 2017, https://www.nejm.org/doi/full/10.1056/ NEJMoa1606468.
References (cont.) 10. “FDA Approves Siponimod - Brand named Mayzent® - for Relapsing Forms of MS Including Active Secondary Progressive MS UPDATE.” National Multiple Sclerosis Society, March 27, 2019, https://www. nationalmssociety.org/About-the-Society/News/FDA-ApprovesSiponimod-Brand-named-Mayzent%C2%AE-for-Re. 11. Kappos, L et al. “Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study.” The Lancet, March 31, 2018, https://www.thelancet.com/journals/lancet/article/PIIS01406736(18)30475-6/fulltext. 12. Vumerity™ [package insert]. Cambridge, MA; Biogen; October 2019. 13. “FDA Approves Oral Vumerity™ (Diroximel Fumarate), Similar to Tecfidera®, for Relapsing MS.” National Multiple Sclerosis Society, Oct. 30, 2019, https://www.nationalmssociety.org/Aboutthe-Society/News/FDA-Approves-Oral-Vumerity™-(DiroximelFumarate),. 14. “A Study of ALKS 8700 in Adults With Relapsing Remitting Multiple Sclerosis (MS) EVOLVE-MS-1.” Clinical Trial NCT02634307, https:// clinicaltrials.gov/ct2/show/NCT02634307. 15. “A Tolerability Study of ALKS 8700 in Subjects With Relapsing Remitting Multiple Sclerosis (RRMS) EVOLVE-MS-2.” Clinical Trial NCT03093324, https://clinicaltrials.gov/ct2/show/ NCT03093324?term=ALKS+8700&draw=1&rank=2. 16. “Banner Receives FDA Tentative Approval for BAFIERTAM for the Treatment of Relapsing Forms of Multiple Sclerosis.” Banner Life Sciences. Business Wire, Jan. 2, 2019, https://www.businesswire. com/news/home/20190102005088/en/Banner-Receives-FDATentative-Approval-BAFIERTAM-Treatment. 17. “Study to Compare GI Tolerability Following Oral Administration of Bafiertam™ or Tecfidera to Healthy Volunteers.” Clinical Trial NCT04022473, https://clinicaltrials.gov/ct2/show/NCT04022473. 18. Cohen, Jeffrey A. et al. “Safety and efficacy of ozanimod versus interferon beta-1a in relapsing multiple sclerosis (RADIANCE): a multicentre, randomised, 24-month, phase 3 trial.” The Lancet Neurology, November 2019, https://www.thelancet.com/article/ S1474-4422(19)30238-8/fulltext. 19. Comi, Giancarlo et al. “Safety and efficacy of ozanimod versus interferon beta-1a in relapsing multiple sclerosis (SUNBEAM): a multicentre, randomised, minimum 12-month, phase 3 trial.” The Lancet Neurology, November 2019, https://www.thelancet.com/ journals/laneur/article/PIIS1474-4422(19)30239-X/fulltext. 20. Payesko, Jenna. “FDA Accepts Ozanimod NDA for Treatment of Relapsing Forms of Multiple Sclerosis.” Neurology Live, June 6, 2019, https://www.neurologylive.com/clinical-focus/fda-acceptsozanimod-nda-for-treatment-of-relapsing-forms-of-multiplesclerosis.
22. “Oral Ponesimod Versus Teriflunomide In Relapsing Multiple Sclerosis (OPTIMUM).” Clinical Trial NCT02425644, April 24, 2015, https://clinicaltrials.gov/ct2/show/NCT02425644. 23. Kish, Troy. “Promising Multiple Sclerosis Agents In Late-Stage Development.” P&T Community, December 2018, https://www. ptcommunity.com/journal/article/full/2018/12/750/promisingmultiple-sclerosis-agents-late-stage-development. 24. “Novartis Phase III ASCLEPIOS trials demonstrate robust efficacy of ofatumumab in patients with relapsing multiple sclerosis.” Novartis, Sept. 13, 2019, https://www.novartis.com/news/media-releases/ novartis-phase-iii-asclepios-trials-demonstrate-robust-efficacyofatumumab-patients-relapsing-multiple-sclerosis. 25. “TG Therapeutics, Inc. Announces Final Phase 2 Multiple Sclerosis Data Presentation at the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Annual Meeting.” TG Therapeutics, March 1, 2019, http://ir.tgtherapeutics.com/newsreleases/news-release-details/tg-therapeutics-inc-announces-finalphase-2-multiple-sclerosis-1. 26. Davio, Kelly. “Sandoz to Commercialize Biosimilar of MS Drug, Natalizumab.” Sept. 3, 2019, https://www.centerforbiosimilars.com/ news/sandoz-to-commercialize-biosimilar-of-ms-drug-natalizumab. 27. “Efficacy and Safety of the Biosimilar Natalizumab PB006 in Comparison to Tysabri® (Antelope).” Clinical Trial NCT04115488, Oct. 4, 2019, https://www.clinicaltrials.gov/ct2/show/ NCT04115488?term=PB006&draw=2&rank=1. 28. “Drugs@FDA: FDA-Approved Drugs.” U.S. Food and Drug Administration, https://www.accessdata.fda.gov/scripts/cder/daf/ index.cfm. 29. “Glenmark Pharmaceuticals Receives Tentative ANDA Approval for Dimethyl Fumarate Delayed-Release Capsules, 120 mg and 240 mg.” Glenmark Pharmaceuticals Ltd., Oct. 9, 2019, https://www. prnewswire.com/in/news-releases/glenmark-pharmaceuticalsreceives-tentative-anda-approval-for-dimethyl-fumarate-delayedrelease-capsules-120-mg-and-240-mg-880935531.html. 30. Tice, Jeffrey A. et al. “Disease-Modifying Therapies for RelapsingRemitting and Primary-Progressive Multiple Sclerosis: Effectiveness and Value.” Institute for Clinical and Economic Review, March 6, 2017, https://icer-review.org/wp-content/uploads/2016/08/CTAF_ MS_Final_Report_030617.pdf. 31. Sharaf, Ravi N. et al. “Siponimod for the Treatment of Secondary Progressive Multiple Sclerosis: Effectiveness and Value.” Institute for Clinical and Economic Review, June 20, 2019, https:// icer-review.org/wp-content/uploads/2018/10/ICER_MS_Final_ Evidence_Report_062019.pdf.
21. “New Head-to-Head Phase 3 Study Data Show Ponesimod Superiority Versus Aubagio® (teriflunomide) 14 mg in Adults with Relapsing Multiple Sclerosis (MS).” Johnson & Johnson, Sept. 11, 2019, https://www.jnj.com/new-head-to-head-phase-3-study-datashow-ponesimod-superiority-versus-aubagio-teriflunomide-14-mgin-adults-with-relapsing-multiple-sclerosis-ms.
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Introducing MRx Navigate: Whole Patient Care Meets Digital Innovation The new medical management program MRx Navigate offers integrated high-touch and high-tech solutions to enhance and simplify the healthcare experience for health plans and their members. In October 2019, Magellan Rx Management (MRx) introduced a new multifaceted, holistic medical management program, MRx Navigate, to support MRx pharmacy benefit manager, employer, and government clients by providing an integrated view of the member and to offer standalone services for other clients. Through MRx Navigate, members have access to a coach or care manager when they are newly diagnosed with a health condition, recently discharged from the hospital, interested in making a lifestyle change, or have questions about healthcare decisions. After an initial connection is made, MRx Navigate staff will proactively reach out to members and provide comprehensive education and adherence programs to improve healthcare decision-making and engagement. Caroline Carney, M.D., M.Sc., FAPM, CPHQ Chief Medical Officer Magellan Rx Management
MRx Navigate eliminates gaps in care and improves adherence through digital tools, online resources, and apps â€” and by leveraging analytics that identify members at risk for nonadherence or ineffective medical and pharmacy utilization. Driven by data-led, evidence-based algorithms, the program uses data from multiple sources to identify members in need of care-management or disease-management outreach and determine the intensity of intervention needed. Additionally, utilization-management support is provided for medical and behavioral health requests for services. MRx Navigate is a comprehensive program including four different programs to cover multiple facets of care management.
1. Navigate Change With the objective of assisting members on their road to recovery, Navigate Change connects members with nurses, behavioral health professionals, and clinical pharmacists. The Navigate Change team works to ensure members receive the proper medications, education, and network resources that will
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help them avoid a return visit to the hospital. Care managers take customized approaches based on membersâ€™ individual needs, assessing impacts to quality of life and financial costs. Clinical pharmacists are available to assist members with medications by reviewing compliance, side effects, interactions, and any questions or concerns raised by a member. Navigate Change has targeted disease states for transitions in both care and care management (Table 1). Internal data suggests that access to a collaborative team of a pharmacist and care manager can reduce hospital readmissions by 50%.
Table 1. Targeted Disease States Transitions in Care
Asthma/COPD Behavioral Health Congestive Heart Failure CVA/Stroke Diabetes Heart Disease Readmissions
Cancer High-Risk Pregnancy Pain Management Transplants Dialysis Large Claims Multiple ER Visits Out-of-Network
2. Navigate PopHealth The population health management program Navigate PopHealth reviews for gaps in care and implements a care plan to reduce or eliminate identified gaps. Informed by data analytics, Navigate PopHealth identifies members who have chronic health conditions and who may be at risk of nonadherence, coordinates care, and reviews social determinants of health that may be impacting health outcomes. Once members are
Informed by data analytics, Navigate PopHealth identifies members who have chronic health conditions and who may be at risk of nonadherence, coordinates care, and reviews social determinants of health that may be impacting health outcomes. identified for gaps in care and/or nonadherence, member engagement is initiated by an appropriate care manager (nurse, pharmacist, or behavioral health specialist). Once outreach is initiated, the care manager and member agree to a scheduled contact cycle where the care plan goals and challenges will be reviewed and discussed. Through Navigate PopHealth, members will also have access to educational materials and resources to make the best healthcare decisions. Members with specific conditions (Figure 1) will have access to a variety of resources. Nurses, pharmacists, and behavioral
Figure 1. PopHealth Chronic Health Conditions
Congestive Heart Failure
Chronic Obstructive Pulminary Disease
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MRX NAVIGATE | Continued
health professionals consult with members to help them manage their chronic conditions and can assist in discussions with members’ physicians.
consistent with the standards required under the program’s certification by the National Committee for Quality Assurance. A standard suite of reports to track trends and identify opportunities is regularly reviewed with clients.
3. Navigate Wellness
Objectives and Commitments:
Navigate Wellness aims to identify diseases and increase members’ quality of life through educational tools and resources. Onsite biometric screenings, flu shot clinics, and mobile mammograms educate members about their health and wellness and keep them healthy by preventing more serious and costly complications. Onsite programs, challenges, educational resources, webinars, and wellness coaches help members set and achieve their wellness goals. Navigate Wellness helps members focus on a healthier lifestyle, which impacts their day-to-day activities both at work and at home.
• • • • • •
Prevent fraud, waste, and abuse Refer members into care management Minimize readmission through transition of care Provide medically necessary care based on nationally recognized clinical guidelines Efficiently manage turnaround times Provide comprehensive peer-to-peer review
Where offered, wellness programs have had a positive impact on employees. At worksites offering a wellness program, a higher rate of employees exercised regularly and actively managed their weight. Onsite programs include flu shot clinics, mobile mammograms, biometric screenings, wellness seminars, and health fairs. Navigate Wellness also provides access to virtual resources, including personal wellness coaches, wellness challenges, videos, newsletters, blog posts, health risk assessments, nutritional assessments, and sleep tips.
4. Navigate UM The utilization management program Navigate UM focuses on ensuring members receive the proper medical and behavioral healthcare. The program covers prior authorization for medical and behavioral services, concurrent review of inpatient admissions, transition of care assessment, and appeal management. It documents requests for review in an integrated platform connected to available care-management services and utilizes industryleading evidence-based care guidelines. The Navigate UM team of intake specialists, nurses, and physicians perform these services
Unlock the Possibilities for Better Care To learn more about how Magellan Rx Management and MRx Navigate can help your organization, contact us at MRxInquiries@magellanhealth.com or visit magellanrx.com.
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IN ADVANCED FIBROSIS DUE TO NASH
HOW CLOSE ARE PATIENTS TO
THE TIPPING POINT™? Visit www.nashtippingpoint.com to learn more
Use of the “UK traffic sign: risk of falling rocks ahead” is licensed under the Open Government Licence version 1.0 (https://NationalArchives.gov.uk/doc/open-government-licence/version/1/) (OGL v1.0). Tipping Point and NASH Tipping Point are trademarks of Intercept Pharmaceuticals, Inc. The Intercept logo is a registered trademark of Intercept Pharmaceuticals, Inc. New York, NY 10001 | T: 844-782-ICPT | F: 646-747-1001 © 2020 Intercept Pharmaceuticals, Inc. All rights reserved. US-PP-NAS-0476 02/20
Gene Therapy: Changing Market Landscape and Pipeline As more gene therapies for larger patient populations enter the pipeline, payers must meet the immense challenge of how to fund the coverage. Once just a pipe dream, gene therapy has become a reality. Several groundbreaking gene therapies have received FDA approval since 2017,1 offering significant treatment advancements and, in some cases, even cure. While gene therapy has been a long time coming, there will certainly be a learning curve for patients, payers, and providers as these innovative therapies are incorporated into clinical practice.
