Magellan Rx Report - Spring 2021

Page 1

Magellan Rx Report Spring 2021

COVID-19: Impact on Delivery of Care

Wet AMD: Changing Landscape and Payer Implications

Rare Neuromuscular Diseases: Management Strategies

IV Iron: Managed Care Implications

Magellan Rx Report MEDICAL AND PHARMACY BENEFIT MANAGEMENT Spring 2021

Multiple Myeloma:

Treatment Update, CAR-T Therapy, and Impact

magellanrx.com/mrxreport


IN THIS ISSUE | Spring 2021

2

Managed Care Newsstand

22

Multiple Myeloma:

4

COVID-19:

28

Rare Neuromuscular Diseases:

13

Wet AMD:

33

IV Iron:

17

Mental Health Update:

38

Pipeline

Impact on Delivery of Care

Changing Treatment Landscape and Payer Implications

Digital Therapeutics, Drug Pipeline, and COVID-19 Impact

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

Treatment Update, CAR-T, and Impact

Treatment and Management Strategies

Managed Care Impact

CMO, Magellan Health

Steve Cutts, Pharm.D.

Haita Makanji, Pharm.D.

VP, Clinical Strategy and Innovation, Specialty

magellanrx.com Editor Lindsay Speicher, J.D.

Project Manager, Magellan Method lspeicher@magellanhealth.com 401-344-1105

Advertising, Sales and Distribution Carole Kallas ckallas@magellanhealth.com 401-344-1132

The content of Magellan Rx 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.

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

Yousaf Ali M.D., FACR

Misty Greficz

Director, Marketing

Chief, Division of Rheumatology, Mount Sinai West; Professor of Medicine, Icahn School of Medicine at Mount Sinai

Joe Tavares

Steven L. D’Amato, B.S.Pharm.

Corrado Panno

Joseph Mikhael M.D., M.Ed., FRCPC, FACP

Stacy Inman, Pharm.D.

Natalie Tate, Pharm.D., MBA, BCPS

SVP, Sales and Business Development, Specialty VP, Business Development, Magellan Method Senior Clinical Project Manager, Magellan Method

Alex Baratz

Senior Director, Clinical Project & Program Management

Carole Kallas TM

Editorial Advisory Board Mona M. Chitre, Pharm.D., CGP

Project Manager

Brian Kinsella, Esq. Senior Legal Counsel

Executive Director, New England Cancer Specialists

Chief Medical Officer, International Myeloma Foundation Vice President, Pharmacy Management, BlueCross BlueShield of Tennessee

Steve Marciniak, R.Ph.

Director II, Medical Benefit Drug Management, BlueCross BlueShield of Michigan

Saira A. Jan, M.S., Pharm.D.

Director of Pharmacy Strategy and Clinical Integration, Horizon BlueCross BlueShield of New Jersey

Alina Young

Associate Legal Counsel

Lilly Ackley

VP, Corporate Communications

Kristen Durocher

Director, External Communications

ISSN: 2159-5372

10444M


A NOTE FROM OUR CMO

Dear Managed Care Colleagues, Welcome to our spring 2021 issue of the Magellan Rx Report! his year is off to an exciting start following the U.S. Food and Drug Administration’s (FDA) issuance of emergency use authorization for two COVID-19 vaccines at the end of 2020 and an additional authorization issued in late February. While COVID-19 is still very much at the forefront, we are seeing advancements in other healthcare spaces as well. So far this year, the FDA has already approved 14 novel therapies, with several more in the queue for the remainder of 2021. Magellan Rx Management is committed to keeping our readers informed with timely content focused on the ongoing global health crisis, as well as other important clinical advances and managed care trends.

In another article, we discuss the treatment landscape of wet age-related macular degeneration specifically focusing on the introduction of biosimilars in this market and the potential impact on all stakeholders (page 13). Other timeline topics in this issue include a look at management of the rare neuromuscular disease space (page 28) and the impact of IV iron on managed care (page 33). As always, the issue is rounded out with our pipeline update (page 38) and managed care newsstand (page 2). To learn more about Magellan Rx Management and our support for 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!

Our cover story (page 22) highlights the changing treatment landscape of multiple myeloma, including the emergence of CAR-T therapies and the anticipated impact on managed care. Sincerely, A feature article focuses on the impact of COVID-19 on the delivery of care and how the increased use of telehealth and home care may change healthcare in a post-pandemic world (page 4).

Caroline Carney, M.D., M.Sc., FAPM, CPHQ Chief edical cer Magellan Health & Magellan Rx Management

We outline mental health updates in another story (page 17), in which we discuss the utility and opportunities presented by digital therapeutics in mental health, the robust pipelines across mental health indications, and the current and long-term impact COVID-19 has had on mental health.

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 President Biden Sworn In as 46th President and COVID-19 and Healthcare Among Top Priorities President Biden was sworn in as the nation’s 46th president on Jan. 20. Addressing the COVID-19 pandemic and healthcare challenges are top priorities as he begins his term in o ce On March the president signed into law a sweeping $1.9 trillion COVID-19 relief package which immediately pro ided stimulus payments to more than of indi iduals and families he bill also pro ides billion in aid to states and localities more than billion to help reopen schools and additional billions to accelerate accination and testing across the country Additionally the bill includes a significant increase in funding for mental health and addiction ser ices In addition to the recently signed stimulus package President Biden issued executi e orders on his first day in o ce including directing that masks be worn in all federal facilities re oining the orld Health Organization and creating a COVID-19 response coordinator as the hite House mo es to assert a more national strategy to fight the pandemic On an he issued another executi e orders hese include establishing community accination centers across the country expanding accine production and personal protecti e equipment a ailability through the Defense Production Act and requiring masks to be worn at all airports and other transportation facilities as well as during tra el on planes trains and buses and on all federal property he orders also require testing for all international tra elers and direct that federal agencies quickly es-

2 | Magellan Rx Report | Spring 2021

tablish guidance for schools during the pandemic he president has stated that his goal is to ha e million people accinated within days He also issued a number of executi e orders on an addressing the Affordable Care Act (ACA) as part of his effort to build and strengthen this landmark legislation that was passed when he ser ed as ice president. he administration also announced on Jan. 20 a freeze on all regulations that ha e not yet taken effect his is a common step a new administration takes when assuming o ce as it allows the new administration to re iew any of the last-minute rules the pre ious administration issued he guidance calls for agencies to re iew pending rules and to recommend whether the rules should be delayed for up to 6 days pending further re iew including taking action to seek additional public comment his action does not automatically mean all rules will be frozen here are a number of rules that ha e not yet been finalized including the rump administration rules to eliminate rebates in the Part D program to establish Most Fa ored Nation drug pricing or to implement changes to prior authorization among others

Rebate Rule Delayed In response to litigation brought by the Pharmaceutical Care Management Association challenging the Medicare Part D rebate rule the Biden administration agreed to postpone the effecti e date of the pro isions of the rule relating to the elimination of the regulatory discount safe harbor for retrospecti e rebates from an to an Judge John D. Bates of the U.S. District Court for the District of Columbia entered an order memorializing the agreement (signed an ) to postpone all pro i-

sions” of the Rule “that were scheduled to take effect on an until an holding the case in abeyance during HHS re iew of the rule sub ect to the continued consent of the parties and calling for a oint status report not later than April his agreement follows closely on the heels of the HHS OIG delaying certain pro isions of the rebate rule including a new safe harbor for ser ice fees that manufacturers pay to PBMs to March hese pro isions are not affected by the legal order

President Biden Issues Executive Order to Strengthen Medicaid On an President Biden issued an xecuti e Order on Strengthening Medicaid and the Affordable Care Act he executi e order directs the heads of agencies to re iew existing regulations orders guidance documents policies and any other similar agency actions that limit access to healthcare and consider actions to strengthen access to care through Medicaid and ACA he executi e order establishes that it is the administration s policy to protect and strengthen Medicaid and ACA and to make high-quality healthcare accessible and affordable for e ery American Specifically as part of this re iew the order directs agencies to examine: Policies or practices that may undermine protections for people with pre-existing conditions including complications related to CO IDunder ACA. Demonstrations and wai ers as well as policies that may reduce co erage under or otherwise undermine Medicaid or ACA. Policies or practices that may undermine the Health Insurance


Marketplace or the indi idual small group or large group markets for health insurance in the U.S. Policies or practices that may present unnecessary barriers to indiiduals and families attempting to access Medicaid or ACA co erage including for midyear enrollment Policies or practices that may reduce the affordability of co erage or financial assistance for co erage including for dependents. Agencies must consider whether to suspend re ise or rescind such policies or actions that are inconsistent with the administration s policy identified in the executi e order and consider additional actions to strengthen and protect access to care. Additionally the order specifically reokes two rump administration actions xecuti e Order 6 Minimizing the Economic Burden of Patient Protection and Affordable Care Act Pending Repeal and xecuti e Order Promoting Healthcare Choice and Competition across the United States which led to rulemaking to expand short-term limited-duration plans association health plans and Health Reimbursement Arrangements he agencies are directed to re iew policies stemming from these orders.

CMS Moves to Rescind Medicaid Work Requirements On Feb Centers for Medicare and Medicaid Ser ices (CMS) Acting Administrator Cheri Richter sent letters to se eral states announcing CMS is beginning a process to determine whether to withdraw their appro ed work requirements demonstration wai er Under the rump administration CMS granted appro als of wai ers to eight states that would allow them to implement

a contro ersial rump-era rule that requires Medicaid beneficiaries to work in order to recei e co erage he letters are the first step in unwinding the rule CMS will pro ide states with a written notice and an opportunity to request a hearing before determining whether to suspend modify or withdraw the wai ers According to the aiser Family Foundation eight states ha e been appro ed for work-requirement wai ers se en ha e applications pending and four are waiting for court decisions. CMS’ action follows an executi e order issued by President Biden in anuary asking agencies to consider actions that could strengthen and protect healthcare access.