Gene Therapy: 101
Natalie A. Tate, PharmD, MBA, BCPS Vice President, Pharmacy BlueCross BlueShield of Tennessee
To best understand the complexities of gene therapy in clinical development and, ultimately, in clinical practice, it is critical to understand how gene therapy works. Gene therapy is essentially the use of genetic material to manipulate a patient’s cells in order to treat an inherited or acquired genetic disease.2-4 The genetic material that is inserted directly into the cell is typically nonfunctional and may include nucleic acids, viruses, or genetically engineered microorganisms. This genetically engineered vector is used to deliver the gene to the desired location. Viruses, one of the most efficient vectors utilized, insert genetic material into the cell by infecting the cell, but modifications prevent that virus from causing disease in the human host.2-4 Commonly utilized viruses include retroviruses, which integrate their genetic material into chromosomes in the human cell, and adenoviruses, which introduce deoxyribonucleic acid (DNA) into the nucleus of the cell but not into the chromosome.2-4
Currently Available Gene Therapies Luxturna® (voretigene neparvovec-rzyl) Luxturna® received FDA approval in December 2017, making it the first directly administered gene therapy approved in the U.S. that targets disease caused by mutations in a specific gene.5 Leading up to the approval, the FDA granted Luxturna® the Priority Review, Breakthrough Therapy, and
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Orphan Drug designations, and, following approval, the manufacturer, Spark Therapeutics, received a Rare Pediatric Disease Priority Review Voucher.6 Specifically, Luxturna® was approved for the treatment of children and adult patients with confirmed biallelic retinal pigment epithelium (RPE65) mutation-associated retinal dystrophy — an inherited form of vision loss that may cause complete blindness in certain patients.5, 6 The RPE65 gene encodes an enzyme that is essential for normal vision; mutations in the RPE65 gene result in reduced or absent RPE65 activity, inhibiting the visual cycle and resulting in visual impairment. For individuals with biallelic RPE65 mutation-associated retinal dystrophy, progressive deterioration of vision occurs over time, typically during childhood or adolescence, and progresses to complete blindness. Biallelic RPE65 mutation-associated retinal dystrophy affects somewhere between 1,000 and 2,000 individuals in the U.S.5, 6 Luxturna® utilizes an adeno-associated viral (AAV) vector to deliver a normal copy of the human RPE65 gene to the retinal cells in order to restore vision.6 These retinal cells are then able to produce normal protein that converts light to an electrical signal within the retina.6, 7 As such, Luxturna® should only be given to patients who have viable retinal cells. Luxturna® is administered via subretinal injection into each eye separately, with a minimum of six days between injections. Patients are also given a course of oral prednisone to mitigate any potential immune reactions.6, 7 The safety and efficacy of Luxturna® was evaluated in a clinical program that included 41 patients between the ages of 4 and 44 years.8 In the phase three trial (n=31), 20 patients were randomly assigned to treatment with Luxturna®.8 At baseline, patients had best corrected visual acuity of 20/60 or worse in each eye or visual field less than 20 degrees in any meridian, or both, with sufficient viable retina and the ability to perform standardized multiluminance mobility testing (MLMT) within the luminance range evaluated.8 The MLMT is a test that evaluates a patient’s ability to maneuver through an obstacle course at various light levels. One year after treatment, the mean bilateral MLMT change score was 1.8 light levels in the intervention group, compared to 0.2 light levels in the control group (difference 1.6; 95% confidence interval 0.72 to 2.41; p=0.0013). Of the patients treated with Luxturna®, 65% successfully passed the MLMT at the lowest luminance level tested (one lux, equivalent to a moonless night), demonstrating the maximum possible improvement.8
Zolgensma® (onasemnogene abeparvovec-xioi) In May 2019, the FDA approved the second gene therapy, Zolgensma®, for the treatment of spinal muscular atrophy (SMA) in children less than two years of age, who get the most severe
form of SMA.9 As with Luxturna®, the FDA granted Zolgensma® the Fast Track, Breakthrough Therapy, and Priority Review designations leading up to approval, and awarded the manufacturer, Novartis, a Rare Pediatric Disease Priority Review Voucher.10 SMA is a rare genetic disease that represents the leading genetic cause of infant mortality.11 SMA is caused by a mutation in the survival motor neuron 1 (SMN1) gene, which encodes the survival motor neuron (SMN) protein essential for the maintenance and function of motor neurons in the brain and spinal cord that control muscle movement throughout the body.10, 11 When functional SMN protein is lacking, motor neurons die, resulting in debilitating and potentially fatal muscle weakness. Zolgensma® is approved for infantile-onset SMA. Infants with this form of SMA typically display symptoms between birth and six months of age; these may include problems holding their head up, swallowing, and breathing. Unfortunately, affected children are not expected to survive past early childhood.10, 11 Zolgensma® is an AAV vector-based gene therapy that works by delivering a fully functional copy of the human SMN gene into the target motor neuron cells.10, 12 A single intravenous administration promotes the expression of the SMN protein in the patient’s motor neurons, improving both muscle function and the patient’s survival.10 The efficacy and safety of Zolgensma® was evaluated in an ongoing clinical trial as well as a completed clinical trial that included 36 pediatric patients with infantile-onset SMA between the ages of two weeks and eight months at study entry.10, 12 All patients had genetically-confirmed biallelic SMN1 gene deletions, two copies
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GENE THERAPY | Continued Current Market Landscape
With the advancement of gene therapy technology, there has been an explosion of activity within the pipeline.
With the advancement of gene therapy technology, there has been an explosion of activity within the gene therapy pipeline. According to the Alliance for Regenerative Medicine’s first-quarter report for 2019, there were 372 clinical trials for gene therapy in progress, 58% of which were phase two and 9% of which were phase three.14 Notably, the number of clinical trials increased 17% yearover-year from the 319 trials that were ongoing in the first three months of 2018.14 Following the approval of the first gene therapy, Luxturna®, former FDA Commissioner Scott Gottlieb stated that “we’re at a turning point when it comes to this novel form of therapy,” and that he believes “gene therapy will become a mainstay in treating, and maybe curing, many of our most devastating and intractable diseases.”6 With excitement around gene therapy and the robustness of the pipeline, the FDA anticipates approving 10 to 20 cell and gene therapies per year starting in 2025.9
of the SMN2 gene, and absence of the c.859G>C modification in exon 7 of the SMN2 gene, which predicts a milder phenotype.12 The primary efficacy data included in the package insert was based on data from 21 patients enrolled in the ongoing clinical trial. The efficacy of Zolgensma® was established on the basis of survival and achievement of developmental motor milestones such as sitting without support.12 As of the March 2019 data cutoff, 19 of 21 patients enrolled in the trial were alive without permanent ventilation, which was considered event-free survival. Of the two patients no longer enrolled, one patient died at age 7.8 months due to disease progression and one patient withdrew from the study at age 11.9 months.12 By the data cutoff, 13 of the 19 patients continuing in the trial had reached 14 months of age without permanent ventilation. Furthermore, 10 of the 21 patients initially enrolled (47.6%) were able to sit without support for 30 seconds or more between 9.2 and 16.9 months of age (mean, 12.1 months).12 Comparatively, based on the natural history of disease in SMA, only 25% of these patients would be expected to survive without permanent ventilation beyond 14 months of age. It is important to note that Zolgensma® does have a boxed warning for acute serious liver injury and elevated aminotransferases.12
There are hundreds of gene therapies currently in early-stage development, and a few that may receive FDA approval within the next year.14 One such product, valoctocogene roxaparvovec by BioMarin, is an investigational AAV-based gene therapy currently being studied for adults with hemophilia A.15 Hemophilia A, also known as Factor VIII deficiency, is an X-linked genetic disorder caused by missing or defective Factor VIII, which is an essential clotting protein. Individuals with the most severe form — which approximately 60% of those with hemophilia A have — may experience spontaneous, painful bleeds into the muscle tissue or joints.16 The current standard of care for hemophilia A includes a prophylactic regimen of replacement Factor VIII infusions administered intravenously two to three times per week. Unfortunately, affected individuals may continue to experience bleeds and progressive, debilitating joint damage.15
Zolgensma® appears to offer a transformative approach to the treatment of a form of SMA that impacts 450 to 500 infants born each year. It quickly became the most expensive drug in the world, at a staggering $2,125,000 per patient.9 Novartis does offer a payment plan that divides the total cost of the one-time treatment into five yearly installments of $425,000.9 Although the cost seems extreme, the existing SMA competitor product, Spinraza® (nusinersen), costs $750,000 for the first year and $375,000 annually thereafter for the patient’s lifetime.9, 13 After five years, Spinraza®, which offers a temporary fix to the genetic mutations in SMA, costs $2,175,000, which is similar in cost to the potentially curative gene therapy.9, 13
Valoctocogene roxaparvovec works by delivering a functional copy of the B-domain-deleted Factor VIII gene, and it is given as a single dose.16 Three-year follow-up data from an ongoing phase one/two study was presented at the 2019 Congress of the International Society on Thrombosis and Haemostasis.17 The phase one/two study was an open-label, dose-escalation study that enrolled 13 men. Patients were included in the study if they had severe hemophilia A with residual Factor VIII levels ≤1 IU/dL and were exposed to Factor VIII concentrates or cryoprecipitate for at least 150 days.17 All study subjects received a single dose of valoctocogene roxaparvovec, at 6 x 1013 v/kg (n=6) or 4 x 1013 vg/kg (n=6). After three years of follow-up, subjects in both dose groups required fewer infusions
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Gene Therapy Pipeline Valoctocogene Roxaparvovec
of Factor VIII per year, with reductions from baseline of 96% in the 6 x 1013 v/kg dose group and 97% in the 4 x 1013 v/kg dose group.17 Of note, the Factor VIII expression reached a plateau at approximately 20% at year three, and the study investigators noted that Factor VIII expression levels were expected to decline over time.17 The investigators noted that current projections conservatively estimate the persistence of bleeding control for at least eight years post-administration, and longer if the Factor VIII expression plateaus are maintained.17 In addition to improvements in Factor VIII expression, study subjects in both groups experienced significant reductions in the annualized bleeding rate.17 In the year prior to treatment, subjects in the 6 x 1013 v/kg dose group experienced a mean of 16.3 bleeds, compared to 0.9 bleeds in the first year post-treatment, 0.2 bleeds in the second year, and 0.7 in the third year (p-value not reported).17 This represents a 96% reduction in mean annualized bleeding rates. Similar reductions in annualized bleeding rate were observed in the 4 x 1013 v/kg dose group.17 Valoctocogene roxaparvovec has been awarded the Breakthrough Therapy and Orphan Drug designations by the FDA, and in December 2019, BioMarin announced the submission of a Biologics License Application to the FDA, initially seeking accelerated approval based on phase one/two data.15 While valoctocogene roxaparvovec is likely to be the first gene therapy for hemophilia
A to reach the market, there are a handful of competitors in latestage development in what has become one of the most competitive therapeutic areas in the emerging field of gene therapy.18 Additional gene therapies in development for hemophilia A include SPK-8011 from Spark Therapeutics and SB-525 from Sangamo and Pfizer. While SB-525 is the furthest out, Sangamo and Pfizer announced promising phase one/two data that demonstrated that patients who received the highest dose of SB-525 were sustaining normal levels of Factor VIII clotting protein at the interim analysis.18 As excitement for new gene therapies in hemophilia builds, a survey of 25 doctors who treated approximately 3,000 patients with hemophilia in the U.S. and Europe found that 28% intend to prescribe valoctocogene roxaparvovec to eligible patients within two years of launch, and 39% would prescribe within five years.18 While the cost is not yet known, it will likely be substantial — some studies have estimated that the average cost of managing a patient with hemophilia in the U.S. is approximately $140,000 to $155,000 annually.19-22 For patients who develop inhibitors and require more Factor VIII concentrate, the cost of management can jump to $697,000 to $1 million per year.19-22 It is important to note that these estimates are based on current treatment and management of hemophilia and are likely much lower than the cost of managing hemophilia with emerging gene therapies. In an interview, the CEO of BioMarin drew comparisons between valoctocogene roxaparvovec and Zolgensma®, with each product competing against a current standard of care.23 He stated that it may “be difficult for payers to pay more” for the gene therapy than the equivalent cost of five years of hemophilia care, which may suggest that there are plans to utilize a similar five-year payment strategy for valoctocogene roxaparvovec.23
Zynteglo® (formerly known as LentiGlobin®) Zynteglo® is an investigational gene therapy from Bluebird Bio being studied for the treatment of transfusion-dependent β thalassemia (TDT).24 β thalassemia, an inherited genetic disease, results in defective red blood cells that are unable to carry oxygen appropriately. Severe cases require frequent blood transfusions, which may be associated with a toxic accumulation of iron in the blood.24 Zynteglo® works by delivering functional copies of a modified form of the beta-globin gene into a patient’s own hematopoietic stem cells (HSC).25 Once a patient has the functional gene, they have the potential to produce HbAT87Q, which is gene therapy-derived hemoglobin, at levels that eliminate or drastically reduce the need for transfusions of donor HSC.25 The efficacy and safety of Zynteglo® were evaluated in a completed phase one/two study, as well as two ongoing phase three studies.25
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GENE THERAPY | Continued
The phase one/two study enrolled 18 patients, including 10 who did not have a β0/β0 genotype and eight who did have a β0/β0 genotype. After completion of the two-year study, all 18 patients enrolled in a long-term follow-up study.25 Of the 10 patients who did not have a β0/β0 genotype, eight achieved transfusion independence (no transfusion for at least 12 months and maintenance of weighted hemoglobin ≥9 g/dL).25 Of the patients with a β0/β0 genotype, three of the eight achieved transfusion independence and maintained a median weighted average hemoglobin ranging from 9.5 to 10.1 g/dL for a median duration of 16.4 months.25 In March 2019, Zynteglo® received regulatory approval in the EU and set a price of $1.8 million USD.26 Bluebird Bio has told their investors to expect a regulatory submission to the FDA by the end of 2019. Although they haven’t announced their intentions with pricing in the U.S., they did suggest that the product has an “intrinsic value” of $2.1 million.26
Managed Care Implications Undoubtedly, gene therapy has and will continue to make waves in the managed care world. With each new therapy that is approved, the question of how much the market is willing to pay for innovation arises. It seems obvious that curative therapies for devastating, deadly diseases would be covered; however, with upfront costs exceeding $2 million per patient, funding this coverage becomes a major challenge. While many gene therapies may actually save money in the long term, the initial payer may never accrue those savings due to the rate at which patients change health insurer. This could disincline payers from providing coverage from such costly therapies, thus limiting access for patients. A payer survey showed that four out of five national payers and nine out of 16 regional payers reported “very high” concern with regard to managing the potential financial risk and impact of gene therapies.27 In the same survey, nearly one-third of small-employer third-party administrators and managed Medicaid plans indicated they were likely to exclude coverage for gene therapies due to the associated financial challenges.27 Naturally, this could lead to a disparity in access for patients based on their specific payer, resulting in patients shopping for payers with more favorable criteria for these emerging therapies. Furthermore, in the not-so-distant past, payers only had to worry about the one or two patients in their plan with a rare disease who may be candidates for gene therapy. Now, as the gene therapy pipeline expands to a greater number of therapeutic areas, including genetic diseases that impact more people, the potential pool of patients is ever-increasing. In addition to the growing treatment pool, there are several other challenges with gene therapy. Ques-
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With each new therapy that is approved, the question of how much the market is willing to pay for innovation arises. tions around the efficacy and the durability of effect remain. Manufacturers of gene therapy products justify their hefty price tags by arguing that these therapies offer potentially curative effects; however, many are concerned about those patients who fail to respond and, for those that do respond, whether those effects will truly last 10 years and beyond. For those patients who lose effect after several years, will it be possible to treat them again, and will it be financially feasible? With all these challenges and unanswered questions facing payers, it will be imperative to take a proactive approach, staying abreast of the gene therapy pipeline and the data supporting these products. Many gene therapies target patients with specific characteristics such as mutations. Given the cost and the fact that gene therapies may only work for patients with certain characteristics, access to patient screening is essential to ensure that only the appropriate patients receive treatment. In light of the questions around efficacy and durability, value-based contracting will likely gain new traction in the gene therapy arena, as payers seek contracts that reimburse for gene therapy that does not maintain its effect or does not work at all. As we have already seen to some degree, manufacturers are also getting creative in the pricing of their gene therapies, offering payment plans in lieu of larger, upfront payments. Despite these efforts, payers and manufacturers will need to continue working together to identify solutions that can bring these innovative therapies to the patients who need them.