X-Waiver Guidance Rescinded Telehealth Clinical guidelines around treatment for opioid use disorder (OUD) announced in mid- anuary under the rump administration were pulled back by the Biden administration he guidance sought to remo e certain requirements to obtain a wai er ( x-wai er ) to prescribe buprenorphine which were seen as beyond the scope of authority that the statute allowed. Currently the law allows physicians to apply for an x-wai er to prescribe buprenorphine for the treatment of opioid addiction or dependence outside of an opioid treatment program (O P) if certain requirements are met (e g eight hours of training) he x-wai er requirements which were meant to allow primary care pro iders to treat OUD are seen by many as a hurdle to treatment access

Exchanges Reopened for Special Enrollment Period

The executive order directs the heads of agencies to review existing regulations, orders, guidance documents, policies, and any other similar agency actions that limit access to healthcare and consider actions to strengthen access to care through Medicaid and the Afforda le Care Act.

enrollment period from Feb through May in order to allow those impacted by the pandemic to sign up for co erage he Department is committed to ensuring that we deploy e ery a ailable resource during the Public Health Emergency his Special nrollment Period will ensure more indi iduals and families ha e access to quality affordable health co erage during this unprecedented time said HHS Acting Secretary Norris Cochran.

he federal Healthcare go xchange reopened for a three-month special

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COVID-19: Impact on Delivery of Care The ongoing public health crisis has changed how care is delivered, with increasing utilization of telehealth and home care. For the past year, the COVID-19 pandemic has transformed nearly every aspect of healthcare and healthcare delivery. Innovation was key in ensuring that patients received optimum care while remaining as safe and as healthy as possible. Particularly during times of high transmission rates and peak surges, close contact put patients, providers, and other healthcare professionals at high risk for exposure. Howe er tools and inno ati e solutions allowed pro iders to treat patients in a safe e cient way during this public health crisis.

Lindsay C. Speicher, J.D. Project Manager Magellan Method

Telehealth Telehealth is a means for providers to use telecommunication technologies to provide care for patients without requiring physical proximity. Most commonly, patients and providers can have real-time appointments via video chat or on the phone. Other methods of telehealth include chat messaging, emailing, and remote patient monitoring. A wide variety of care can be provided via telehealth, including wellness visits, prescriptions, dermatology, eye exams, nutrition counseling, mental health counseling, and some urgent care conditions. During the last week of March 2020, there was a 154% increase in telehealth visits from the same period in 2019.1 A 2020 survey reported that 79% of U.S. specialists said their use of telemedicine technology increased during the pandemic; fewer than half of cardiologists, gastroenterologists, pulmonologists, and respiratory specialists surveyed reported using telehealth prior to the pandemic.2 The survey reported that more than 75% of specialists would continue using virtual care technology in some capacity after the pandemic.2 Physicians are providing care via telehealth to between 50 and 175 times as many patients as they were prior to the pandemic.3, 4 While just 11% of patients reported using telehealth in 2019, around 46% of patients reported using telehealth to replace canceled in-person visits in 2020.3, 4 In a July 2020 survey, 40% of patients reported canceling upcoming appointments, and an additional 12% reported need-

4 | Magellan Rx Report | Spring 2021


ing care but not actively scheduling or receiving care.5 While the long-term impact of delayed care will vary depending on the condition and required maintenance, the impact and cost to the healthcare system could be substantial.5 Telehealth provides an alternative delivery method to maintain continuity of care as a solution for delayed preventive, chronic, or routine care. After the changes in healthcare delivery experienced in 2020, 57% of providers reported having a more favorable view of telehealth than they did before the pandemic, and 64% reported that they are more comfortable using it.3, 4 Due to the pandemic, the U.S. Centers for Medicare and Medicaid Services (CMS) has temporarily allowed telehealth to be used for more than 80 new services.3, 4 Many commercial payers have responded to COVID-19 by expanding access to telehealth services and in some cases waiving out-of-pocket costs for telehealth in order to provide members with safe opportunities to receive care.3, 4 This shift, however temporary, may result in strengthening patient and provider preferences for telehealth, embedding it in healthcare delivery.3, 4

Impact Virtual visits could account for a quarter trillion, or about 20%, of what Medicare, Medicaid, and commercial payers spend on outpatient o ce and home and health isits 4 In comparison, prior to 2020, telehealth accounted for only an estimated $3 billion.

here are fi e models for irtual care 4 1. On-demand virtual urgent care: an alternative to some emergency department (ED) visits or urgent care visits. 2. irtual o ce visits an alternati e to in-person o ce consultations during which physical exams or procedures are not required. 3. ear virtual o ce visits provides patients access to care outside a pro ider s o ce combining irtual physician consultations with “near-home” sites for testing and immunizations. 4. irtual home health services virtual visits, remote monitoring, and digital patient-engagement tools can enable a portion of certain services to be delivered remotely, such as evaluations, patient and caregiver education, physical therapy, occupational therapy, and speech therapy. 5. Tech enabled home medication administration an alternative to outpatient infusible and injectable drug administration, which would leverage remote monitoring to help manage patients and monitor symptoms, provide patients with training for selfadministration and use telehealth for o ersight of staff Shifting these care offerings to telehealth could result in changes in the overall care-delivery system, including an avoidance of 20% of all D isits irtual deli ery of of healthcare o ce isits and outpatient volume with an additional 9% delivered nearly virtually, virtualization of 35% of regular home health attendant services, and a 2% shift of all outpatient (OP) volume to the home setting with tech-enabled medical administration.3, 4 With the

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The latest COVID-19 landscape

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ongoing pandemic, these trends are expected to continue in the coming months (or longer). Virtual visits and telehealth could potentially account for about $250 billion of Medicare, Medicaid, and commercial spend on outpatient isits o ce isits and home and health visits, while they only accounted for $3 billion prior to the pandemic.3, 4 This shift in care is not without challenges. Providers noted concerns around security workflow integration reimbursement and effecti eness of telehealth isits as compared to in-person isits 4 Additionally, while 76% of patients reported interest in telehealth, only 46% have actually used it, which could indicate a gap in patient education around telehealth availability and access.4 o ensure telehealth continues to operate in an effecti e manner after the pandemic, healthcare stakeholders can strategize accordingly by classifying patient populations whose remote interactions could be scaled up with home-based or virtual care and building capabilities of the clinician workforce to support virtual care.4

ome Infusion and are Given the ongoing pandemic, site-of-care was a center point of discussion, with home infusion encouraged where appropriate. In April 2020, CMS released guidelines for the coverage of home infusion during the pandemic allowing flexibility for patients and providers to determine the best care solution for ongoing treatment.6 In the guidelines CMS relaxed the definition of

6 | Magellan Rx Report | Spring 2021

“homebound” to extend to at-risk patients who need to stay home to avoid COVID-19 exposure; CMS also relaxed the requirement for physician supervision in order to allow providers and clinics the flexibility to broaden the ser ices typically offered in the home setting.6 Site-of-care initiatives have shown trends shifting toward home infusions Specifically Penn Medicine launched Cancer Care at Home prior to the pandemic, in February 2020. However, during a seven-week period from March through April 2020, the program saw a 700% increase in home infusion referrals.7 Another initiative, headed by Option Care Health (“Option”), a company specializing in in-home infusion, aimed to support hospitals by assisting with the discharge of patients requiring infusion therapy.8, 9 Option reallocated a portion of its clinicians to areas with high rates of COVID-19 transmission to facilitate home infusion therapy.8, 9 Through this initiative, Option has worked with patients, respective payers, and hospitals to coordinate a safe discharge home and smooth transition to home infusion.8, 9 Strategies like these highlight the growing need to provide care in a safe home environment where appropriate, as well as the need for policies to integrate home care options.8, 9 Globally, the demand for home infusion therapies has increased in correlation to the pandemic — one report noted the market for home infusion is expected to hit $49.5 billion by 2027, growing at a compound annual growth rate of 11.7% during the pandemic.10 The market increased from $20.2 billion in 2019 to $22.9 billion in 2020, with growth attributed to the augmented adoption of home infusion treatment by chronic-disease patients due to COVID-19 risks.10

Impact CMS partially acknowledged the trend toward home care in its 11 final home health payment rule released in October In the rule, CMS estimated that Medicare payments to home health agencies will increase by $390 million.11 The National Home Infusion Association reported that there are currently 1,500 pharmacies across the U S that offer infusion therapies illustrating a growth in demand over recent years.12 However, this trend toward home infusion and care has received criticism from some groups, such as the Community Oncology Alliance, which argues that home infusion for chemotherapy, cancer immunotherapy, and supportive drugs are not ideal, as home infusion “by a provider who may not be a trained oncology nurse and may not recognize or be prepared to treat any of the serious adverse reactions that frequently occur is of significant concern.”13


Globally, the demand for home infusion therapies has increased in correlation to the pandemic — one report noted the market for home infusion is expected to hit $49.5 billion by 2027, growing at a compound annual growth rate of 11.7% during the pandemic. e t teps Moving forward, the impact of the COVID-19 pandemic has paved the way for continued shifts in care-delivery trends. While CMS and commercial payers have expanded access to alternative modes of care delivery in light of the pandemic,14 it is uncertain whether this access will remain flexible or return to its prepandemic state. If these shifts toward alternative care delivery continue even as the pandemic resolves, payers will likely focus on developing strategic initiati es to effecti ely manage care and ensure that care options are available to appropriate patients. As noted, it will be essential to ensure that qualified and well-trained professionals are delivering care in whatever capacity available in order to guarantee patients are recei ing the safest most effecti e care he influence of the current pandemic on care deli ery has created opportunity to innovate in order to improve health outcomes; howe er it will remain key to effecti ely manage the increasingly popular telehealth and home infusion trends.

eferences 1.

Koonin, Lisa et al. “Trends in the Use of Telehealth During the Emergence of the COVID-19 Pandemic — United States, January¬– March 2020.” Weekly, Oct. 30, 2020. 69(43);1595-1599. https:// www.cdc.gov/mmwr/volumes/69/wr/mm6943a3.htm.

2.

Jercich, Kat. “Vast majority of specialists increased use of telehealth tech during COVID-19 pandemic.” Healthcare IT News, Aug. 26, 2020, https://www.healthcareitnews.com/news/vast-majorityspecialists-increased-use-telehealth-tech-during-covid-19pandemic.

3.

Henry, T.A. “After COVID-19, $250 billion in care could shift to telehealth.” American Medical Association, June 18, 2020, https:// www.ama-assn.org/practice-management/digital/after-covid-19250-billion-care-could-shift-telehealth.

4.

Bestsennyy, Oleg et al. “Telehealth: A quarter-trillion-dollar postCOVID-19 reality?” McKinsey & Company, May 29, 2020, https:// www.mckinsey.com/industries/healthcare-systems-and-services/ our-insights/telehealth-a-quarter-trillion-dollar-post-covid-19reality.

5.

“Understanding the hidden costs of COVID-19’s potential impact on US healthcare.” McKinsey & Company, Sept. 4, 2020, https://www. mckinsey.com/industries/healthcare-systems-and-services/ourinsights/understanding-the-hidden-costs-of-covid-19s-potentialimpact-on-us-healthcare.

6.

“Update on Home Infusion & Medicare During COVID-19 Pandemic.” GBS/CIDP Foundation International, April 2, 2020, https://www.gbs-cidp.org/update-on-home-infusion-medicareduring-covid-19-pandemic/.

7.

Laughlin, Amy et al. “Accelerating the Delivery of Cancer Care at Home During the COVID-19 Pandemic.” NEJM Catalyst, July 7, 2020, https://catalyst.nejm.org/doi/full/10.1056/cat.20.0258.

8.

Donlan, Andrew. “Coronavirus Paving the Way for Home Infusion Services Moving Forward.” Home Health Care News, April 21, 2020, https://homehealthcarenews.com/2020/04/coronavirus-pavingthe-way-for-home-infusion-services-moving-forward/.

9.

Benefits Cloud-Based echnology Brings to Home Infusion During COVID-19.” Option Care Health, Sept. 3, 2020, https:// optioncarehealth com news -benefits-cloud-based-technologybrings-to-home-infusion-during-covid-19.

10. “Impact Analysis of COVID-19 on Home Infusion Therapy Market: Global Opportunity Analysis and Industry Forecast, 2020-2027.” Research Dive, 2020, https://www.researchdive.com/covid-19insights/360/home-infusion-therapy-market#myQueryForm. 11.

“CMS Finalizes Calendar Year 2021 Payment and Policy Changes for Home Health Agencies and Calendar Year 2021 Home Infusion herapy Benefit Centers for Medicare Medicaid Ser ices Oct 29, 2020, https://www.cms.gov/newsroom/fact-sheets/cmsfinalizes-calendar-year-payment-and-policy-changes-homehealth-agencies-and-calendar-year.

12. “Infusion FAQs.” National Home Infusion Association, http://w.nhia. org/faqs.cfm. 13. Inserro, Allison. “Home Infusion Services for Part B Drugs in the Spotlight Amid COVID-19 Regulatory Changes.” The American Journal of Managed Care, April 10, 2020, https://www.ajmc.com/ view/home-infusion-services-for-part-b-drugs-in-the-spotlightamid-covid19-regulatory-changes. 14. “Health Insurance Providers Respond to Coronavirus (COVID-19).” America’s Health Insurance Plans, March 10, 2021, https://www. ahip.org/health-insurance-providers-respond-to-coronaviruscovid-19/.

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For your appropriate adult patients with moderately to severely active UC and CD when other therapies have not worked well enough or cannot be tolerated

Entyvio works through a gut-selective MOA by specifically binding to the α4β7 integrin and blocking its interaction with MAdCAM-1, which is mainly expressed on gut endothelial cells.1 Remission was evaluated at Week 52.1 Individual results may vary.

INDICATIONS Adult Ulcerative Colitis (UC) ENTYVIO (vedolizumab) is indicated in adults for the treatment of moderately to severely active UC. Adult Crohn’s Disease (CD) ENTYVIO (vedolizumab) is indicated in adults for the treatment of moderately to severely active CD.

IMPORTANT SAFETY INFORMATION • ENTYVIO (vedolizumab) for injection is contraindicated in patients who have had a known serious or severe hypersensitivity reaction to ENTYVIO or any of its excipients. • Infusion-related reactions and hypersensitivity reactions including anaphylaxis, dyspnea, bronchospasm, urticaria, flushing, rash, and increased blood pressure and heart rate have been reported. These reactions may occur with the first or subsequent infusions and may vary in their time of onset from during infusion or up to several hours post-infusion. If anaphylaxis or other serious infusion-related or hypersensitivity reactions occur, discontinue administration of ENTYVIO immediately and initiate appropriate treatment.

IMPORTANT SAFETY INFORMATION (continued)

• Patients treated with ENTYVIO are at increased risk for developing infections. Serious infections have been reported in patients treated with ENTYVIO, including anal abscess, sepsis (some fatal), tuberculosis, salmonella sepsis, Listeria meningitis, giardiasis, and cytomegaloviral colitis. ENTYVIO is not recommended in patients with active, severe infections until the infections are controlled. Consider withholding ENTYVIO in patients who develop a severe infection while on treatment with ENTYVIO. Exercise caution in patients with a history of recurring severe infections. Consider screening for tuberculosis (TB) according to the local practice. • Progressive multifocal leukoencephalopathy (PML), a rare and often fatal opportunistic infection of the central nervous system (CNS), has been reported with systemic immunosuppressants, including another integrin receptor antagonist. PML is caused by the John Cunningham (JC) virus and typically only occurs in patients who are immunocompromised. One case of PML in an ENTYVIO-treated patient with multiple contributory factors has been reported in the post marketing setting (e.g., human immunodeficiency virus [HIV]

ENTYVIO is a trademark of Millennium Pharmaceuticals, Inc., registered with the U.S. Patent and Trademark Office and is used under license by Takeda Pharmaceuticals America, Inc. All other trademarks are the property of their respective owners. ©2021 Takeda Pharmaceuticals U.S.A., Inc. All rights reserved. Printed in U.S.A. US-VED-0049v2.0 02/21


For your appropriate adult patients with moderately to severely active UC and CD

ONLY ENTYVIO COMBINES

GUT SELECTIVITY

Entyvio helps address inflammation where it occurs—in the gut1 Entyvio specifically binds to the α4β7 integrin and blocks the interaction between the α4β7 integrin and MAdCAM-1, which is mainly expressed on the GI tract endothelial cells

SAFETY FOR THE LONG TERM

LONG-TERM REMISSION

2-7

1,8,9

Clinical trials evaluated safety in more than 3300 patients (UC and CD).1 A separate open-label study of up to 7 years demonstrated consistent results across safety parameters10-12*

UC and CD patients achieved remission at Week 52 vs placebo in study populations that included bio-naïve and anti-TNFα–experienced patients1,8,9 Individual results may vary

1,10-12

*In a single-arm, open-label extension study of 2243 patients who received Entyvio with a median exposure of 1072.0 days (range 1 to 3412 days).

ONLY ENTYVIO IS THE

FASTEST GROWING FIRST-LINE BIOLOGIC

FOR UC AND CD PATIENTS COMBINED13† 8 Biologics included Entyvio, Humira®, FOR UC AND CD PATIENTS * Remicade® (infliximab), and Stelara® (ustekinumab)‡

OFFERS RESULTS FROM

HEAD-TO-HEAD STUDY ENTYVIO HUMIRA®

OF BIOLOGICS IN MODERATE TO SEVERE UC14-16 §

(vedolizumab)

(adalimumab)

†Based on an analysis of data in SHA database comparing patient counts from year-to-year absolute growth information from December 2018 to November 2020 with "first line" defined as a new start in patients with UC or CD who had no UC or CD biologic drug claims for the past 3 years. ‡Humira® (AbbVie Inc. Chicago, IL); Remicade® (Janssen Biotech, Inc. Horsham, PA); Stelara® (Janssen Biotech, Inc. Horsham, PA). §Humira® (AbbVie Inc. North Chicago, IL). For information related to adalimumab, please see AbbVie.com.