“Approved Cellular and Gene Therapy Products.” U.S. Food and Drug Administration, March 29, 2019, https://www.fda.gov/vaccinesblood-biologics/cellular-gene-therapy-products/approved-cellularand-gene-therapy-products.
“Gene therapy vs. cell therapy.” American Society of Gene & Cell Therapy, https://annualmeeting.asgct.org/about_gene_therapy/ genevscell.php.
“Guidance for Industry: Gene Therapy Clinical Trials — Observing Subjects for Delayed Adverse Events.” U.S. Food and Drug Administration, Nov. 4, 2015, https://www.fda.gov/media/72225/ download.
“How does gene therapy work?” Genetics Home Reference, Aug. 15, 2017, http://ghr.nlm.nih.gov/primer/therapy/procedures
Darrow, J.J. “Luxturna: FDA documents reveal the value of a costly gene therapy.” Drug Discovery Today, April 2019, https://www.ncbi. nlm.nih.gov/pubmed/30711576.
“FDA approves novel gene therapy to treat patients with a rare form of inherited vision loss.” U.S. Food and Drug Administration, Dec. 18, 2017, https://www.fda.gov/news-events/press-announcements/ fda-approves-novel-gene-therapy-treat-patients-rare-forminherited-vision-loss.
Luxturna [package insert], Philadelphia, PA, Spark Therapeutics, 2017.
Russell, S. et al. “Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65-mediated inherited retinal dystrophy: a randomised controlled, open-label, phase 3 trial.” The Lancet, Aug. 2017, https://www.ncbi.nlm.nih.gov/ pubmed/28712537.
Cross, Ryan. “FDA approves second gene therapy, Zolgensma, to treat spinal muscular atrophy in infants.” Chemical & Engineering News, May 30, 2019, https://cen.acs.org/business/FDA-approvessecond-gene-therapy/97/i22.
10. “FDA approves innovative gene therapy to treat pediatric patients with spinal muscular atrophy, a rare disease and leading genetic cause of infant mortality.” U.S. Food and Drug Administration, May 24, 2019, https://www.fda.gov/news-events/press-announcements/ fda-approves-innovative-gene-therapy-treat-pediatric-patientsspinal-muscular-atrophy-rare-disease. 11. “About SMA.” Cure SMA, 2019, https://www.curesma.org/aboutsma/ 12. Zolgensma® [package insert], Bannockburn, IL, AveXis, Inc, 2019. 13. Spinraza® [package insert], Cambridge, MA, Biogen, 2019. 14. Philippidis, Alex. “25 Up-and-Coming Gene Therapies of 2019.” Genetic Engineering & Biotechnology News, May 20, 2019, https:// www.genengnews.com/a-lists/25-up-and-coming-gene-therapiesof-2019/. 15. “BioMarin Submits Biologics License Application to U.S. Food and Drug Administration for Valoctocogene Roxaparvovec to Treat Hemophilia A.” BioSpace, Dec. 23, 2019, https://investors.biomarin. com/2019-12-23-BioMarin-Submits-Biologics-License-Applicationto-U-S-Food-and-Drug-Administration-for-ValoctocogeneRoxaparvovec-to-Treat-Hemophilia-A.
16. “Hemophilia A.” National Hemophilia Foundation, 2020, https:// www.hemophilia.org/Bleeding-Disorders/Types-of-BleedingDisorders/Hemophilia-A. 17. “Valoctocogene Roxaparvovec Continues to Improve Bleeding Outcomes in Patients With Hemophilia A.” ASH Clinical News, Sept. 1, 2019, https://www.ashclinicalnews.org/on-location/ other-meetings/valoctocogene-roxaparvovec-continues-improvebleeding-outcomes-patients-hemophilia/. 18. Bell, Jacob. “BioMarin confirms timeline for hemophilia gene therapy, putting pressure on rivals.” BioPharma Dive, July 8, 2019, https://www.biopharmadive.com/news/biomarin-confirmstimeline-for-hemophilia-gene-therapy-putting-pressureon/558279/. 19. Chen, S. L. “Economic costs of hemophilia and the impact of prophylactic treatment on patient management.” American Journal of Managed Care, April 2016, https://www.ncbi.nlm.nih. gov/pubmed/27266809. 20. Escobar, M. “Health economics in haemophilia: a review from the clinician’s perspective.” Haemophilia, May 2010, https://www. ncbi.nlm.nih.gov/pubmed/20586799. 21. Guh, S. et al. “Healthcare expenditures for males with haemophilia and employer-sponsored insurance in the United States, 2008.’ Haemophilia, March 2012, https://www.ncbi.nlm.nih.gov/ pubmed/22151000. 22. Chen, S. L. “Economic costs of hemophilia and the impact of prophylactic treatment on patient management.” American Journal of Managed Care, April 2016, https://www.ncbi.nlm.nih. gov/pubmed/27266809. 23. Lash, Alex. “With Sliver of Data, BioMarin to Seek OK for Hemophilia Gene Therapy.” Xconomy, May 28, 2019, https:// xconomy.com/san-francisco/2019/05/28/with-sliver-of-databiomarin-to-seek-ok-for-hemophilia-gene-therapy/. 24. Terry, Mark. “BlueBird Bio presents more data on its $1.8 million gene therapy Zynteglo.” BioSpace, June 14, 2019, https://www. biospace.com/article/bluebird-bio-presents-more-data-on-its-18-million-gene-therapy-zynteglo/. 25. “bluebird bio presents long-term efficacy and safety data from clinical studies of LentiGlobin® gene therapy for transfusiondependent β-thalassemia (TDT) at 24th European Hematology Association (EHA) Congress.” BusinessWire, June 14, 2019, https:// www.businesswire.com/news/home/20190614005119/en/ bluebird-bio-Presents-Long-Term-Efficacy-Safety-Data. 26. Weintraub, Arlene. “bluebird tees up its first gene therapy approval with Zynteglo thumbs-up in EU.” FiercePharma, March 29, 2019, https://www.fiercepharma.com/pharma/europe-setsup-first-bluebird-gene-therapy-approval-thumbs-up-thalassemiatreatment. 27. Ciarametaro, Michael et al. “Are Payers Ready to Address the Financial Challenges Associated With Gene Therapy?” HealthAffairs, June 28, 2018, https://www.healthaffairs.org/ do/10.1377/hblog20180626.330036/full/.
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Rare Liver Disease Update: Nonalcoholic Steatohepatitis As the prevalence of NASH approaches that of Type 2 diabetes, new therapies to address chronic liver disease will soon reshape the treatment landscape for liver disease patients. Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the world and the precursor to nonalcoholic steatohepatitis (NASH). NASH is a progressive form of NAFLD and can potentially lead to cirrhosis and the mortality associated with it. NASH has also quickly become a leading cause of liver transplantation and hepatocellular carcinoma.1 In the U.S., economic models estimate that 6.7 million adults live with NASH. 2017 saw 232,000 incident cases, and total estimated lifetime costs for NASH patients totaled $222.6 billion, with advanced-stage patients costing $95.4 billion.1
Lester Lachuk, Pharm.D., MBA VP, Corporate Pharmacy BlueCross BlueShield of Western New York
Cause and Pathogenesis of NASH Steatosis (infiltration of liver cells by fat) causes damage to the liver and leads to progressive liver fibrosis. NASH causes greater liver damage than isolated steatosis and often leads to liver-related illness and death. An analysis of over 8.5 million persons from 22 countries showed that over 80% of persons with NASH are overweight or obese, 72% have dyslipidemia, and 44% have received a diagnosis of Type 2 diabetes. Because of this, NASH is considered to be a hepatic form of metabolic syndrome, a systemic disorder associated with visceral adiposity.2 NASH is closely linked to liver fibrosis, which results in scarring. The level or degree of fibrosis is determined by biopsy and staged from F0 to F4. The stages of fibrosis scoring are as follows: F0 — no fibrosis, F1 — portal fibrosis without septa, F2 — portal fibrosis with few septa, F3 — bridging septa between central and portal veins, and F4 — cirrhosis. Studies show that a quarter of NASH patients have stage F2 fibrosis or higher when diagnosed.2 A certain level of fibrosis is expected in NASH patients, as it remains after liver wounds heal. Septa in the liver are made up of collagen and connecting tissue and reorganize the structure of the liver, decreasing its ability to function properly.
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Progression of fibrosis in the liver is variable. A cohort of patients was studied by looking at sequential biopsies over a period of decades. Findings showed that patients progressed at a rate of one stage per decade, meaning a patient in stage F2 could progress to cirrhosis within 20 years. Variations in this rate of progression were seen among patients in whom healing of NASH had taken place, creating the possibility of a nonlinear prediction of progression in some cases.2 The cause of NASH has been linked to inherited and environmental factors. Factors contributing to the development of NASH include inflammation, hyperinsulinemia — or insulin resistance — and changes in lipid homeostasis. Genetic studies indicate certain polymorphisms in phospholipase can promote the development of NASH and related liver damage. Gene expression changes can be seen without altering the DNA code itself. Studies have observed families with a history of adult-onset obesity to look at alterations that dysregulate metabolic pathways controlling adiposity, insulin sensitivity, and tissue generation or regeneration. Studies continue to investigate these factors to determine if there is a link to developing NASH.
Environmental Factors Modifiable internal and external risk factors are also being evaluated for any link to NASH. Early studies in genetically modified obese mice with metabolic syndrome and fatty livers revealed an abnormal microbiome with hepatic inflammatory signals leading to insulin resistance, hepatic steatosis, and NASH. Work continues in
Management of metabolic syndrome and screening for cancer in patients with NASH and cirrhosis need to be incorporated early on in treatment. this area to determine if models seen in mice can be used to guide providers on the treatment of humans using therapies such as antibiotics, probiotics, or prebiotics to prevent or treat NASH. Sleep patterns and an increased risk of hepatic steatosis are also being studied in mice. Prolonged disruption of the circadian rhythms in mice with fatty livers has shown disruption in two nuclear hormone receptors, leading to development of NASH. This may be relevant in patients with a history of shift work, which disrupts ideal sleep habits. It is believed that liver health is dependent on metabolic responses working together as a network to regulate energy supply and demand.