IMPORTANT SAFETY INFORMATION (continued)

infection with a CD4 count of 300 cells/mm3 and prior and concomitant immunosuppression). Although unlikely, a risk of PML cannot be ruled out. Monitor patients for any new or worsening neurological signs or symptoms. Typical signs and symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes. If PML is suspected, withhold dosing with ENTYVIO and refer to a neurologist; if confirmed, discontinue ENTYVIO dosing permanently. • There have been reports of elevations of transaminase and/or bilirubin in patients receiving ENTYVIO. ENTYVIO should be discontinued in patients with jaundice or other evidence of significant liver injury. • Prior to initiating treatment with ENTYVIO, all patients should be brought up to date with all immunizations according to current immunization guidelines. Patients receiving ENTYVIO may receive non-live vaccines and may receive live vaccines if the benefits outweigh the risks.

IMPORTANT SAFETY INFORMATION (continued)

• Most common adverse reactions (incidence ≥3% and ≥1% higher than placebo): nasopharyngitis, headache, arthralgia, nausea, pyrexia, upper respiratory tract infection, fatigue, cough, bronchitis, influenza, back pain, rash, pruritus, sinusitis, oropharyngeal pain, and pain in extremities.

Please see Brief Summary of Full Prescribing Information on adjacent pages. CD = Crohn's disease; GI = gastrointestinal; MAdCAM-1 = mucosal addressin cell adhesion molecule-1; MOA = mechanism of action; TNFα = tumor necrosis factor alpha; UC = ulcerative colitis. References: 1. Entyvio (vedolizumab) prescribing information. Takeda Pharmaceuticals. 2. Briskin M, Winsor-Hines D, Shyjan A, et al. Am J Pathol. 1997;151(1):97-110. 3. Fedyk E, Wyant T, Yang LL, et al. Inflamm Bowel Dis. 2012;18(11):2107-2119. 4. Milch C, Wyant T, Xu J, et al. J Neuroimmunol. 2013;264:123-126. 5. Soler D, Chapman T, Yang LL, et al. J Pharmacol Exp Ther. 2009;330(3):864-875. 6. Wyant T, Fedyk E, Abhyankar B. J Crohns Colitis. 2016;10(12):1437-1444. 7. Wyant T, Leach T, Sankoh S, et al. Gut. 2015;64(1):77-83. 8. Data on file. Final CSR C13006, September 2012. Takeda Pharmaceuticals USA, Inc. 9. Data on file. Final CSR C13007, October 2012. Takeda Pharmaceuticals, USA, Inc. 10. Loftus EV Jr, Feagan BG, Panaccione R, et al. Aliment Pharmacol Ther. 2020;1-13. doi:10.1111/apt16060. 11. Data on file. Final CSR C13008, April 2020. Takeda Pharmaceuticals USA, Inc. 12. Data on file. Internal communication, October 2020. Takeda Pharmaceuticals USA, Inc. 13. Data on file. Fastest growing first-line biologic, January 2021. Takeda Pharmaceuticals USA, Inc. 14. Sands BE, Peyrin-Biroulet L, Loftus EV Jr, et al. N Engl J Med. 2019;381(13):1215-1226. 15. Data on file. AGA Abstracts 416a, May 2019. Takeda Pharmaceuticals USA, Inc. 16. Data on file. Varsity Oral Presentation, May 2019. Takeda Pharmaceuticals USA, Inc.

For more information on how you can help your patients, visit EntyvioHCP.com.


BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION ENTYVIO (vedolizumab) for injection, for intravenous use FULL PRESCRIBING INFORMATION INDICATIONS AND USAGE ENTYVIO is indicated in adults for the treatment of: • moderately to severely active ulcerative colitis. • moderately to severely active Crohn’s disease. CONTRAINDICATIONS ENTYVIO is contraindicated in patients who have had a known serious or severe hypersensitivity reaction to ENTYVIO or any of its excipients (such as dyspnea, bronchospasm, urticaria, flushing, rash and increased heart rate) [see Warnings and Precautions]. WARNINGS AND PRECAUTIONS Infusion-Related Reactions and Hypersensitivity Reactions Infusion-related reactions and hypersensitivity reactions have been reported, including anaphylaxis, dyspnea, bronchospasm, urticaria, flushing, rash, and increased blood pressure and heart rate [see Adverse Reactions]. These reactions may occur with the first or subsequent infusions of ENTYVIO and may vary in their time of onset from during infusion or up to several hours post-infusion. If anaphylaxis or other serious infusion-related or hypersensitivity reactions occur, discontinue administration of ENTYVIO immediately and initiate appropriate treatment. Infections Patients treated with ENTYVIO are at increased risk for developing infections [see Adverse Reactions]. The most commonly reported infections in clinical trials occurring at a rate greater on ENTYVIO than placebo involved the upper respiratory and nasal mucosa (e.g., nasopharyngitis, upper respiratory tract infection). Serious infections have also been reported in patients treated with ENTYVIO, including anal abscess, sepsis (some fatal), tuberculosis, salmonella sepsis, Listeria meningitis, giardiasis and cytomegaloviral colitis. ENTYVIO is not recommended in patients with active, severe infections until the infections are controlled. Consider withholding treatment in patients who develop a severe infection while on treatment with ENTYVIO. Exercise caution when considering the use of ENTYVIO in patients with a history of recurring severe infections. Consider screening for tuberculosis (TB) according to the local practice. For progressive multifocal leukoencephalopathy (PML), see Warnings and Precautions. Progressive Multifocal Leukoencephalopathy PML, a rare and often fatal opportunistic infection of the central nervous system (CNS), has been reported with systemic immunosuppressants, including another integrin receptor antagonist. PML is caused by the John Cunningham (JC) virus and typically only occurs in patients who are immunocompromised. One case of PML in an ENTYVIO-treated patient with multiple contributory factors has been reported in the postmarketing setting (e.g., human immunodeficiency virus [HIV] infection with a CD4 count of 300 cells/mm3 and prior and concomitant immunosuppression). Although unlikely, a risk of PML cannot be ruled out. Monitor patients on ENTYVIO for any new onset, or worsening, of neurological signs and symptoms. Typical signs and symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes. The progression of deficits usually leads to death or severe disability over weeks or months. If PML is suspected, withhold dosing with ENTYVIO and refer to a neurologist; if confirmed, discontinue dosing permanently. Liver Injury There have been reports of elevations of transaminase and/or bilirubin in patients receiving ENTYVIO. In general, the combination of transaminase elevations and elevated bilirubin without evidence of obstruction is generally recognized as an important predictor of severe liver injury that may lead to death or the need for a liver transplant in some patients. ENTYVIO should be discontinued in patients with jaundice or other evidence of significant liver injury [see Adverse Reactions]. Live and Oral Vaccines Prior to initiating treatment with ENTYVIO, all patients should be brought up to date with all immunizations according to current immunization guidelines. Patients receiving ENTYVIO may receive non-live vaccines (e.g., influenza vaccine injection) and may receive live vaccines if the benefits outweigh the risks. There are no data on the secondary transmission of infection by live vaccines in patients receiving ENTYVIO [see Adverse Reactions].

ADVERSE REACTIONS The following topics are also discussed in detail in the Warnings and Precautions section: • Infusion-Related Reactions and Hypersensitivity Reactions [see Warnings and Precautions] • Infections [see Warnings and Precautions] • Progressive Multifocal Leukoencephalopathy [see Warnings and Precautions] • Liver Injury [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 trials of another drug and may not reflect the rates observed in practice. The data described below reflect exposure to ENTYVIO in 3,326 patients and healthy volunteers in clinical trials, including 1,396 exposed for greater than one year, and 835 exposed for greater than two years. The safety data described in Table 2 are derived from four controlled Phase 3 trials (UC Trials I and II, and CD Trials I and III); data from patients receiving open-label ENTYVIO treatment at Weeks 0 and 2 (prior to entry into UC Trial II and CD Trial III) and from Weeks 6 to 52 (non-responders at Week 6 of UC Trial I and CD Trial I) are included. In these trials, 1,434 patients received ENTYVIO 300 mg for up to 52 weeks, and 297 patients received placebo for up to 52 weeks. Of these, 769 patients had ulcerative colitis and 962 patients had Crohn’s disease. Patients were exposed for a mean duration of 259 days (UC Trials I and II) and 247 days (CD Trials I and III). Adverse reactions were reported in 52% of patients treated with ENTYVIO and 45% of patients treated with placebo (UC Trials I and II: 49% with ENTYVIO and 37% with placebo; CD Trials I and III: 55% with ENTYVIO and 47% with placebo). Serious adverse reactions were reported in 7% of patients treated with ENTYVIO compared to 4% of patients treated with placebo (UC Trials I and II: 8% with ENTYVIO and 7% with placebo; CD Trials I and III: 12% with ENTYVIO and 9% with placebo). The most common adverse reactions (reported by ≥3% of patients treated with ENTYVIO in the UC Trials I and II and CD Trials I and III combined group and ≥1% higher than in combined placebo group) were nasopharyngitis, headache, arthralgia, nausea, pyrexia, upper respiratory tract infection, fatigue, cough, bronchitis, influenza, back pain, rash, pruritus, sinusitis, oropharyngeal pain and pain in extremities (Table 2). Table 2. Adverse Reactions in ≥3% of ENTYVIO-Treated Patients and ≥1% Higher than in Placebo (UC Trials I and II* and CD Trials I and III*) ENTYVIO† (N=1434)

Placebo‡ (N=297)

Nasopharyngitis Headache

13% 12%

7% 11%

Adverse Reaction

Arthralgia

12%

10%

Nausea

9%

8%

Pyrexia

9%

7%

Upper respiratory tract infection

7%

6%

Fatigue

6%

3%

Cough

5%

3%

Bronchitis

4%

3%

Influenza

4%

2%

Back pain

4%

3%

Rash

3%

2%

Pruritus

3%

1%

Sinusitis

3%

1%

Oropharyngeal pain

3%

1%

Pain in extremities

3%

1%

*Data from patients receiving open-label ENTYVIO treatment at Weeks 0 and 2 (prior to entry into UC Trial II and CD Trial III) and from Weeks 6 to 52 (non-responders at Week 6 of UC Trial I and CD Trial I) are included. † Patients who received ENTYVIO for up to 52 weeks. ‡ Patients who received placebo for up to 52 weeks.

Safety data for patients (n=279) in UC Trials I and II and CD Trials I and III who received ENTYVIO at Weeks 0 and 2 and were then randomized to placebo at Week 6 for up to 52 weeks, and for patients (n=416) in CD Trial II, a 10 week Crohn’s disease trial, are similar to those listed in Table 2.


Infusion-Related Reactions and Hypersensitivity Reactions Serious infusion-related reactions and hypersensitivity reactions including anaphylaxis have been reported following ENTYVIO administration in clinical trials [see Warnings and Precautions]. In UC Trials I and II and Crohn’s Trials I and III, one case of anaphylaxis [one out of 1,434 patients treated with ENTYVIO (0.07%)] was reported by a Crohn’s disease patient during the second infusion (symptoms reported were dyspnea, bronchospasm, urticaria, flushing, rash and increased blood pressure and heart rate) and was managed with discontinuation of infusion and treatment with antihistamine and intravenous hydrocortisone. In UC Trials I and II and CD Trials I and III, 4% of patients treated with ENTYVIO and 3% of patients treated with placebo experienced an infusion-related reaction (IRR). The most frequently observed IRR in the patients treated with ENTYVIO (reported more than twice) were nausea, headache, pruritus, dizziness, fatigue, infusion-related reaction, pyrexia, urticaria and vomiting (each of these adverse reactions occurred in <1% in all patients treated with ENTYVIO) and no individual adverse reaction reported occurred at a rate above 1%. These reactions generally occurred within the first two hours after the infusion and resolved with no treatment or following antihistamine and/or IV hydrocortisone treatment. Less than 1% of patients treated with ENTYVIO had IRRs assessed by the investigator as severe, and IRRs requiring discontinuation of study treatment occurred in <1%. In clinical trials, for patients with mild IRRs or hypersensitivity reactions, physicians were allowed to pretreat with standard medical treatment (e.g., antihistamine, hydrocortisone and/or acetaminophen) prior to next infusion. Infections In UC Trials I and II and CD Trials I and III, the rate of infections was 0.85 per patient-year in the patients treated with ENTYVIO and 0.7 per patient-year in the patients treated with placebo [see Warnings and Precautions]. The infections consisted primarily of nasopharyngitis, upper respiratory tract infection, sinusitis and urinary tract infection. Two percent of patients discontinued ENTYVIO due to infections. In UC Trials I and II and CD Trials I and III, the rate of serious infections was 0.07 per patient-year in patients treated with ENTYVIO and 0.06 per patient-year in patients treated with placebo. Serious infections were more common in Crohn’s disease patients than ulcerative colitis patients, and anal abscesses were the most frequently reported serious adverse reaction in Crohn’s disease patients. Over 48 months, there was no increase in the rate of serious infections. In controlled- and open-label long-term extension trials in adults treated with ENTYVIO, serious infections have been reported, including anal abscess, sepsis (some fatal), tuberculosis, salmonella sepsis, Listeria meningitis, giardiasis and cytomegaloviral colitis. In UC Trials I and II and CD Trials I and III, sepsis, including bacterial sepsis and septic shock, was reported in four of 1,434 (0.3%) patients treated with ENTYVIO and in two of 297 patients treated with placebo (0.7%). During these trials, two Crohn’s disease patients treated with ENTYVIO died due to reported sepsis or septic shock; both patients had significant comorbidities and a complicated hospital course that contributed to the deaths. In an open-label, long-term extension trial, additional cases of sepsis (some fatal), including bacterial sepsis and septic shock, were reported. The rate of sepsis in patients with ulcerative colitis or Crohn’s disease receiving ENTYVIO was two per 1,000 patient-years. In clinical trials, all patients were screened for tuberculosis. One case of latent, pulmonary tuberculosis was diagnosed during the controlled trials with ENTYVIO. Additional cases of pulmonary tuberculosis were diagnosed during the open-label trial. All of these observed cases occurred outside the United States, and none of the patients had extrapulmonary manifestations. Liver Injury There have been reports of elevations of transaminase and/or bilirubin in patients receiving ENTYVIO [see Warnings and Precautions]. In UC Trials I and II and CD Trials I and III, three patients reported serious adverse reactions of hepatitis, manifested as elevated transaminases with or without elevated bilirubin and symptoms consistent with hepatitis (e.g., malaise, nausea, vomiting, abdominal pain, anorexia). These adverse reactions occurred following two to five ENTYVIO doses; however, based on case report information it is unclear if the reactions indicated drug-induced or autoimmune etiology. All patients recovered following discontinuation of therapy with some requiring corticosteroid treatment. In controlled trials, the incidence of ALT and AST elevations ≥3x ULN was <2% in patients treated with ENTYVIO and in patients treated with placebo. In the open-label trial, one additional case of serious hepatitis was observed. Malignancies In UC Trials I and II and CD Trials I and III, malignancies (excluding dysplasia and basal cell carcinoma) were reported in six of 1,434 (0.4%) patients treated with ENTYVIO, including colon cancer (n=2), transitional cell carcinoma (n=1),

breast cancer (n=1), carcinoid tumor of the appendix (n=1) and squamous cell carcinoma (n=1). Malignancy was reported in one of 297 (0.3%) patients treated with placebo (squamous cell carcinoma). Malignancies (excluding dysplasia and basal cell carcinoma) observed during the ongoing open-label long-term extension trial included B-cell lymphoma, breast cancer, colon cancer, malignant hepatic neoplasm, malignant lung neoplasm, malignant melanoma, lung cancer of primary neuroendocrine carcinoma, renal cancer and squamous cell carcinoma. Overall, the number of malignancies in the clinical trials was small; however, long-term exposure was limited. Live and Oral Vaccines There are no data on the secondary transmission of infection by live vaccines in patients receiving ENTYVIO. In a placebo-controlled study of healthy volunteers, 61 subjects were given a single ENTYVIO 750 mg dose (2.5 times the recommended dose), and 62 subjects received placebo followed by intramuscular vaccination with Hepatitis B surface antigen and oral cholera vaccine. After intramuscular vaccination with three doses of recombinant Hepatitis B surface antigen, those treated with ENTYVIO did not have lower rates of protective immunity to Hepatitis B virus. However, those exposed to ENTYVIO did have lower seroconversion rates and anti-cholera titers relative to placebo after receiving the two doses of a killed, oral cholera vaccine. The impact on other oral vaccines and on nasal vaccines in patients is unknown. Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. 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, comparison of the incidence of antibodies to vedolizumab in the studies described below with the incidence of antibodies in other studies or to other products may be misleading. In UC Trials I and II and CD Trials I and III, in patients who received ENTYVIO, the frequency of antibodies detected in patients was 13% at 24 weeks after the last dose of study drug (greater than five half-lives after last dose). During treatment, 56 of 1,434 (4%) of patients treated with ENTYVIO had detectable anti-vedolizumab antibody at any time during the 52 weeks of continuous treatment. Nine of 56 patients were persistently positive (at two or more study visits) for anti-vedolizumab antibody and 33 of 56 patients developed neutralizing antibodies to vedolizumab. Among eight of these nine subjects with persistently positive anti-vedolizumab antibody and available vedolizumab concentration data, six had undetectable and two had reduced vedolizumab concentrations. None of the nine subjects with persistently positive anti-vedolizumab antibody achieved clinical remission at Weeks 6 or 52 in the controlled trials. Postmarketing Experience The following adverse reactions have been identified during post-approval use of ENTYVIO. 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. Immune system disorders: Anaphylaxis [see Warnings and Precautions] DRUG INTERACTIONS Natalizumab Because of the potential for increased risk of PML and other infections, avoid the concomitant use of ENTYVIO with natalizumab. TNF Blockers Because of the potential for increased risk of infections, avoid the concomitant use of ENTYVIO with TNF blockers. Live Vaccines Live vaccines may be administered concurrently with ENTYVIO only if the benefits outweigh the risks [see Warnings and Precautions]. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ENTYVIO during pregnancy. Information about the registry can be obtained by calling 1-877-TAKEDA7 (1-877-825-3327). Risk Summary Available pharmacovigilance data, data from the ongoing pregnancy registry, and data from published case reports and cohort studies in pregnant women have not identified an ENTYVIO associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. There are risks to the mother and the fetus associated with inflammatory bowel disease in pregnancy (see Clinical Considerations). No fetal harm was observed in