Diagnosis and Current Treatment Options The differentiation between patients with hepatic steatosis and patients with NASH is critical when considering a course of treatment. Staging of liver fibrosis is the first diagnostic tool used to determine severity of disease, and accurate staging is necessary because the development of NASH is closely related to a diagnosis of F2 or higher. The risk of death increases 50% to 80% as fibrosis increases from F2 to F3 or F4.2 Patients at risk for fatty liver and subsequent NASH typically include individuals who are overweight, over the age of 45, have metabolic syndrome, and are insulin-resistant. Because liver fibrosis severity can vary within the liver, multiple samples may be needed to determine the level of disease. Less-invasive diagnostic tests are available to diagnose cirrhosis and exclude a diagnosis of NASH. Patients will be worked up for presence of steatosis by ultrasound and then other disorders — e.g. hepatitis, alcohol consumption, etc. — will be excluded. The only way to definitively diagnose NASH today is by visualizing ballooning and inflammation by biopsy. Physicians will diagnose NASH based on risk factors and
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RARE LIVER DISEASE UPDATE | Continued
exclusion of other disorders, then use noninvasive techniques to determine level of fibrosis. Less-invasive tests to diagnose NASH are being developed and may include panels of serum biomarkers, imaging tests, and dynamic tests of liver function. Management of metabolic syndrome and screening for cancer in patients with NASH and cirrhosis need to be incorporated early on in treatment. Lifestyle modifications are typically the first line of treatment to reduce the risk of liver fibrosis progressing to NASH. For overweight or obese patients, weight-loss goals of 7% of current body weight, limiting consumption of fructose-enriched beverages, limiting consumption of alcohol (less than one drink per day for women and less than two drinks per day for men), and drinking two or more caffeinated cups of coffee a day are recommended lifestyle modifications that can aid in reducing this risk. Caffeinated coffee reduces the risk of liver fibrosis in several liver diseases including nonalcoholic fatty liver disease.2 In terms of pharmacologic treatments, clinical trials have been underway for many years to find a drug to treat NASH. There are therapies in phase two or phase three development designed to work within the liver to decrease metabolic stress and reduce inflammation and the degree of fibrosis (Table 1). Table 1. Pharmacotherapies for Nonalcoholic Steatohepatitis Evaluated in Phase Two or Phase Three Clinical Trials2 Pharmacologic Agent
Therapeutic Target Metabolic Stress
Vitamin E †
Pioglitazone (PPAR-γ agonist) †
Obeticholic acid (FXR agonist) †
Chemokine receptor 2 and 5 antagonists
PPAR-α and PPAR-Δ agonists
Lysyl oxidase-like 2 inhibitor
Bovine milk colostrum
Stress-activated kinase 1 inhibitor
As some patients transition through multiple stages of liver disease to NASH and, potentially, to carcinoma, the burden of disease and associated costs can be substantial. After assessing the costs for this type of progression of liver disease, researchers concluded that advanced NASH is associated with higher lifetime economic burden. focusing on already-FDA-approved therapies indicated for other conditions. Other studies also focus on disease states in combination with NASH, such as Type 2 diabetes, osteoarthritis, obesity, and hyperlipidemia. These other disease states fall in line with the correlation of metabolic syndrome and inflammation as a precursor to NASH. Two studies looking at obeticholic acid (Ocaliva®) for the treatment of NASH have progressed through successful phase three trials. The REGENERATE study looked at adult patients with a diagnosis of NASH and a fibrosis stage of F2 to F3, or F1 with at least one accompanying comorbidity. The study ran for 18 months and the primary endpoints included were fibrosis improvement (>1 stage) with no worsening of NASH or NASH resolution with no worsening of fibrosis; the study was considered successful if either endpoint was met.3, 4
†This agent was superior to placebo in a randomized clinical trial. Abbreviations: FGF=fibroblast growth factor; FXR=farnesoid X receptor; PPAR= peroxisome proliferator-activated receptor
Presently, there are at least 700 trials in various stages, from not yet recruiting to withdrawn to completed. Currently, seven studies have been withdrawn, 42 have terminated, with or without results, and 301 have been completed. There are also 98 studies in research phases three and four. Many of these clinical trials are
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The analysis was performed as an intention to treat, with patients receiving at least one dose of treatment during the study period. A total of 1,968 patients with F1 to F3 fibrosis were enrolled between December 2015 and October 2018. Patients were stratified into three groups: placebo, obeticholic acid 10 mg, or obeticholic acid 25 mg. An improvement endpoint was achieved by 12% of patients in the placebo arm, 18% of patients in the obeticholic
acid 10 mg arm, and 23% of patients in the obeticholic acid 25 mg arm. The most common adverse effect across all three groups was pruritus, ranging from 19% in the placebo arm to 51% in the obeticholic acid 25 mg arm.3 The primary endpoint of improving fibrosis with no worsening of NASH in patients with F2 or F3 fibrosis at 18 months was met by obeticholic acid 25 mg. Based on the FDA efficacy endpoints for NASH, which is improvement of fibrosis by at least one stage with no worsening of NASH, obeticholic acid is likely predictive of clinical benefit. The FDA has not issued final guidance on Intercept’s obeticholic acid as of yet, which would include the dosing to treat NASH; additional guidance is expected from the FDA in summer 2020.4 Additional therapies, though further from FDA approval, can be found in the NASH therapeutic pipeline (Table 2).
Table 2. NASH Therapeutic Pipeline Oral
Mechanism of Action
Tobira Takeda Allergan
Stearoyl-CoA desaturase-1 (SCD-1) inhibitor
Peroxisome proliferator-activated receptor (PPAR) agonist
Madrigal Pharmaceuticals Inc.
Thyroid hormone receptor agonist
Impact on Payers and Managed Care As some patients transition through multiple stages of liver disease to NASH and, potentially, to carcinoma, the burden of disease and associated costs can be substantial. After assessing the costs for this type of progression of liver disease, researchers concluded that advanced NASH is associated with higher lifetime economic burden.1 It is estimated that a patient with NASH will have a lifetime cost of $77,000 for disease treatment alone, which does not include cost for a liver transplant if necessary.1 The prevalence of NASH is expected to grow by 10.8 million cases by 2060, with a total cost burden of $359 billion.1 Initiating treatment at the appropriate time of disease progression can have a positive impact on patients’ quality of life while possibly decreasing cost to payers.
As therapies are still in the approval process, it is hard to determine what the cost of treatment will look like. Since it is known that NASH is related to the metabolic syndrome, lifestyle modifications should be discussed early on as a treatment option, and additional comorbidities of increased weight and lipid levels should be addressed early. As pharmaceutical agents become available to treat NASH, improved and more-effective management presents the opportunity for the associated economic and health burden to stabilize over time. Patient-support programs are available to help patients better manage their health. These programs may include personalized coaching to improve health through engagement, motivational interviewing, and targeted education. In some instances, programs may include a suite of digital products focusing on specialty medication education, disease-management strategies, personalized care plans and treatment goals, and improved care coordination. Other types of programs focus on overall wellness or targeted disease states, including diabetes, heart disease, and cancer. As the prevalence of NASH approaches that of Type 2 diabetes and the direct costs to treat NAFLD exceed $100 billion, it is essential that all stakeholders understand more about this disease state. Research has shown a connection to metabolic disease and inflammation and fibrosis of the liver. With this knowledge, therapies to target the underlying cause of fibrosis in the liver, to slow or stop progression, and to heal fibrotic areas have gained traction over the last few years. New therapies should be available soon to change the course of therapy for patients with NASH and undoubtedly reshape the treatment landscape for these patients.
Younossi, Zobair M. et al. “Burden of Illness and Economic Model for Patients With Nonalcoholic Steatohepatitis in the United States.” Hepatology, Jan. 8, 2019, https://www.ncbi.nlm.nih.gov/ pubmed/30180285.
Diehl, Anna M., M.D., and Christopher Day, M.D. “Cause, Pathogenesis, and Treatment of Nonalcoholic Steatohepatitis.” New England Journal of Medicine, Nov. 23, 2017, https://www.nejm.org/ doi/full/10.1056/NEJMra1503519.
Younossi, Zobair M. et al. “Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial.” The Lancet, Dec. 14, 2019, https://www.ncbi.nlm.nih.gov/pubmed/31813633.
Neuschwander-Tetri, Brent A. et al. “Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebocontrolled trial.” The Lancet, Nov. 6, 2014, https://www.thelancet. com/journals/lancet/article/PIIS0140-6736(14)61933-4/fulltext.
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Not actual patients.
Indications and Usage
Saxenda® (liraglutide) injection 3 mg is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adult patients with an initial body mass index (BMI) of 30 kg/m2 or greater (obesity) or 27 kg/m2 or greater (overweight) in the presence of at least one weight-related comorbid condition (eg, hypertension, type 2 diabetes mellitus, or dyslipidemia)
Limitations of Use
• Saxenda® is not indicated for the treatment of type 2 diabetes • Saxenda® and Victoza® both contain the same active ingredient, liraglutide, and therefore should not be used together. Saxenda® should not be used in combination with any other GLP-1 receptor agonist • Saxenda® has not been studied in patients taking insulin. Saxenda® and insulin should not be used together • The safety and efficacy of Saxenda® in combination with other products for weight loss, including prescription drugs, over-the-counter drugs, and herbal preparations, have not been established
Important Safety Information WARNING: RISK OF THYROID C-CELL TUMORS
Liraglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors at clinically relevant exposures in both genders of rats and mice. It is unknown whether Saxenda® causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as the human relevance of liraglutide-induced rodent thyroid C-cell tumors has not been determined. Saxenda® is contraindicated in patients with a personal or family history of MTC and in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Counsel patients regarding the potential risk of MTC with use of Saxenda® and inform them of symptoms of thyroid tumors (eg, a mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with Saxenda®.
Saxenda® is contraindicated in: • Patients with a personal or family history of MTC or MEN 2 • Patients with a prior serious hypersensitivity reaction to liraglutide or to any of the product components • Pregnancy
Warnings and Precautions • Risk of Thyroid C-cell Tumors: If serum calcitonin is measured and found to be elevated, the patient should be further evaluated. Patients with thyroid nodules noted on physical examination or neck imaging should also be further evaluated • Acute Pancreatitis: Acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, has been observed in patients treated with liraglutide postmarketing. Observe patients carefully for signs and symptoms of pancreatitis (persistent severe abdominal pain, sometimes radiating to the back with or without vomiting). If pancreatitis is suspected, discontinue Saxenda® promptly and if pancreatitis is confirmed, do not restart • Acute Gallbladder Disease: Substantial or rapid weight loss can increase the risk of cholelithiasis; however, the incidence of acute gallbladder disease was greater in patients treated with Saxenda® than with placebo even after accounting for the degree of weight loss. If cholelithiasis is suspected, gallbladder studies and appropriate clinical follow-up are indicated
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WHEN IT COMES TO LOSING WEIGHT AND KEEPING IT OFF
WE HAVE THE
NOW YOU CAN GIVE US THE
Give them the power to choose a way forward by adding Saxenda®. To manage the chronic disease of obesity, willpower alone isn’t enough. Combined with a reduced-calorie meal plan and increased physical activity, Saxenda® can help patients lose weight and keep it off.1 When patients with obesity lose weight, one response of their bodies involves an increase in the hunger hormone, and a decrease in satiety hormones including glucagon-like peptide (GLP-1)—undermining their ability to lose weight and keep it off.2 Saxenda®, which is 97% similar to the native gut hormone GLP-1, activates receptors in the braina to increase satiety and thereby reduce food intake.1,a Half of patients taking Saxenda® who achieved ≥5% body weight loss at 1 year maintained it at 3 years in a 3-year study (vs 25% and 10% for placebo, respectively).1,b —————— In a cardiovascular outcomes (CVOT) trial, NO increased risk of MACE observed with liraglutide 1.8 mg in patients with type 2 diabetes and cardiovascular disease.1,c Rate of primary component MACE endpoints was 1302 (608 [13.0%] with liraglutide 1.8 mg and 694 [14.9%] with placebo). Efficacy of doses below 3 mg has not been established for chronic weight management.
People living with obesity want you to ask them about their weight-loss attempts. Tell them how adding Saxenda® can help them lose weight and keep it off.
Shown in animal models.1 A 160-week, randomized, double-blind, placebo-controlled study that evaluated the percentage of patients who achieved ≥5% weight loss at both 1 and 3 years. Adults with pre-diabetes and a BMI of ≥30 or ≥27 with at least one weight-related comorbidity were randomized to receive once-daily Saxenda® (n=1,505) or placebo (n=749), added to lifestyle intervention, including increased physical activity and a 500-kcal/day-deficit diet. Study included: 4 weeks of dose escalation; 156 weeks at full dose; and 12-week off-drug observational period. Mean baseline body weight was 233.9 lb; mean BMI was 38.3. 817 Saxenda® patients vs 182 on placebo, and 391 patients on Saxenda® and 74 on placebo lost ≥5% at 1 and 3 years, respectively.1,3 c Major Adverse Cardiovascular Event (MACE) defined as: cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke. Results from a randomized trial of 9340 patients with inadequately controlled type 2 diabetes and cardiovascular disease treated with liraglutide 1.8 mg or placebo in addition to standard of care treatments for type 2 diabetes for a median duration of 3.5 years. Patients either were 50 years of age or older with established, stable cardiovascular, cerebrovascular, peripheral vascular disease, chronic renal failure or chronic heart failure (80% of patients), or were 60 years of age or older and had other specified risk factors of vascular disease (20% of patients). The primary endpoint was the time from randomization to first occurrence of a major adverse cardiovascular event. 96.8% of the patients completed the trial.1 a
Important Safety Information (cont’d) • Risk of Hypoglycemia with Concomitant Use of Anti-Diabetic Therapy: When Saxenda® is used with an insulin secretagogue (eg, a sulfonylurea) serious hypoglycemia can occur. Consider lowering the dose of the insulin secretagogue to reduce the risk of hypoglycemia. Monitor blood glucose parameters prior to starting Saxenda® and during treatment and adjust anti-diabetic drugs as needed • Heart Rate Increase: Mean increases in resting heart rate of 2 to 3 beats per minute (bpm) were observed in patients treated with Saxenda®. Monitor heart rate at regular intervals and inform patients to report palpitations or feelings of a racing heartbeat while at rest during treatment with Saxenda®. Discontinue Saxenda® in patients who experience a sustained increase in resting heart rate • Renal Impairment: Acute renal failure and worsening of chronic renal failure, which may sometimes require hemodialysis, have been reported, usually in association with nausea, vomiting, diarrhea, or dehydration. Use caution when initiating or escalating doses of Saxenda® in patients with renal impairment • Hypersensitivity Reactions: Serious hypersensitivity reactions (eg, anaphylaxis and angioedema) have been reported in patients treated with liraglutide. If a hypersensitivity reaction occurs, patients should stop taking Saxenda® and promptly seek medical advice • Suicidal Behavior and Ideation: In clinical trials, 9 (0.3%) of 3,384 patients treated with Saxenda® and 2 (0.1%) of the 1,941 treated with placebo reported suicidal ideation; one of the patients treated with Saxenda® attempted suicide. Monitor patients on Saxenda® for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Discontinue treatment if patients experience suicidal thoughts or behaviors. Avoid Saxenda® in patients with a history of suicidal attempts or active suicidal ideation