animal reproduction studies with intravenous administration of vedolizumab to rabbits and monkeys at dose levels 20 times the recommended human dosage (see Data). The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and miscarriage is 15 to 20%, respectively. Clinical Considerations Disease-associated maternal and embryo/fetal risk Published data suggest that the risk of adverse pregnancy outcomes in women with inflammatory bowel disease (IBD) is associated with increased disease activity. Adverse pregnancy outcomes include preterm delivery (before 37 weeks of gestation), low birth weight (less than 2,500 g) infants, and small for gestational age at birth. Fetal/Neonatal adverse reactions ENTYVIO administered during pregnancy could affect immune responses in the in utero exposed newborn and infant. The clinical significance of low levels of ENTYVIO in utero-exposed infants is unknown. The safety of administering live or live-attenuated vaccines in exposed infants is unknown. Data Animal Data A reproduction study has been performed in pregnant rabbits at single intravenous doses up to 100 mg/kg administered on gestation Day 7 (about 20 times the recommended human dosage) and has revealed no evidence of impaired fertility or harm to the fetus due to vedolizumab. A pre- and post-natal development study in monkeys showed no evidence of any adverse effect on pre- and post-natal development at intravenous doses up to 100 mg/kg (about 20 times the recommended human dosage). Lactation Risk Summary Available published literature suggests the presence of vedolizumab in human milk. The effects of local gastrointestinal exposure and expected low systemic exposure to vedolizumab on the breastfed infant are unknown. There are no data on the effects of vedolizumab on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ENTYVIO and any potential adverse effects on the breastfed infant from ENTYVIO or from the underlying maternal condition. Pediatric Use Safety and effectiveness of ENTYVIO in pediatric patients have not been established. Geriatric Use Clinical trials of ENTYVIO did not include sufficient numbers of subjects aged 65 and over (46 Crohn’s and ulcerative colitis patients aged 65 and over were treated with ENTYVIO during controlled Phase 3 trials) to determine whether they respond differently from younger subjects. However, no overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients. Manufactured by: Takeda Pharmaceuticals America, Inc. Deerfield, IL 60015 U.S. License No. 1898 Revised: March 2020 ENTYVIO is a trademark of Millennium Pharmaceuticals Inc. and is used under license by Takeda Pharmaceuticals America, Inc. All other trademark names are the property of their respective owners. ©2014 – 2020 Takeda Pharmaceuticals America, Inc. For more information, go to www.ENTYVIO.com or call 1-877-TAKEDA-7 (1-877-825-3327). VMB245 R4_Brf04/20


Wet Age-Related Macular Degeneration: Changing reatment Landscape and Impact merging therapies including biosimilars will present new opportunities and challenges in the management of wAMD Age-related macular degeneration (AMD) is an eye disease that impacts 11 million Americans and 170 million worldwide.1 Specifically cases of wet AMD (wAMD) are anticipated to increase to million in the U S by wAMD costs the healthcare industry 6 billion annually and costs are expected to increase proportionate to prevalence.

Sneha Sharma, Pharm.D. Clinical Medical Pharmacy Liaison Magellan Rx Management

wAMD occurs due to macular damage of the retina and is the leading cause of se ere ision loss in the he condition is characterized by new abnormal blood essels growing under the retina which U.S. may leak blood or other fluids and result in scarring of the macula wAMD leads to blurriness in ision which causes a continual loss of central ision as well as macular changes when left untreated Risk factors include ha ing a poor diet being o erweight smoking being older than ha ing high blood pressure and ha ing a family history of the disease

Current Treatment Considerations for wAMD wAMD is a chronic disease that while treatable is not curable he goal of treatment is to achie e and maintain a dry macula Current a ailable first-line treatments for wAMD are anti- ascular endothelial growth factor ( GF) in ectable drugs including compounded or reconstituted be acizumab (A astin®) which is not FDA-appro ed for use but accepted as standard of care aflibercept ( L A®) ranibizumab (LUC N IS®) pegaptanib (Macugen®) and brolucizumab-dbll (B O U®).1 Mihir Patel, Pharm.D. Vice President, Pharmacy Services PacificSource

he standard of care for patients with wAMD is typically be acizumab (dosed e ery four weeks) ranibizumab (dosed e ery four weeks) or aflibercept (dosed e ery eight weeks) While brolucizumab may be dosed up to e ery weeks pro ider input has indicated this drug is being used as a last line due to the associated risk of intraocular inflammation compared to a risk in the other preferred drugs. Additionally pegaptanib (Macugen®) has very little utilization.

Visit us online at magellanrx.com/mrxreport | 13


WET AMD | Continued

Table 1. Cost of Anti-VEGF Therapies Drug

A D Dose and re uency

bevacizumab (Avastin ) ®

aflibercept (

L A®)

mg monthly mg monthly for first mg e ery weeks

ranibizumab (LUC N IS®)

mg monthly

pegaptanib (Macugen®)

mg e ery 6 weeks

Brolucizumab-dbll (B O U®)

6 mg monthly for first 6 mg e ery weeks

Cost/Dose (ASP+6%)

Annual Cost per ye

6 doses then

6

6

doses then

o reduce in ection burden in patients with wAMD two anti- GF treatment approaches ha e been used treat-and-extend ( ) and pro re nata (PRN) 6 he approach extends the dosing inter al in two-week increments to a maximum of to 6 weeks and if disease acti ity is obser ed the inter al will be reduced accordingly Using the PRN approach patients must comply with monthly monitoring but in ections are delayed unless recurrent disease acti ity is obser ed; the key to successful PRN approach is frequent consistent monitoring.6

is expected to continue 10 From to 6 the number of ophthalmic drug in ections increased from to million.11 In Medicare Ad antage the ophthalmic in ections aflibercept and ranibizumab are the fourth- and fifth-highest in spend with increases of and respecti ely since the pre ious year According to the Magellan Rx Management Medical Pharmacy rend Report ophthalmic anti- GF in ections were the second-highest per member per month (PMPM) Medicare cost for medical benefit drugs in behind oncology

ach a ailable therapy has been pro en effecti e to treat wAMD; the differences between options are regimen and safety profiles Clinical trials practice training and patient status commonly factor into the choice of drug Be acizumab although off-label for wAMD is endorsed by the American Academy of Ophthalmology (AAO) and is widely used 7 Howe er there are some concerns about compounding the drug including inconsistent potency particulate contamination in syringes and syringe malfunctions 8 hus while bevacizumab is a clinically appropriate drug and recommended by the AAO it is not a preference for many pro iders due to the offlabel use and the concern regarding compounding.

he cost for ophthalmic drug therapy ranges from to per eye annually his cost does not include o ce isits imaging by optical coherence tomography to measure disease progression transportation concerns or any other associated or indirect costs See able for a breakdown of cost per ophthalmic drug

arly diagnosis and patient education are key for effecti e treatment of wAMD reatment duration and access to isits can present a challenge to some patients especially gi en the intraocular route of administration 9 Patients must be aware of the importance of treatment adherence and persistence; adherence concerns may weigh into the therapy decision-making process for pro iders 9

Treatment Costs wAMD and associated therapies are a Medicare top 10 spend in drug therapy Centers for Medicare Medicaid Ser ices (CMS) data from shows the spend for aflibercept was more than billion making it the top drug spend in 6 and this trend

14 Magellan Rx Report Spring

Biosimilar Pipeline Se eral biosimilars of ophthalmic drugs are in de elopment Be acizumab- ikg (L NA A® Outlook herapeutics) is currently in phase three trials and is the first anticipated launch The initial trial was a superiority trial comparing bevacizumab-vikg to ranibizumab. It demonstrated well-tolerated safety with no ocular ad erse e ents related to inflammation and outcomes reported were a three-line visual acuity gain. he phase three trial is ongoing with results expected in of Biosimilars for ranibizumab (Lupin and Formycon) and aflibercept (Biogen and Amgen) are undergoing phase three trials as well.

Other Emerging Therapies Abicipar pegol15, 16 Abicipar pegol (Allergan) is a smaller molecule recombinant DARPin


Table 2. wAMD Biosimilar Pipeline14 Drug

Company

be acizumab- ikg (L F B SB-

NA A ) ®

(ranibizumab biosimilar) (aflibercept biosimilar)

Mechanism of Action

oute of Dosage

Status

Outlook herapeutics

Anti-

GF

I

phase three

Formycon; Santo Holding

Anti-

GF

I

phase three

Samsung Bioepis; Biogen

Anti-

GF

I

phase three

ABP

(aflibercept biosimilar)

Amgen

Anti-

GF

I

phase three

SCD

(aflibercept biosimilar)

Sam Chun Dung

Anti-

GF

I

phase three

Lupin

Anti-

GF

I

phase three

LUB

(ranibizumab biosimilar)

protein In une the FDA issued a Complete Response Letter (CRL) in response to the biologics license application for abicipar pegol he CRL indicated that the rate of intraocular inflammation obser ed following the administration of mg ml of abicipar pegol in the phase three studies resulted in an unfa orable benefitrisk in the treatment of wAMD he rate of reported intraocular inflammation was about ; Allergan is further studying abicipar pegol in a MAPL study with the ob ecti e to remo e drug impurities to reduce drug-induced inflammation

Faricimab17 Faricimab (Roche) has two mechanisms of action anti- GF and Ang- to help reduce inflammation due to increased receptor binding In the phase two S AIR A trial faricimab demonstrated clinically meaningful isual-acuity gains at a 6 mg dose from baseline to se en letters and fluid reductions at 6 weeks dosing compared to ranibizumab e ery four weeks he trial included 6 treatment-na e patients; two patients recei ing faricimab reported intraocular inflammation As the patient population for trials increases the rate of this ad erse e ent may be impacted

Ranibizumab Port Delivery System18 The ranibizumab port delivery system is under phase three and extension studies within ARCH A comparing the implant to ranibizumab he port is the size of a grain of rice but it requires surgery. The previous study ladder was done with treatmentexperienced patients In phase two of the study patients showed to be dose-dependent with the high-concentration dosing arm having the best outcomes in visual acuity. The high-dose arm had similar results to ranibizumab administered ia I and was well tolerated with inflammation Results were similar in safety and

e cacy to mg of ranibizumab Ranibizumab in ANCHOR and MARINA studies had less than inflammation rates he port would require refill e ery six months

Potential Impact and Payer Considerations Despite the substantial patient burden of wAMD a reported to of Medicare patients treated with anti- GF discontinue treatment.19 Hesitance about in ections and lack of patient education can lead to the discontinuation of anti- GF treatment; howe er cost is often a ma or factor in this decision As the anti- GF treatment becomes increasingly competitive with the development and imminence of biosimilars for aflibercept and ranibizumab the burden of cost on patients may become more manageable Medicare member coinsurance could ary for the biosimilar due to lack of pricing standardization he price will determine Medicare patients coinsurance which could potentially result in Medicare patients ha ing higher out-of-pocket spend for biosimilars than commercially insured patients As in any specialty space there are patient-assistance programs set up such as Health ell CDF and PANF that may help patients with out-of-pocket expenses Howe er pricing for biosimilars will need to be monitored and formulary management strategies should be used to help alle iate any disparities. Management strategies should be developed using historical utilization patterns and step therapy programs should be considered along with recommendations from key opinion leaders and pro ider-focused education regarding wAMD and the broader ophthalmology market As the pre alence of wAMD increases more drugs in the pipeline will create a more competitive landscape where biosimilar drugs and pricing strategies will help to lower costs.

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WET AMD | Continued

References 1.

“Age-Related Macular Degeneration (AMD) Data and Statistics.” National Institute of Health uly https www nei nih go learn-about-eye-health resources-for-health-educators eye-healthdata-and-statistics age-related-macular-degeneration-amd-dataand-statistics.

Medical Pharmacy rend Report Magellan Rx Management https www magellanrx com documents mrx-medicalpharmacy-trend-reportpdf Outlook herapeutics Doses First Patient in the Second Phase Clinical rial for ONSin et AMD Outlook herapeutics uly 6 https www globenewswire com newsrelease 6 en outlook-therapeutics-dosesfirst-patient-in-the-second-phase- -clinical-trial-for-ons-inwet-amd.html

Pennington atie and Margaret DeAngelis pidemiology of age-related macular degeneration (AMD): associations with cardio ascular disease phenotypes and lipid factors ye and ision 6 https www ncbi nlm nih go pmc articles PMC

IPD Analytics http

Boyd ierstan hat Is Macular Degeneration American Academy of Ophthalmology an 6 https www aao org eye-health diseases amd-macular-degeneration

Allergan an Abb ie Company and Molecular Partners Recei e Complete Response Letter from FDA on Biologics License Application for Abicipar pegol Abb ie une 6 https news abb ie com news press-releases allergan-an-abb iecompany-and-molecular-partners-receive-complete-responseletter-from-fda-on-biologics-license-application-for-abicipar-pegol htm.

homas Michael et al Comparati e effecti eness of aflibercept for the treatment of patients with neo ascular age-related macular degeneration Clinical Ophthalmology Mar https www ncbi nlm nih go pmc articles PMC Mon s ordi et al Risk of Inflammation Retinal asculitis and Retinal Occlusion-Related ents with Brolucizumab Post Hoc Re iew of HA and HARRI R American Academy of Ophthalmology No https www aao ournal org article S 6 -6 ( ) - fulltext 6

Baumal Caroline et Age-Related Macular Degeneration reatment Ad ances to Reduce the In ection Burden A MC May https www a mc com iew wet-agerelated-maculardegeneration-treatment-ad ances-to-reduce-the-in ection-burden

7.

Ge er ohn AAO Be acizumab ops Anti- GF Choice in AMD MedPage oday Oct https www medpagetoday org meetingco erage aao 6 pass=

8.

anderBeek Brian et al he association between compounding be acizumab and post-in ection endophthalmitis AMA Ophthalmolog Oct https www ncbi nlm nih go pmc articles PMC 6 6

9.

Gerson effry How arly Diagnosis Can Impro e AMD Outcomes Re iew of Optometry Sept https www re iewofoptometry com article how-early-diagnosis-can-impro eamd-outcomes.

10.

Medicare Part B Drug Spending Dashboard Centers for Medicare Medicaid Ser ices Oct www cms go Research-StatisticsData-and-Systems Statistics- rends-and-Reports Information-onPrescription-Drugs MedicarePartB

11. Ginsburg Paul and George illiams reatment-Specific Payment Approaches he Case of Macular Degeneration HealthAffairs No https www healthaffairs org do hblog 66 full

16 Magellan Rx Report Spring

ipdanalytics com

6

unimoto Derek et al cacy and Safety of Abicipar in Neo ascular Age-Related Macular Degeneration Ophthalmology Oct https pubmed ncbi nlm nih go

17.

hanani A et al cacy of ery Four Monthly and uarterly Dosing of Faricimab s Ranibizumab in Neo ascular Age-Related Macular Degeneration he S AIR A Phase Randomized Clinical rial AMA Ophthalmology https www semanticscholar org paper cacy-of- ery-Four-Monthly-and- uarterly-Dosinghanani-Patel b db 6 e b ecfc6 6cd dce fddc cf

18.

Phase III data shows Roche s Port Deli ery System with ranibizumab enabled o er of patients to go six months between treatments for neo ascular age-related macular degeneration Roche uly https www globenewswire com news-release 66 6 en Phase-III-datashow-Roche-s-Port-Delivery-System-with-ranibizumab-enabledo er- -of-patients-to-go-six-months-between-treatments-forneovascular-age-related-macular-degeneration.html.

19. Mulligan aren et al conomic alue of Anti- ascular ndothelial Growth Factor reatment for Patients with et Age-Related Macular Degeneration in the United States AMA Ophthalmology an https www ncbi nlm nih go pmc articles PMC6 6 text=Approximately to of treatment within the first year text=Although cost is cited as therapies is a ailable off Dlabel


Mental Health Update: Digital herapeutics Drug Pipeline and COVID-19 Impact The mental health space has seen many advances in the development of digital therapies and robust pipelines across many indications as well as challenges brought on by the CO ID- pandemic The public health crisis throughout the past year has made the importance of mental health management more apparent than e er ith an e er-expanding digital therapeutics offering and pipeline treatment innovations for an array of mental health conditions are on the horizon.1 The mental health space is also experiencing broad pipelines for depression schizophrenia and bipolar disorder As an increasing number of individuals are reporting a negative impact on their mental health due to the COVID-19 pandemic treatment and inter entions will be prioritized in the coming years as the world reco ers from the pandemic and its long-lasting implications.

Digital Therapeutics in Mental Health Stacy Inman, Pharm.D. Senior Clinical Project Manager Magellan Method

Digital therapeutics defined by the Digital herapeutics Alliance as e idence-based therapeutic inter entions dri en by high-quality software programs to pre ent manage or treat a medical disorde or disease are changing the landscape of mental health management and increasing access to care Generally these therapeutics enable therapy by expanding the role of human support Specifically digital therapeutics ha e emerged as a new method of pre enting managing or treating chronic beha ior-modifiable disease Digital therapeutics are currently in de elopment for a wide range of mental health or beha ioral health conditions including substance-use disorder opioid-use disorder chronic insomnia schizophrenia attention deficit hyperacti ity disorder autism spectrum disorder ma or depressi e disorder post-traumatic stress disorder generalized anxiety and more See able for some therapies currently in the digital therapeutics pipeline. he utility of digital therapeutics has become more apparent with the ongoing CO ID- pandemic In light of this the Food and Drug Administration (FDA) issued final guidance on the enforcement policy 4 for digital health de ices for the treatment of psychiatric disorders during CO IDin April The guidance intended to expand availability to digital health devices and applied to computerized beha ioral therapy de ices and other health de ices for psychiatric disorders as well as low-risk wellness and digital health products for mental health or psychiatric conditions.4 The guidance made clear

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MENTAL HEALTH UPDATE | Continued

that the policy is intended to remain in effect for the duration of the CO ID- public health emergency; howe er patient and proider preference for these modalities may increase with more access and use.4

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Therapy Pipeline Despite a diverse array of available therapies for mental health conditions clinicians still look to no el agents in hopes of improved outcomes.5 The current psychiatric pipeline is robust across depression schizophrenia and bipolar disorder and shows potential inno ati e treatments he pipeline promises new therapies that draw upon established mechanisms of action as well as therapeutic ad ances to potentially pro ide hope for effecti e treatment to patients with suboptimal outcomes 5 The pipeline across these mental health conditions can be found in Tables 2-4.