• The most common adverse reactions, reported in ≥5% are: nausea, hypoglycemia, diarrhea, constipation, vomiting, headache, decreased appetite, dyspepsia, fatigue, dizziness, abdominal pain, and increased lipase
• Saxenda® causes a delay of gastric emptying, and has the potential to impact the absorption of concomitantly administered oral medications. Monitor for potential consequences of delayed absorption of oral medications concomitantly administered with Saxenda®
Use in Specific Populations
• There are no data on the presence of liraglutide in human breast milk; liraglutide was present in the milk of lactating rats • Saxenda® has not been studied in patients below 18 years of age and is not recommended for use in pediatric patients • Saxenda® slows gastric emptying. Saxenda® has not been studied in patients with preexisting gastroparesis
Please see Brief Summary of Information about Saxenda® on the following pages. References 1. Saxenda® [package insert]. Plainsboro, NJ: Novo Nordisk Inc; 2018. 2. Sumithran P, Prendergast LA, Delbridge E, et al. Long-term persistence of hormonal adaptations to weight loss. N Engl J Med. 2011;365(17):1597-1604. 3. le Roux CW, Astrup A, Fujioka K, et al; for the SCALE Obesity and Prediabetes NN8022-1839 Study Group. 3 years of liraglutide versus placebo for type 2 diabetes risk reduction and weight management in individuals with prediabetes: a randomised, double-blind trial [published online February 22, 2017]. Lancet. doi:10.1016/S0140-6736(17)30069-7. Saxenda® and Victoza® are registered trademarks of Novo Nordisk A/S. Novo Nordisk is a registered trademark of Novo Nordisk A/S. © 2020 Novo Nordisk Printed in the U.S.A. US20SX00016 March 2020
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Saxenda® (liraglutide) injection Rx Only BRIEF SUMMARY. Please consult package insert for full prescribing information. WARNING: RISK OF THYROID C-CELL TUMORS: Liraglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors at clinically relevant exposures in both genders of rats and mice. It is unknown whether Saxenda® causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as the human relevance of liraglutide-induced rodent thyroid C-cell tumors has not been determined [see Warnings and Precautions]. Saxenda® is contraindicated in patients with a personal or family history of MTC and in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Counsel patients regarding the potential risk of MTC with use of Saxenda® and inform them of symptoms of thyroid tumors (e.g., a mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with Saxenda® [see Contraindications, Warnings and Precautions]. INDICATIONS AND USAGE: Saxenda® is indicated as an adjunct to a reducedcalorie diet and increased physical activity for chronic weight management in adult patients with an initial body mass index (BMI) of 30 kg/m2 or greater (obese), or 27 kg/m2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Limitations of Use: Saxenda® is not indicated for the treatment of type 2 diabetes mellitus. Saxenda® and Victoza® both contain the same active ingredient, liraglutide, and therefore should not be used together. Saxenda® should not be used in combination with any other GLP-1 receptor agonist. Saxenda® has not been studied in patients taking insulin. Saxenda® and insulin should not be used together [see Warnings and Precautions]. The safety and effectiveness of Saxenda® in combination with other products intended for weight loss, including prescription drugs, over-thecounter drugs, and herbal preparations, have not been established. CONTRAINDICATIONS: Saxenda® is contraindicated in: Patients with a personal or family history of medullary thyroid carcinoma (MTC) or patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) [see Warnings and Precautions]; Patients with a prior serious hypersensitivity reaction to liraglutide or to any of the product components [see Warnings and Precautions]; Pregnancy [see Use in Specific Populations]. WARNINGS AND PRECAUTIONS: Risk of Thyroid C-cell Tumors: Liraglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors (adenomas and/or carcinomas) at clinically relevant exposures in both genders of rats and mice. Malignant thyroid C-cell carcinomas were detected in rats and mice. It is unknown whether Saxenda® will cause thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as the human relevance of liraglutide-induced rodent thyroid C-cell tumors has not been determined. Cases of MTC in patients treated with liraglutide have been reported in the postmarketing period; the data in these reports are insufficient to establish or exclude a causal relationship between MTC and liraglutide use in humans. Saxenda ® is contraindicated in patients with a personal or family history of MTC or in patients with MEN 2. Counsel patients regarding the potential risk for MTC with the use of Saxenda® and inform them of symptoms of thyroid tumors (e.g., a mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with Saxenda ®. Such monitoring may increase the risk of unnecessary procedures, due to low test specificity for serum calcitonin and a high background incidence of thyroid disease. Significantly elevated serum calcitonin may indicate MTC, and patients with MTC usually have calcitonin values greater than 50 ng/L. If serum calcitonin is measured and found to be elevated, the patient should be further evaluated. Patients with thyroid nodules noted on physical examination or neck imaging should also be further evaluated. Acute Pancreatitis: Based on spontaneous postmarketing reports, acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, has been observed in patients treated with liraglutide. After initiation of Saxenda®, observe patients carefully for signs and symptoms of pancreatitis (including persistent severe abdominal pain, sometimes radiating to the back and which may or may not be accompanied by vomiting). If pancreatitis is suspected, Saxenda® should promptly be discontinued and appropriate management should be initiated. If pancreatitis is confirmed, Saxenda® should not be restarted. In Saxenda® clinical trials, acute pancreatitis was confirmed by adjudication in 9 (0.3%) of 3291 Saxenda-treated patients and 2 (0.1%) of 1843 placebo-treated patients. In addition, there were 2 cases of acute pancreatitis in Saxenda-treated patients who prematurely withdrew from these clinical trials, occurring 74 and 124 days after the last dose. There were 2 additional cases in Saxenda-treated patients, 1 during an off-treatment follow-up period within 2 weeks of discontinuing Saxenda ®, and 1 that occurred in a patient who completed treatment and was off-treatment for 106 days. Liraglutide has been studied in a limited number of patients with a history of pancreatitis. It is unknown if patients with a history of pancreatitis are at higher risk for development of pancreatitis on Saxenda®. Acute Gallbladder Disease: In Saxenda® clinical
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trials, 2.2% of Saxenda-treated patients reported adverse events of cholelithiasis versus 0.8% of placebo-treated patients. The incidence of cholecystitis was 0.8% in Saxenda-treated patients versus 0.4% in placebo-treated patients. The majority of Saxenda-treated patients with adverse events of cholelithiasis and cholecystitis required cholecystectomy. Substantial or rapid weight loss can increase the risk of cholelithiasis; however, the incidence of acute gallbladder disease was greater in Saxenda-treated patients than in placebo-treated patients even after accounting for the degree of weight loss. If cholelithiasis is suspected, gallbladder studies and appropriate clinical follow-up are indicated. Risk for Hypoglycemia with Concomitant Use of Anti-Diabetic Therapy: The risk for serious hypoglycemia is increased when Saxenda® is used in combination with insulin secretagogues (for example, sulfonylureas) in patients with type 2 diabetes mellitus. Therefore, patients may require a lower dose of sulfonylurea (or other concomitantly administered insulin secretagogues) in this setting [see Adverse Reactions]. Saxenda® should not be used in patients taking insulin. Saxenda® can lower blood glucose. Monitor blood glucose parameters prior to starting Saxenda® and during Saxenda® treatment in patients with type 2 diabetes. If needed, adjust co-administered anti-diabetic drugs based on glucose monitoring results and risk of hypoglycemia. Heart Rate Increase: Mean increases in resting heart rate of 2 to 3 beats per minute (bpm) were observed with routine clinical monitoring in Saxenda-treated patients compared to placebo in clinical trials. More patients treated with Saxenda ®, compared with placebo, had changes from baseline at two consecutive visits of more than 10 bpm (34% versus 19%, respectively) and 20 bpm (5% versus 2%, respectively). At least one resting heart rate exceeding 100 bpm was recorded for 6% of Saxenda-treated patients compared with 4% of placebo-treated patients, with this occurring at two consecutive study visits for 0.9% and 0.3%, respectively. Tachycardia was reported as an adverse reaction in 0.6% of Saxenda-treated patients and in 0.1% of placebo-treated patients. In a clinical pharmacology trial that monitored heart rate continuously for 24 hours, Saxenda® treatment was associated with a heart rate that was 4 to 9 bpm higher than that observed with placebo. Heart rate should be monitored at regular intervals consistent with usual clinical practice. Patients should inform health care providers of palpitations or feelings of a racing heartbeat while at rest during Saxenda ® treatment. For patients who experience a sustained increase in resting heart rate while taking Saxenda®, Saxenda® should be discontinued. Renal Impairment: In patients treated with GLP-1 receptor agonists, including Saxenda®, there have been reports of acute renal failure and worsening of chronic renal failure, sometimes requiring hemodialysis [see Adverse Reactions]. Some of these events were reported in patients without known underlying renal disease. A majority of the reported events occurred in patients who had experienced nausea, vomiting, or diarrhea leading to volume depletion. Some of the reported events occurred in patients receiving one or more medications known to affect renal function or volume status. Altered renal function has been reversed in many of the reported cases with supportive treatment and discontinuation of potentially causative agents, including liraglutide. Use caution when initiating or escalating doses of Saxenda® in patients with renal impairment [see Use in Specific Populations]. Hypersensitivity Reactions: There have been reports of serious hypersensitivity reactions (e.g., anaphylactic reactions and angioedema) in patients treated with liraglutide [see Contraindications and Adverse Reactions]. If a hypersensitivity reaction occurs, the patient should discontinue Saxenda® and other suspect medications and promptly seek medical advice. Anaphylaxis and angioedema have been reported with other GLP-1 receptor agonists. Use caution in a patient with a history of anaphylaxis or angioedema with another GLP-1 receptor agonist because it is unknown whether such patients will be predisposed to these reactions with Saxenda®. Suicidal Behavior and Ideation: In Saxenda® clinical trials, 9 (0.3%) of 3384 Saxenda-treated patients and 2 (0.1%) of the 1941 placebo-treated patients reported suicidal ideation; one of these Saxenda-treated patients attempted suicide. Patients treated with Saxenda® should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Discontinue Saxenda ® in patients who experience suicidal thoughts or behaviors. Avoid Saxenda® in patients with a history of suicidal attempts or active suicidal ideation. ADVERSE REACTIONS: The following serious adverse reactions are described below or elsewhere in the prescribing information: Risk of Thyroid C-Cell Tumors [see Warnings and Precautions]; Acute Pancreatitis [see Warnings and Precautions]; Acute Gallbladder Disease [see Warnings and Precautions]; Risk for Hypoglycemia with Concomitant Use of Anti-Diabetic Therapy [see Warnings and Precautions]; Heart Rate Increase [see Warnings and Precautions]; Renal Impairment [see Warnings and Precautions]; Hypersensitivity Reactions [see Warnings and Precautions]; Suicidal Behavior and Ideation [see Warnings and Precautions]. Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. Saxenda® was evaluated for safety in 5 double-blind, placebo controlled trials that included 3384 overweight or obese patients treated with Saxenda® for a treatment period up to 56 weeks (3 trials), 52 weeks (1 trial), and 32 weeks (1 trial). All patients received study drug in addition to diet and exercise counseling. In these trials, patients received Saxenda® for a mean treatment duration of 46 weeks (median, 56 weeks). Baseline characteristics included a mean age of 47 years, 71% women, 85% white, 39% with hypertension, 15% with type 2 diabetes, 34% with dyslipidemia, 29% with a BMI greater than 40 kg/m2, and 9% with cardiovascular disease. In one of the 56-week trials, a subset of patients (with abnormal glucose measurements at randomization) were enrolled for a placebo-
controlled 160-week period instead, followed by a 12-week off-treatment follow-up. For those participating in this 160-week period, patients received Saxenda® for a mean treatment duration of 110 weeks (median, 159 weeks). For all trials, dosing was initiated and increased weekly to reach the 3 mg dose. In clinical trials, 9.8% of patients treated with Saxenda® and 4.3% of patients treated with placebo prematurely discontinued treatment as a result of adverse reactions. The most common adverse reactions leading to discontinuation were nausea (2.9% versus 0.2% for Saxenda® and placebo, respectively), vomiting (1.7% versus less than 0.1%), and diarrhea (1.4% versus 0%). Adverse reactions reported in greater than or equal to 2% of Saxenda-treated patients and more frequently than in placebo-treated patients are shown in Table 3. Table 3. Adverse Reactions Reported in Greater Than or Equal to 2% of Saxenda-treated Patients and More Frequently than with Placebo* Placebo Saxenda N = 1941 N = 3384 % % Gastrointestinal Disorders Nausea 13.8 39.3 Diarrhea 9.9 20.9 Constipation 8.5 19.4 Vomiting 3.9 15.7 Dyspepsia 2.7 9.6 Abdominal Pain 3.1 5.4 Upper Abdominal Pain 2.7 5.1 Gastroesophageal Reflux Disease 1.7 4.7 Abdominal Distension 3.0 4.5 Eructation 0.2 4.5 Flatulence 2.5 4.0 Dry Mouth 1.0 2.3 Metabolism and Nutrition Disorders 12.7 23.0 Hypoglycemia in T2DM1 Decreased Appetite 2.3 10.0 Nervous System Disorders Headache 12.6 13.6 Dizziness 5.0 6.9 General Disorders and Administration Site Conditions Fatigue 4.6 7.5 Injection Site Erythema 0.2 2.5 Injection Site Reaction 0.6 2.5 Asthenia 0.8 2.1 Infections and Infestations Gastroenteritis 3.2 4.7 Urinary Tract Infection 3.1 4.3 Viral Gastroenteritis 1.6 2.8 Investigations Increased Lipase 2.2 5.3 Psychiatric Disorders Insomnia 1.7 2.4 Anxiety 1.6 2.0 1 Documented symptomatic (defined as documented symptoms of hypoglycemia in combination with a plasma glucose less than or equal to 70 mg/dL) in patients with type 2 diabetes (Study 2). See text below for further information regarding hypoglycemia in patients with and without type 2 diabetes. T2DM = type 2 diabetes mellitus * Adverse reactions for trials with treatment period up to 56 weeks Hypoglycemia: Saxenda® can lower blood glucose. In a clinical trial involving patients with type 2 diabetes mellitus and overweight or obesity, severe hypoglycemia (defined as requiring the assistance of another person) occurred in 3 (0.7%) of 422 Saxenda-treated patients and in none of the 212 placebo-treated patients. Each of these 3 Saxenda-treated patients was also taking a sulfonylurea. In the same trial, among patients taking a sulfonylurea, documented symptomatic hypoglycemia (defined as documented symptoms of hypoglycemia in combination with a plasma glucose less than or equal to 70 mg/dL) occurred in 48 (43.6%) of 110 Saxendatreated patients and 15 (27.3%) of 55 placebo-treated patients. The doses of sulfonylureas were reduced by 50% at the beginning of the trial per protocol. The frequency of hypoglycemia may be higher if the dose of sulfonylurea is not reduced. Among patients not taking a sulfonylurea, documented symptomatic hypoglycemia occurred in 49 (15.7%) of 312 Saxenda-treated patients and 12 (7.6%) of 157 placebo-treated patients. In Saxenda ® clinical trials involving patients without type 2 diabetes mellitus, there was no systematic capturing or reporting of hypoglycemia, as patients were not provided with blood glucose meters or hypoglycemia diaries. Spontaneously reported symptomatic episodes of unconfirmed hypoglycemia were reported by 46 (1.6%) of 2962 Saxenda-treated patients and 19 (1.1%) of 1729 placebo-treated patients. Fasting plasma glucose values obtained at routine clinic visits less than or equal to 70 mg/dL, irrespective of hypoglycemic symptoms, were
reported as “hypoglycemia” in 92 (3.1%) Saxenda-treated patients and 13 (0.8%) placebo-treated patients. Gastrointestinal Adverse Reactions: In the clinical trials, approximately 68% of Saxenda-treated patients and 39% of placebo-treated patients reported gastrointestinal disorders; the most frequently reported was nausea (39% and 14% of patients treated with Saxenda® and placebo, respectively). The percentage of patients reporting nausea declined as treatment continued. Other common adverse reactions that occurred at a higher incidence among Saxendatreated patients included diarrhea, constipation, vomiting, dyspepsia, abdominal pain, dry mouth, gastritis, gastroesophageal reflux disease, flatulence, eructation and abdominal distension. Most episodes of gastrointestinal events were mild or moderate and did not lead to discontinuation of therapy (6.2% with Saxenda® versus 0.8% with placebo discontinued treatment as a result of gastrointestinal adverse reactions). There have been reports of gastrointestinal adverse reactions, such as nausea, vomiting, and diarrhea, associated with volume depletion and renal impairment [see Warnings and Precautions]. Asthenia, Fatigue, Malaise, Dysgeusia and Dizziness: Events of asthenia, fatigue, malaise, dysgeusia and dizziness were mainly reported within the first 12 weeks of treatment with Saxenda ® and were often co-reported with gastrointestinal events such as nausea, vomiting, and diarrhea. Immunogenicity: Patients treated with Saxenda® may develop anti-liraglutide antibodies. Anti-liraglutide antibodies were detected in 42 (2.8%) of 1505 Saxendatreated patients with a post-baseline assessment. Antibodies that had a neutralizing effect on liraglutide in an in vitro assay occurred in 18 (1.2%) of 1505 Saxendatreated patients. Presence of antibodies may be associated with a higher incidence of injection site reactions and reports of low blood glucose. In clinical trials, these events were usually classified as mild and resolved while patients continued on treatment. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, the incidence of antibodies to Saxenda® cannot be directly compared with the incidence of antibodies of other products. Allergic Reactions: Urticaria was reported in 0.7% of Saxenda-treated patients and 0.5% of placebo-treated patients. Anaphylactic reactions, asthma, bronchial hyperreactivity, bronchospasm, oropharyngeal swelling, facial swelling, angioedema, pharyngeal edema, type IV hypersensitivity reactions have been reported in patients treated with liraglutide in clinical trials. Cases of anaphylactic reactions with additional symptoms such as hypotension, palpitations, dyspnea, and edema have been reported with marketed use of liraglutide. Anaphylactic reactions may potentially be life-threatening. Injection Site Reactions: Injection site reactions were reported in approximately 13.9% of Saxenda-treated patients and 10.5% of placebo-treated patients. The most common reactions, each reported by 1% to 2.5% of Saxenda-treated patients and more commonly than by placebo-treated patients, included erythema, pruritus, and rash at the injection site. 0.6% of Saxenda-treated patients and 0.5% of placebo-treated patients discontinued treatment due to injection site reactions. Breast Cancer: In Saxenda® clinical trials, breast cancer confirmed by adjudication was reported in 17 (0.7%) of 2379 Saxendatreated women compared with 3 (0.2%) of 1300 placebo-treated women, including invasive cancer (13 Saxenda- and 2 placebo-treated women) and ductal carcinoma in situ (4 Saxenda- and 1 placebo-treated woman). The majority of cancers were estrogen- and progesterone-receptor positive. There were too few cases to determine whether these cases were related to Saxenda®. In addition, there are insufficient data to determine whether Saxenda® has an effect on pre-existing breast neoplasia. Papillary Thyroid Cancer: In Saxenda® clinical trials, papillary thyroid carcinoma confirmed by adjudication was reported in 8 (0.2%) of 3291 Saxenda-treated patients compared with no cases among 1843 placebo-treated patients. Four of these papillary thyroid carcinomas were less than 1 cm in greatest diameter and 4 were diagnosed in surgical pathology specimens after thyroidectomy prompted by findings identified prior to treatment. Colorectal Neoplasms: In Saxenda® clinical trials, benign colorectal neoplasms (mostly colon adenomas) confirmed by adjudication were reported in 20 (0.6%) of 3291 Saxenda-treated patients compared with 7 (0.4%) of 1843 placebo-treated patients. Six positively adjudicated cases of malignant colorectal neoplasms were reported in 5 Saxenda-treated patients (0.2%, mostly adenocarcinomas) and 1 in a placebo-treated patient (0.1%, neuroendocrine tumor of the rectum). Cardiac Conduction Disorders: In Saxenda® clinical trials, 11 (0.3%) of 3384 Saxenda-treated patients compared with none of the 1941 placebotreated patients had a cardiac conduction disorder, reported as first degree atrioventricular block, right bundle branch block, or left bundle branch block. Hypotension: Adverse reactions related to hypotension (that is, reports of hypotension, orthostatic hypotension, circulatory collapse, and decreased blood pressure) were reported more frequently with Saxenda ® (1.1%) compared with placebo (0.5%) in Saxenda® clinical trials. Systolic blood pressure decreases to less than 80 mmHg were observed in 4 (0.1%) Saxenda-treated patients compared with no placebo-treated patients. One of the Saxenda-treated patients had hypotension associated with gastrointestinal adverse reactions and renal failure [see Warnings and Precautions]. Laboratory Abnormalities: Liver Enzymes: Increases in alanine aminotransferase (ALT) greater than or equal to 10 times the upper limit of normal were observed in 5 (0.15%) Saxenda-treated patients (two of whom had ALT greater than 20 and 40 times the upper limit of normal) compared with 1 (0.05%) placebotreated patient during the Saxenda® clinical trials. Because clinical evaluation to exclude alternative causes of ALT and aspartate aminotransferase (AST) increases was not done in most cases, the relationship to Saxenda® is uncertain. Some
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increases in ALT and AST were associated with other confounding factors (such as gallstones). Serum Calcitonin: Calcitonin, a biological marker of MTC, was measured throughout the clinical development program [see Warnings and Precautions]. More patients treated with Saxenda® in the clinical trials were observed to have high calcitonin values during treatment, compared with placebo. The proportion of patients with calcitonin greater than or equal to 2 times the upper limit of normal at the end of the trial was 1.2% in Saxenda-treated patients and 0.6% in placebo-treated patients. Calcitonin values greater than 20 ng/L at the end of the trial occurred in 0.5% of Saxenda-treated patients and 0.2% of placebo-treated patients; among patients with pre-treatment serum calcitonin less than 20 ng/L, none had calcitonin elevations to greater than 50 ng/L at the end of the trial. Serum Lipase and Amylase: Serum lipase and amylase were routinely measured in the Saxenda® clinical trials. Among Saxenda-treated patients, 2.1% had a lipase value at anytime during treatment of greater than or equal to 3 times the upper limit of normal compared with 1.0% of placebo-treated patients. 0.1% of Saxenda-treated patients had an amylase value at anytime in the trial of greater than or equal to 3 times the upper limit of normal versus 0.1% of placebo-treated patients. The clinical significance of elevations in lipase or amylase with Saxenda® is unknown in the absence of other signs and symptoms of pancreatitis [see Warnings and Precautions]. Post-Marketing Experience: The following adverse reactions have been reported during post-approval use of liraglutide, the active ingredient of Saxenda®. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Neoplasms: Medullary thyroid carcinoma [see Warnings and Precautions]; Gastrointestinal Disorders: Acute pancreatitis, hemorrhagic and necrotizing pancreatitis, sometimes resulting in death [see Warnings and Precautions]; Metabolism and Nutrition Disorders: Dehydration resulting from nausea, vomiting and diarrhea [see Adverse Reactions]; Renal and Urinary Disorders: Increased serum creatinine, acute renal failure or worsening of chronic renal failure, sometimes requiring hemodialysis [see Warnings and Precautions]; General Disorders and Administration Site Conditions: Allergic reactions: rash and pruritus [see Adverse Reactions]; Immune System Disorders: Angioedema and anaphylactic reactions [see Warnings and Precautions]; Hepatobiliary Disorders: Elevations of liver enzymes, hyperbilirubinemia, cholestasis and hepatitis [see Adverse Reactions] DRUG INTERACTIONS: Oral Medications: Saxenda® causes a delay of gastric emptying, and thereby has the potential to impact the absorption of concomitantly administered oral medications. In clinical pharmacology trials, liraglutide did not affect the absorption of the tested orally administered medications to any clinically relevant degree. Nonetheless, monitor for potential consequences of delayed absorption of oral medications concomitantly administered with Saxenda®. USE IN SPECIFIC POPULATIONS: Pregnancy: Risk Summary: Saxenda® is contraindicated during pregnancy because weight loss offers no potential benefit to a pregnant woman and may result in fetal harm [see Clinical Considerations]. There are no available data with liraglutide in pregnant women to inform a drug associated risk for major birth defects and miscarriage. Saxenda® should not be used during pregnancy. If a patient wishes to become pregnant, or pregnancy occurs, treatment with Saxenda® should be discontinued. Animal reproduction studies identified increased adverse embryofetal developmental outcomes from exposure during pregnancy. Liraglutide exposure was associated with early embryonic deaths and an imbalance in some fetal abnormalities in pregnant rats administered liraglutide during organogenesis at doses that approximate clinical exposures at the maximum recommended human dose (MRHD) of 3 mg/day. In pregnant rabbits administered liraglutide during organogenesis, decreased fetal weight and an increased incidence of major fetal abnormalities were seen at exposures below the human exposures at the MRHD [see Animal Data]. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage of clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations: Disease-associated maternal and/or embryofetal risk: A minimum weight gain, and no weight loss, is recommended for all pregnant women, including those who are already overweight or obese, due to the necessary weight gain that occurs in maternal tissues during pregnancy. Animal Data: Liraglutide has been shown to be teratogenic in rats at or above 0.8-times systemic exposures in obese humans resulting from the maximum recommended human dose (MRHD) of 3 mg/day based on plasma area under the time-concentration curve (AUC) comparison. Liraglutide has been shown to cause reduced growth and increased total major abnormalities in rabbits at systemic exposures below exposure in obese humans at the MRHD based on plasma AUC comparison. Female rats given subcutaneous doses of 0.1, 0.25 and 1 mg/kg/day liraglutide beginning 2 weeks before mating through gestation day 17 had estimated systemic exposures 0.8-, 3-, and 11-times the exposure in obese humans at the MRHD based on plasma AUC comparison. The number of early embryonic deaths in the 1 mg/kg/day group increased slightly. Fetal abnormalities and variations in kidneys and blood vessels, irregular ossification of the skull, and a more complete state of ossification occurred at all doses. Mottled liver and minimally kinked ribs occurred at the highest dose. The incidence of fetal malformations in liraglutide-treated groups exceeding concurrent and historical controls were misshapen oropharynx and/or narrowed opening into larynx at 0.1 mg/kg/day and umbilical hernia at 0.1 and 0.25 mg/kg/day. Pregnant rabbits given subcutaneous doses of 0.01, 0.025 and 0.05 mg/kg/day liraglutide from gestation day 6 through day 18 inclusive, had estimated systemic exposures less than the exposure in obese
44 | Magellan Rx Report | Spring 2020
humans at the MRHD of 3 mg/day at all doses, based on plasma AUC comparison. Liraglutide decreased fetal weight and dose-dependently increased the incidence of total major fetal abnormalities at all doses. The incidence of malformations exceeded concurrent and historical controls at 0.01 mg/kg/day (kidneys, scapula), greater than or equal to 0.01 mg/kg/day (eyes, forelimb), 0.025 mg/kg/day (brain, tail and sacral vertebrae, major blood vessels and heart, umbilicus), greater than or equal to 0.025 mg/kg/day (sternum) and at 0.05 mg/kg/day (parietal bones, major blood vessels). Irregular ossification and/or skeletal abnormalities occurred in the skull and jaw, vertebrae and ribs, sternum, pelvis, tail, and scapula; and dose-dependent minor skeletal variations were observed. Visceral abnormalities occurred in blood vessels, lung, liver, and esophagus. Bilobed or bifurcated gallbladder was seen in all treatment groups, but not in the control group. In pregnant female rats given subcutaneous doses of 0.1, 0.25 and 1 mg/kg/day liraglutide from gestation day 6 through weaning or termination of nursing on lactation day 24, estimated systemic exposures were 0.8-, 3-, and 11-times exposure in obese humans at the MRHD of 3 mg/day, based on plasma AUC comparison. A slight delay in parturition was observed in the majority of treated rats. Group mean body weight of neonatal rats from liraglutide-treated dams was lower than neonatal rats from control group dams. Bloody scabs and agitated behavior occurred in male rats descended from dams treated with 1 mg/ kg/day liraglutide. Group mean body weight from birth to postpartum day 14 trended lower in F2 generation rats descended from liraglutide-treated rats compared to F2 generation rats descended from controls, but differences did not reach statistical significance for any group. Lactation: Risk Summary: There are no data on the presence of liraglutide in human milk, the effects on the breastfed infant, or effects on milk production. Liraglutide was present in the milk of lactating rats (see Data). The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Saxenda® and any potential adverse effects on the breastfed infant from Saxenda® or from the underlying maternal condition. Data: In lactating rats, liraglutide was present unchanged in milk at concentrations approximately 50% of maternal plasma concentrations. Pediatric Use: Safety and effectiveness of Saxenda® have not been established in pediatric patients. Saxenda® is not recommended for use in pediatric patients. Geriatric Use: In the Saxenda® clinical trials, 232 (6.9%) of the Saxenda-treated patients were 65 years of age and over, and 17 (0.5%) of the Saxenda-treated patients were 75 years of age and over. No overall differences in safety or effectiveness were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Renal Impairment: There is limited experience with Saxenda® in patients with mild, moderate, and severe renal impairment, including end-stage renal disease. However, there have been postmarketing reports of acute renal failure and worsening of chronic renal failure with liraglutide, which may sometimes require hemodialysis [see Warnings and Precautions and Adverse Reactions]. Saxenda® should be used with caution in this patient population. Hepatic Impairment: There is limited experience in patients with mild, moderate, or severe hepatic impairment. Therefore, Saxenda® should be used with caution in this patient population. Gastroparesis: Saxenda® slows gastric emptying. Saxenda® has not been studied in patients with pre-existing gastroparesis. OVERDOSAGE: Overdoses have been reported in clinical trials and post-marketing use of liraglutide. Effects have included severe nausea and severe vomiting. In the event of overdosage, appropriate supportive treatment should be initiated according to the patient’s clinical signs and symptoms. More detailed information is available upon request.
Version: 5 Saxenda® and Victoza® are registered trademarks of Novo Nordisk A/S. PATENT Information: http://novonordisk-us.com/patients/products/productpatents.html Manufactured by: Novo Nordisk A/S, DK-2880 Bagsvaerd, Denmark For information about Saxenda® contact: Novo Nordisk Inc., 800 Scudders Mill Road, Plainsboro, NJ 08536 1-844-363-4448 © 2014-2018 Novo Nordisk US20SX00007 2/2020
Managing Obesity: Employer Weight-Management Programs and Gaps in Strategies Obesity is the greatest contributor to the economic burden of chronic disease in the U.S.
Lindsay C. Speicher, J.D. Project Manager Magellan Method
Nearly 40% of adults in the U.S. suffer from obesity, a rate that continues to rise every year.1 In 2016, 100.3 million and 80.2 million U.S. residents lived with obesity and overweight, respectively.2 Patients with obesity, a disease known to be chronic and progressive, have a higher prevalence of serious comorbid conditions — including Type 2 diabetes, hypertension, and cardiovascular disease — than those with normal body mass index (BMI).3, 4 The significance of the disease is compounded by its economic impact. Obesity accounts for 47.1% of the total cost of chronic diseases nationwide, making it the greatest contributor to the economic burden of chronic disease in the U.S.2 The estimated annual healthcare costs associated with obesity range from $147 to $210 billion.5 Weight-related complications associated with obesity and overweight (such as Type 2 diabetes, hypertension, and cardiovascular disease) accounted for $480.7 billion in direct healthcare costs in 2016 alone, with another $1.24 trillion in indirect costs due to lost economic productivity.2 Projections by health economists indicate that total annual healthcare costs attributable to obesity will be between $860.7 and $956.9 billion by the year 2030.3 Average medical claims cost per 100 members with obesity ($51,019) is 7.3 times greater than for members without obesity ($7,503).6 Indirect costs related to obesity include job absenteeism — which can range from $3.38 billion to $6.38 billion annually — and lower productivity, or presenteeism, estimated at $506 per worker with obesity per year.7, 8 A study published in November 2019 reported that American employees with obesity cost $1,158 more per person per year than employees without obesity, concluding that obesity was associated with high costs among employees across major U.S. industries.9 Costs associated with lost productivity and absenteeism, in addition to healthcare costs, result in a substantial financial burden for employers, incentivizing many to implement weight-management programs to target obesity in their employee populations. A 2014 poll of large employers revealed that 50% are focusing on weight management, with 20% reporting it would be their top priority in 2015.10 Employers have a variety of options when it comes to weight-management programs. Some include providing access via employer-provided health insurance plans to lifestyle change agents such as wellness coaches to aid behavior modification; online tracking tools to aid in caloric “accounting”; onsite and/or digital behavior-modification classes through commercial weight-loss providers such as WW or online
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MANAGING OBESITY | Continued
A study published in November 2019 reported that employees with obesity cost $1,158 more per person per year than employees without obesity, concluding that obesity was associated with high costs among employees across major U.S. industries.
weight-control programs; healthy alternative food options onsite; and referrals to weight-management content, including education on nutrition and better healthy dietary choices, through an employer-provided insurer website.11 These programs largely mirror each other in offerings, focusing on tracking food and calorie intake and behavior modification. However, the returns seen through offering employees weight-management resources are highly variable; few lead to a meaningful improvement in outcomes, largely due to the heterogeneity of the composition of these programs. Under the Affordable Care Act, employers are permitted to impose penalties and rewards on employees in accordance with specific health-related outcomes, including BMI, blood pressure, and cholesterol; however, only about 5% of large employers utilized this type of program in 2015.12, 13 An online study conducted in 2013 showed 16% of employees reporting that their respective employers require participation in wellness programs to receive full health benefits. The same study showed that while most employees reported that reduced weight is the most common target with outcomes-based incentives in employer wellness programs, which typically rely on often inaccurate self-reporting to track weight change, most of those employees also reported they did not have access to evidence-based, comprehensive obesity treatment in their employer-provided health plan.3 Lack of access to evidence-based obesity treatment is significant when the chronic
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and progressive nature of obesity is taken into account. Considering that more than 60% of Americans are insured through their employers, this presents a substantial barrier to the healthcare that employees with obesity or overweight need.14 Overall, lack of coverage by employer-provided health plans for weight loss treatments â€” such as medical visits for overweight or obesity treatment, behavioral health intervention, anti-obesity pharmacologic treatment, and bariatric surgery â€” is a major obstacle in effectively targeting and managing obesity and overweight in employee populations.15 Employers are in an optimal position to improve obesity- and overweight-related management and treatment by increasing access to appropriate care via benefit design.15
Current Weight-Management Programs Less than 20% of employers in a 2016 poll agreed that their current strategy promoting healthy weight was effective.16 Employee engagement is a major challenge cited by nearly 60% of employers, and about half of employers report a rate of only 10% for employee participation in weight-management programs.10, 17 These low rates of engagement could be attributed to the nature and focus of many employer-provided weight-management programs. One study showed that most employers (more than 80%) provided coverage for bariatric surgery, yet most did not cover weight loss medications.16 While bariatric surgery is a proven effective treatment of obesity for eligible patients, Magellan Rx explored the structure of employer-provided benefit designs focusing largely on bariatric surgery and the associated gap in care for overweight or obese patients who are not eligible for or not interested in this type of intervention.
Benefit structures that focus on bariatric surgery can potentially discourage patients from losing weight or first trying effective treatment alternatives that are much less costly and invasive. In many benefit designs, access to bariatric surgery is conditional upon a specified length — usually three to 12 months — of weight loss and counseling prior to surgery.16 This additional effort and challenge may present a burden employees are unwilling to overcome, thus precluding them from eligibility. Additionally, many employees may not fully participate for the prescribed length of time in an effort to avoid too much weight loss, which may render them ineligible for bariatric surgery. It is important to note that patients with other diseases are not treated with this strategy; for example, a patient with breast cancer would not be expected to attempt to shrink a tumor on their own prior to being eligible for mastectomy. The patient would initially be offered chemotherapy plus surgery to address the medical condition immediately. The approach to successful employer weight-management programs should incorporate resources for all employees that could benefit from weight loss, not exclusively employees qualifying for bariatric surgery. According to the American Association of Clinical Endocrinologists (AACE) guidelines, behavioral therapy is the cornerstone for treating overweight and obesity, and a structured lifestyle intervention program consisting of a healthy meal plan, physical activity, and behavioral interventions should be available. AACE guidelines make clear that an effective approach to treating overweight and obesity includes a behavior-intervention package executed by a multidisciplinary team that includes dietitians, nurses, educators, physical activity trainers or coaches, and clinical psychologists, and that behavioral health specialists such as psychologists or psychiatrists should participate in the treatment of underlying eating disorders, depression, anxiety, psychoses, or other psychological issues that often attribute to overweight or obesity and can impair the effectiveness of lifestyle intervention programs.19 Without proper behavioral health intervention, approaches to obesity and overweight treatment or weight-loss programs often prove ineffective long-term. As AACE notes, other people may need pharmacotherapy to assist in carrying out the reduced-calorie diet recommendations.19
Gaps in Current Weight-Management Benefit Designs For most employers, the decision to commit to and offer access to weight-management support programs becomes centered on the decision to provide coverage for bariatric surgical interventions for employees meeting health plan-recommended, employersupported criteria. Weight-management programs that focus on surgical interventions are, as a result, based around medical ben-
Ultimately, a benefit design that is reliant on surgery precludes employees from preventively addressing obesity. No other chronic disease is treated this way.
efit design. With this benefit-structured focus, employer-provided or -supported weight-management interventions are likely to be considered only once an employee with obesity has reached a degree at which he or she is considered as a candidate for bariatric surgery. Ultimately, a benefit design that is reliant upon bariatric surgery as the primary weight-loss intervention precludes employees from preventively addressing weight gain, overweight, or obesity with employer-sponsored initiatives. No other chronic disease is treated this way, in which surgery is first. As such, current employer-provided weight-management offerings usually fail to provide effective promotion of exercise and healthy eating for a reasonable duration; typically, at least one year would be considered an effective duration in order for meaningful results to be achieved. They are likely to limit the opportunity to offer comprehensively designed, tailored interventions to suit each individual’s clinical status. Ideally, weight-management programs should look beyond offering access to bariatric surgery and should provide access to pharmacotherapy options, behavioral health therapy, and other appropriate therapies that are part of a customized treatment plan based on patients’ weight status, history of weight loss, and obesity-related comorbidities. Due to the complexity of the underlying causes of obesity, management and treatment must be multifaceted.20 Research shows that adherence to a combination of treatment components can lead to greater weight loss, as well as improvement in related health risks.21 A National Institute of Health (NIH) report stated: “Effective weight control involves multiple techniques and strategies including dietary therapy, physical activity, behavior therapy, pharmacotherapy, and surgery, as well as combinations of these strategies.”22 There is a need for a multidisciplinary approach that includes behavioral counseling, support, or education components
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MANAGING OBESITY | Continued
in the current weight-management approach taken by employerprovided benefits, whereas a more effective model would constructively coordinate the medical benefit and pharmacy benefit and integrate within the broader employer-sponsored initiative. Lack of integration across the medical and pharmacy benefits and the employer-sponsored programs presents a significant gap. Evidence of this gap is found when assessing employer-based programs that focus on the prescription drug benefit and access to pharmacologic therapies to support weight-loss efforts. Prescription drug benefit policies governing access to these therapies are not widely available and are typically restrictive; in many cases, pharmacotherapies are not even available as part of the standard pharmacy benefit. When included in the pharmacy benefit drug formulary, weight-loss drugs are likely to require nearly insurmountable prior authorization review and approval processes or have high out-of-pocket costs.
in the design of weight-loss interventions in order to improve longterm success.20 An example of this type of approach may include physical activity, behavior therapy, and pharmacotherapy, where appropriate, with weight-loss surgery as an option where other treatment options have failed.22 Additionally, according to the NIH, after six months of initial weight loss, the rate of weight loss tends to plateau due to the physiologic response to weight loss that defends the higher fat mass, thus promoting weight regain again; thus, after targeted weight loss goals are achieved, individuals must continue multifaceted therapy indefinitely for maintenance.22 A multifaceted weight-management program would likely include a combination of medical benefits, pharmacy benefits, and employer-sponsored programs; managing a program that includes support from various sources can be challenging and would require a unique and targeted benefit design. Access to obesity-targeting pharmacologic agents would be implemented through pharmacy benefits, while programs such as lifestyle coaching and physical activity initiatives are typically employer-sponsored; behavioral therapy, weight-loss surgery, and office visits fall under medical benefits. A certain disjointedness exists
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Patients with obesity need access to behavioral health support. Growing evidence suggests that offering bariatric surgery as the primary solution to obesity can be ineffective, as it does not address the behavioral health of employees with obesity. Studies show 20% of patients experience substantial weight regain after surgery.23 Post-surgery weight regain can often be attributed to addictive behaviors and food urges, as well as lack of selfmonitoring.24 Studies have shown that unrecognized and untreated eating and psychiatric disorders may lead to post-surgery weight regain in some patients; cognitive behavioral treatment has shown more success in treating these types of disorders than programs without a behavioral or psychological component.25 The absence of a program structure that results in early or preventive formal involvement with weight-management programs results in gaps in care, despite employersâ€™ best intentions. Currently, few existing programs intervene in a comprehensive or structured manner prior to the point where members have obesity of a degree that warrants surgical intervention. In an effort to address these challenges, Magellan Rx began to explore the necessary steps to develop a comprehensive weight-management program that includes accessible behavior modification, lifestyle modification, nutritional modification, physical activity, pharmacotherapy, and metabolic surgery.
Moving Forward In the next issue of the Magellan Rx Report, we will explore the paths employers can take to develop and implement these weight-management programs as well as potential challenges they may face.
Hales, Craig M. et al. “Prevalence of Obesity Among Adults and Youth: United States, 2015–2016.” October 2017, Centers for Disease Control and Prevention, https://www.cdc.gov/nchs/ products/databriefs/db288.htm.
Waters, Hugh, and Marlon Graf. “America’s Obesity Crisis: The Health and Economic Costs of Excess Weight.” Milken Institute, October 2018, https://milkeninstitute.org/sites/default/files/reports-pdf/MiAmericas-Obesity-Crisis-WEB.pdf.
Kyle, Theodore K. et al. “US Employee Wellness Programs and Access to Obesity Treatment in Employer-Sponsored Health Insurance.” American Journal of Managed Care, Nov. 15, 2015, http://www.ajmc.com/journals/evidence-based-diabetesmanagement/2015/november-2015/us-employee-wellnessprograms-and-access-to-obesity-treatment-in-employer-sponsoredhealth-insurance.
Ochner, Christopher N. et al. “Treating obesity seriously: when recommendations for lifestyle change confront biological adaptations.” The Lancet: Diabetes and Endocrinology, Feb. 11, 2015, https://www.thelancet.com/journals/landia/article/PIIS22138587(15)00009-1/fulltext.
13. Pollitz, Karen and Matthew Rae. “Workplace Wellness Programs Characteristics and Requirements.” The Henry J. Kaiser Family Foundation, May 19, 2016, http://www.kff.org/private-insurance/ issue-brief/workplace-wellness-programs-characteristics-andrequirements/. 14. David Blumenthal. “Employer-Sponsored Health Insurance in the United States — Origins and Implications.” The New England Journal of Medicine, July 6, 2006, https://www.nejm.org/doi/ full/10.1056/NEJMhpr060703. 15. Nobel, Jeremy et al. “Tipping the Scales on Weight Control: New Strategies for Employers.” Northeast Business Group on Health, August 2016, http://nebgh.org/wp-content/uploads/2016/08/ NEBGH_Tipping-the-Scales-2016.pdf. 16. Chen, Brian and Martha Romney. “Employer Weight Management Benefits and Strategy.” Greater Philadelphia Business Coalition On Health Annual Wellness Summit, September 2016, https://www. gpbch.org/docs/gpbch_employer_weight_management_survey_ final20160914.pdf.
“The State of Obesity 2017: Better Policies for a Healthier America.” Trust for America’s Health, 2017, https://stateofobesity.org/ healthcare-costs-obesity/.
17. Nyce, Steven. “Boosting Wellness Participation Without Breaking the Bank. Willis Towers Watson, July 2010, http:// www.towerswatson.com/en-US/Insights/Newsletters/Americas/ insider/2010/boosting-wellness-participation-without-breakingthe-bank.
Pickering, Laurel et al. “Weight Control and the Workplace: Employers and Health Plans Explore Their Toughest Health Improvement Challenge.” Northeast Business Group on Health, 2013, nebgh.org/wp-content/uploads/2016/04/NEBGH_SC_ WeightControlFINAL10-31-13.pdf.
18. Garvey, W. Timothy et al. “American Association of Clinical Endocrinologists and American College of Endocrinology Clinical Practice Guidelines for Comprehensive Medical Care of Patients with Obesity — Executive Summary.” Endocrine Practice, May 24, 2016, https://www.ncbi.nlm.nih.gov/pubmed/27219496.
Trogdon, Justin G. et al. “Indirect costs of obesity: A review of the current literature.” Obesity Reviews, September 2008, https://www. ncbi.nlm.nih.gov/pubmed/18331420.
Gates, Donna M. et al. “Obesity and presenteeism: the impact of body mass index on workplace productivity.” Journal of Occupational and Environmental Medicine, January 2008, https:// www.ncbi.nlm.nih.gov/pubmed/18188080.
19. Hafekost, Katherine et al. “Tackling overweight and obesity: does the public health message match the science?” BMC Medicine, Feb. 18, 2013, https://bmcmedicine.biomedcentral.com/ articles/10.1186/1741-7015-11-41.
Ramasamy Abhilasha et al. “Direct and Indirect Cost of Obesity Among the Privately Insured in the United States.” Journal of Occupational and Environmental Medicine, November 2019, https://journals.lww.com/joem/Fulltext/2019/11000/Direct_and_ Indirect_Cost_of_Obesity_Among_the.3.aspx#pdf-link.
10. “Large Employers’ 2015 Health Plan Design Survey.” National Business Group on Health, August 2014, http://www.fightthe40. com/AlliancetoFightThe40/assets/File/Studies/2015_NBGH_ health_plan_design_survey.pdf. 11. “Designing and Managing Wellness Programs.” Society for Human Resource Management, June 15, 2016, https://www. shrm.org/resourcesandtools/tools-and-samples/toolkits/pages/ designingandmanagingwellnessprograms.aspx. 12. “About the Affordable Care Act.” Department of Health and Human Services, July 3, 2017, https://www.hhs.gov/healthcare/about-theaca/index.html.
20. Acharya, Sushama D. et al. “Adherence to a behavioral weight loss treatment program enhances weight loss and improvements in biomarkers.” Patient Preference and Adherence, Nov. 3, 2009, https://www.ncbi.nlm.nih.gov/pubmed/19936157. 21. “The Practical Guide: Identification, Evaluation, and Treatment of Overweight and Obesity in Adults.” National Institutes of Health, National Heart, Lung, and Blood Institute Obesity Education Initiative, 2000, https://www.nhlbi.nih.gov/files/docs/guidelines/ prctgd_c.pdf. 22. Karasu, Sylvia R. “Psychotherapy-lite: obesity and the role of the mental health practitioner.” American Journal of Psychotherapy, 2013, https://www.ncbi.nlm.nih.gov//pubmed/23682511. 23. Odom, J. et al. “Behavioral predictors of weight regain after bariatric surgery.” Obesity Surgery, June 25, 2009, https://www. ncbi.nlm.nih.gov/pubmed/19554382. 24. Maleckas, Almantas et al. “Weight regain after gastric bypass: etiology and treatment options.” Gland Surgery, December 2016, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5233838/.
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PI PE LI N E D RU G LIST
PIPELINE DRUG LIST
Expected FDA Approval
Genentech Inc.; Chugai Pharmaceutical Co. Ltd.
HCC (unresectable, first line)
BLA; breakthrough therapy
Genentech; Chugai Pharmaceutical Co. Ltd.; Cipla Limited; PDL BioPharma Inc.
HCC (unresectable, first line)
bimatoprost sustained release
celecoxib and tramadol (E-58425)
Mundipharma International Ltd.; Esteve SA
Moderate to severe pain
Pfizer Inc.; Ono Pharmaceutical Co. Ltd.
CRC (mutant, metastatic, in combination with cetuximab)
Acceleron Pharma Inc.; BristolMyers Squibb Company
Fast track; orphan drug
Acacia Pharma Group PLC; Cosmo Pharmaceuticals N.V.; Hana Pharma Co. Ltd.; Mundipharma International Ltd.; PAION AG; Pharmascience Inc.
UroGen Pharma Ltd.
Bladder cancer (low grade, upper tract)
Breakthrough therapy; fast track; orphan drug
meningococcal conjugate vaccine (Men Quad TT)
Meningococcal vaccines and other meningococcal-specific agents (antibacterial)
Neurocrine Biosciences Inc.; Bial Pharmaceuticals; Ono Pharmaceutical Co. Ltd.; Shanghai Fosun Pharmaceutical Co. Ltd.
Parkinson’s disease (off episodes)
treprostinil patch pump (Trevyent®)
United Therapeutics Corporation; Cipher Pharmaceuticals Inc.
Roche Holding AG; Chugai Pharmaceutical Co. Ltd.
Devic’s disease (NMO)
Breakthrough therapy; orphan drug
AstraZeneca PLC; Cancer Research UK; Merck & Co. Inc.; Pfizer Inc.
Breakthrough therapy; orphan drug
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PI PE LI N E D RU G LIST
PIPELINE DRUG LIST CONT.
Expected FDA Approval
Sumitomo Dainippon Pharma Co. Ltd.
Clovis Oncology, Inc.; Pfizer Inc.
Sumitomo Dainippon Pharma Co. Ltd.; Aquestive Therapeutics Inc.
Parkinson’s disease (off episodes)
Roche Holding AG; Chugai Pharmaceutical Co. Ltd.; PTC Therapeutics Inc.
Breakthrough therapy; fast track; orphan drug
La Jolla Pharmaceutical Company
Breakthrough therapy; orphan drug
nadofaragene firadenovec (Instiladrin®)
FKD Therapies Oy; Ferring Pharmaceuticals
Bladder cancer (high-grade, BCGunresponsive, nonmuscle-invasive)
BLA; breakthrough therapy; fast track
AstraZeneca PLC; Cancer Research UK; Merck & Co. Inc.
Novartis AG; Genmab A/S; GlaxoSmithKline PLC
Foamix Pharmaceuticals Ltd.
Immunomedics, Inc.; Everest Medicines Limited; Royalty Pharma AG
Breast cancer (triple negative, metastatic, >2 prior therapies)
BLA; breakthrough therapy; fast track
Nippon Shinyaku Co. Ltd.
Fast track; orphan drug
Merck & Co. Inc.
Fast track; qualified infectious disease drug
AbbVie Inc.; Neurocrine Biosciences Inc.
Bausch Health Companies Inc.; Eton Pharmaceuticals Inc.
Royalty Pharma AG; Eisai Co. Ltd.; Epizyme Inc.
Follicular lymphoma (relapsed/refractor, 2+ prior therapies)
Fast track; orphan drug
Nabriva Therapeutics PLC
Urinary tract infections (complicated)
Fast track; qualified infectious disease drugs
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PI PE LI N E D RU G LIST
PIPELINE DRUG LIST CONT.
Expected FDA Approval
Evoke Pharma Inc.; Mallinckrodt PLC
Karyopharm Therapeutics; Antengene Corporation; HealthCare Royalty Partners; Ono Pharmaceutical Co. Ltd.; Promedico Ltd.
Diffuse large B-cell lymphoma (relased/ refractory, post >2 multi-drug therapies, bone marrow transplantineligible)
Fast track; orphan drug
obeticholic acid (Ocaliva®)
Intercept Pharmaceuticals Inc.
octreotide acetate (Mycapssa®)
Merck & Co. Inc.; DRI Capital Inc.
Cutaneous squamous cell carcinoma (recurrent, metastatic; not curable with surgery/radiation)
Viela Bio Inc.; Hansoh Pharmaceutical Group Co. Ltd.; Mitsubishi Tanabe Pharma Corporation
Devic’s disease (NMO)
BLA; breakthrough therapy; orphan drug
Allergan PLC; Molecular Partners AG
Dr. Reddy’s Laboratories
Migraine and other headaches
Boehringer Ingelheim GmbH
collagenase clostridium histolyticum
Endo International PLC; BioSpecifics Technologies Corp.
dantrolene sodium (Ryanodex®)
Eagle Pharmaceuticals Inc.
Heat stroke (exertional)
Fast track; orphan drug
Janssen Pharmaceutica; Genmab A/S; Halozyme Therapeutics, Inc.
Verrica Pharmaceticals Inc.
Janssen Pharmaceutica; MorphoSys AG; Otsuka Holdings Co. Ltd.
oxymetazoline hydrochloride (RVL-1201)
Osmotica Pharmaceuticals PLC
Grünenthal GmbH; Acorda Therapeutics Inc.; NeurogesX Inc.
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PI PE LI N E D RU G LIST
PIPELINE DRUG LIST CONT.
Expected FDA Approval
calcipotriene/betamethasone dipropionate (Wynzora™ Cream)
MC2 Therapeutics A/S
lower-sodium oxybate (JZP-258)
Jazz Pharmaceuticals PLC
Corium International Inc.
fluticasone furoate/umeclidinium/ vilanterol (Trelegy Ellipta)
GlaxoSmithKline PLC; Innoviva Inc.; Theravance Biopharma, Inc.
Ultragenyx Pharmaceutical Inc.; Baylor Scott & White Research Institute; UniQuest Pty Limited
Fatty acid oxidation disorders
Fast track; orphan drug
Eli Lilly and Company; Pfizer Inc.
NSCLC (RET-altered); thyroid cancer (RETaltered)
Breakthrough therapy; orphan drug
AstraZeneca PLC; The Medicines Company
Atherosclerosis (in patients with T2DM)
Genentech Inc.; DRI Capital Inc.; Novartis AG; PDL BioPharma Inc.
Merck & Co. Ltd.; 3SBio Inc.; Mundipharma International Ltd.; Samsung Bioepis Co. Ltd.
NSCLC; CRC; glioblastoma; ovarian cancer; RCC
cedazuridine and decitabine (ASTX727)
Otsuka Holdings Co., Ltd.
Catheter complications (prevention of catheter-related bloodstream infection in hemodialysis patients)
Fast track; qualified infectious disease drug
insulin lispro, ultra-rapid (LY900014)
Eli Lilly and Company
flortaucipir F 18
Eli Lilly and Company; Siemens AG
Alzheimer’s disease — imaging
Abbreviations: AMD=age-related macular degeneration; BCG=Bacillus Calmette-Guerin; BLA=biologics license application; CMML=chronic myelomonocytic leukemia; CRC=colorectal cancer; DMD=Duchenne muscular dystrophy; DPN=diabetic peripheral neuropathy; HAP=hospital-acquired pneumonia; HCC=hepatocellular carcinoma; IM=intramuscular; IN=intranasal; IO=intraocular; IV=intravenous; MDS=myelodysplastic syndrome; MM=multiple myeloma; MS=multiple sclerosis; NASH=nonalcoholic steatohepatitis; NF=neurofibromatosis; NMO=neuromyelitis optica; NSCLC=nonsmall cell lung cancer; PA=psoriatic arthritis; PAH=pulmonary arterial hypertension; PH=pulmonary hypertension; PO=oral; RCC=renal cell carcinoma; SL=sublingual; SMA=spinal muscular atrophy; SQ=subcutaneous; T1DM=type 1 diabetes mellitus; T2DM=type 2 diabetes mellitus
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A Missed Opportunity to Recognize Narcolepsy Symptoms Can Have a Significant Impact on Pediatric Patients
Personality and Behavior Anxiety, depression, introversion, feelings of inferiority, and sorrowfulness1-3
About 3.5 times higher likelihood of repeating a grade vs pediatric patients without narcolepsy4*
5 times higher medical costs vs pediatric patients without narcolepsy5†
Visit NarcolepsyLink.com/Pediatric to learn more about pediatric narcolepsy. * Based on a health-related quality of life (HRQL) study assessed through a questionnaire completed by children and adolescents with narcolepsy (N=117) and control subjects (N=69). Academic performance was evaluated in the study.4 † Based on a retrospective, cross-sectional, case-control, claims-based analysis of health care utilization and costs, that included narcolepsy patients ≤18 years of age (N=1427) and control subjects (N=4281).5 References: 1. Nevsimalova S. Narcolepsy in childhood. Sleep Med Rev. 2009;13(2):169-180. 2. Marcus C. Daytime sleepiness in children: when a quiet child is not necessarily a good thing. Paediatr Respir Rev. 2018;25:1-2. 3. Blackwell JE, Alammar HA, Weighall AR, Kellar I, Nash HM. A systematic review of cognitive function and psychosocial well-being in school-age children with narcolepsy. Sleep Med Rev. 2017;34:82-93. 4. Inocente CO, Gustin MP, Lavault S, et al. Quality of life in children with narcolepsy. CNS Neurosci Ther. 2014;20(8):763-771. 5. Reiss Reddy S, Broder MS, Tieu R, et al. Disease burden in pediatric narcolepsy: a claims-based analysis of health care utilization and costs and medical comorbidity. Poster presented at: SLEEP 2018, the 32nd Annual Meeting of the APSS; June 2-6, 2018; Baltimore, MD.
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