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Table 1. Digital Therapeutics Pipeline3 Product reS

Company

Indication

Status

Pear herapeutics

substance use disorder

marketed

Pear herapeutics

opioid use disorder

marketed

Pear-

Pear herapeutics

schizophrenia

marketed

modia

Orexo

substance use disorder

-

deprexis

Orexo

major depressive disorder

-

Akili Interacti e Labs

attention deficit hyperacti ity disorder

marketed

A L-

Akili Interacti e Labs

autism spectrum disorder

pilot

A L-

Akili Interacti e Labs

major depressive disorder

pilot

NightWare

NightWare

post-traumatic stress disorder

marketed

CT-152

Click herapeutics

major depressive disorder

pivotal

Autism Diagnostic

Cognoa

autism spectrum disorder

pivotal

Autism herapeutic

Cognoa

autism spectrum disorder

feasibility

Anxiety Rx

Applied R

generalized anxiety

discovery

Happify

Happify Health

multiple sclerosis-associated depression and anxiety

discovery

reS

-O

ndea orRx

*Marketed temporarily under the FDA Enforcement Policy for Digital Health Devices for Treating Psychiatric Disorders During the Coronavirus Disease 2019 (COVID-19) Public Health Emergency

18 Magellan Rx Report Spring


Table 2. Depression Pipeline6 Drug

Manufacturer

SAG AXS-

(zuranolone) (bupropion; dextromethorphan)

R L-

(d-Methadone)

Type

Indication

Status

Sage herapeutics

GABA Modulators

MDD; PPD

phase three

Axsome herapeutics

NDRI

MDD

phase three phase three

Relmada Therapeutics

NMDA receptor antagonist

MDD

L

(ansofaxine hydrochloride)

Luye Pharma

NDRI

MDD

MIN-

(seltorexant)

Minerva Neurosciences; Janssen

Orexin receptor antagonist

MDD

phase three

NeuroRx

atypical antipsychotic; NMDA receptor agonist

depressive episodes in bipolar I disorder

phase three

Allergan; Abb ie

atypical antipsychotic

MDD

phase three

Indication

Status

Cyclurad (D-cycloserine; lurasidone) RA LAR (cariprazine hydrochloride)

anuary

Table 3. Schizophrenia Pipeline6 Drug

Manufacturer

Type

Minerva Neurosciences; Mitsubishi Tanabe

-H A serotonin receptor antagonist

schizophrenia

phase three

Suno ion Pharmaceuticals

-H A serotonin receptor agonist

schizophrenia

phase three

Nuplazid (pima anserin tartrate)

Acadia Pharmaceuticals

atypical antipsychotic

schizophrenia

phase three

PP6M (paliperidone palmitate)

Janssen

atypical antipsychotic

schizophrenia

pending September

Risperidone ISM

Ro i Pharmaceuticals

atypical antipsychotic

schizophrenia

pending

e a Pharmaceuticals; MedinCell

atypical antipsychotic

schizophrenia

phase three

MRA

schizophrenia

phase three

Indication

Status

MIN-

(roluperidone)

S P- 6

6

6

(risperidone)

arX (xanomeline and trospium)

aruna herapeutics

Table 4. Bipolar Disorder Pipeline6 Drug

Manufacturer

Type

Cyclurad (D-cycloserine; lurasidone)

NeuroRx

atypical antipsychotic; NMDA receptor agonist

bipolar disorder

phase three

CAPL A (lumateperone tosylate)

Intra-Cellular herapies; Bristol Myers Squibb

atypical antipsychotic

bipolar disorder

phase three

BXCL (dexmedetomidine hydrochloride)

BioXcel herapeutics

selective alpha2adrenoreceptor agonist sedative

bipolar disorder

phase three

RA LAR (cariprazine hydrochloride)

Allergan; Abb ie

atypical antipsychotic

bipolar disorder

phase three

ndoxifen

ina Pharmaceuticals; Intas Pharmaceuticals

selective estrogen receptor modulator

bipolar disorder

phase three

G ODON (ziprasidone hydrochloride)

Pfizer

atypical antipsychotic

bipolar disorder

phase three

R XUL I (brexpiprazole)

H Lundbeck A S; Otsuka

atypical antipsychotic

bipolar disorder

phase three

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MENTAL HEALTH UPDATE | Continued

Managed Care Implications

53% of adults in the U.S. reported that stress and worry due to the pandemic have negatively impacted their mental health, compared to 32% in March 2020.

Impact of COVID-19 According to a uly aiser Family Foundation poll of adults in the U S reported that stress and worry due to the pandemic ha e negati ely impacted their mental health compared to in March As the pandemic and resulting economic social and physical implications continue mental health challenges will persist and new barriers will arise for those who already suffered from mental illness or substance-use disorders Another report from the U S Centers for Disease Control and Pre ention noted that anxiety symptoms tripled and depression symptoms quadrupled among adults sur eyed when compared to a survey; two additional studies from April reported that depressi e symptoms and serious psychological distress were three times that measured in Across studies and reports those most affected were those with preexisting mental health issues low-income indi iduals people of color those close to someone who suffered or died from CO IDthose with Asian ethnicity and young adults ages to Income insecurity ob loss grief fear of illness and social isolation are all belie ed to contribute to the negative mental health impact on society. hile this impact is closely tied to the pandemic the implications for mental health are likely to be long-term particularly for those at risk for new or exacerbated mental health challenges It is currently unclear the extent to which the number of those reporting negati e mental health symptoms will increase; howe er if the current trend continues the o erall impact will likely ha e a substantial impact on healthcare Both those who li ed with mental illness or substance-use disorders prior to the pandemic and those who are newly a icted from the pandemic will likely require mental healthcare and management in a post-pandemic world heightening the need for treatment options and access to care for an expanded patient population.

20 Magellan Rx Report Spring

Mo ing forward there will likely be a long-term shift in both the management of mental health and the needs in this space. The promising drug pipeline across mental health indications coupled with the increased utilization and access to digital therapeutics will face payers with both opportunities for better outcomes as well as a need for effecti e management Additionally the broadening population of those who will benefit from mental health treatment and solutions will increase the importance of prioritizing strategic solutions and management in this space.

References 1.

Patel Nisarg and Atul Butte Characteristics and challenges of the clinical pipeline of digital therapeutics Nature Dec https www nature com articles s 6-

2.

Pan uan- u et al he mental health impact of the CO IDpandemic on people with and without depressi e anxiety or obsessive-compulsive disorders: a longitudinal study of three Dutch case-control cohorts he Lancet Psychiatry Feb https www thelancet com ournals lanpsy article PIIS 66( ) - fulltext Panchal Nirmita et al he Implications of CO ID- for Mental Health and Substance Use aiser Family Foundation Aug https www kff org corona irus-co idissue-brief theimplications-of-co id- -for-mental-health-and-substance-use

4.

nforcement Policy for Digital Health De ices for reating Psychiatric Disorders During the Corona irus Disease (CO ID- ) Public Health mergency Guidance for Industry and Food and Drug Administration Staff U S Food Drug Administration April https www fda go regulatoryinformation search-fda-guidance-documents enforcement-policydigital-health-devices-treating-psychiatric-disorders-duringcoronavirus-disease.

5.

Miller ohn he Psychiatric Pipeline Agents to atch Psychiatric imes an https www psychiatrictimes com iew psychiatric-pipeline- -agents-watch

6

IPD Analytics https

ipdanalytics com

Czeisler Mark et al Mental Health Substance Use and Suicidal Ideation During the CO ID- Pandemic United States une U S Centers for Disease Control and Pre ention eekly Aug https www cdc go mmwr olumes 6 wr mm6 a htm ttman Catherine et al Pre alence of Depression Symptoms in US Adults Before and During the CO ID- Pandemic AMA Netw Open Sept https amanetwork com ournals amanetworkopen fullarticle 6 9.

McGinty mma et al Psychological Distress and Loneliness Reported by US Adults in and April AMA une https amanetwork com ournals ama fullarticle 66


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Multiple Myeloma: reatment Update CAR- and Impact merging therapies for multiple myeloma especially CAR- could present exciting opportunities for impro ed outcomes; howe er payers will face challenges managing the associated high costs Multiple myeloma is a rare cancer that affects plasma cells found in the bone marrow where blood cells are made Plasma cells make antibodies that play a key role in helping the immune system fight off infection In patients with multiple myeloma their once-normal plasma cells mutate into cancerous cells that grow out of control and produce an abnormal antibody called M protein 2 As the cancerous cells continue to multiply they lea e little room for normal plasma cells his causes a decrease in red blood cells white blood cells and platelets which potentially leads to anemia excessi e bleeding and decreased ability to fight off infection Furthermore patients with multiple myeloma may experience bone damage hypercalcemia and kidney damage

Michele Bautista Meredith, Pharm.D. Director, Pharmacy Services Sharp Community Medical Group

In the U S an estimated people will be diagnosed with multiple myeloma and it will cause about deaths annually Many drug therapies that treat multiple myeloma are used in combination and therefore dri e the cost up astronomically high with a range of to per treatment 4 ith no cure to this cancer the goal is to pro ide patients with symptom management and help them maintain cancer remission

Current State of Treatment and Guidelines For multiple myeloma current treatments to help control symptoms and slow down disease progression include immunomodulators (lenalidomide pomalidomide thalidomide) proteasome inhibitors (bortezomib carfilzomib or ixazomib) corticosteroids monoclonal antibodies chemotherapy and for eligible patients hematopoietic stem cell transplant (HSC ) 5 For acti e multiple myeloma it is recommended to use triplet therapy to achie e the best response Hematopoietic stem cell transplant is usually suggested for patients under the age of 6 6 Howe er it is important to consider not only age but also the patient s physical health as high-dose chemotherapy is required before recei ing a hematopoietic stem cell transplant 6

22 | Magellan Rx Report | Spring 2021


Current treatments include immunomodulators, proteasome inhibitors, corticosteroids, monoclonal antibodies, chemotherapy, and, for eligible patients, hematopoietic stem cell transplant.

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National Comprehensi e Cancer Network (NCCN) Preferred Drug herapies for Acti e Symptomatic Multiple Myeloma 5 Stem Cell Transplant-Eligible • bortezomib lenalidomide dexamethasone • bortezomib cyclophosphamide dexamethasone Non-Stem Cell Transplant-Eligible • bortezomib lenalidomide dexamethasone • bortezomib cyclophosphamide dexamethasone • lenalidomide low-dose dexamethasone • daratumumab bortezomib melphalan prednisone Along with primary treatment ad uncti e therapy is used to impro e safety side effects or effecti eness of the primary treatment 5 hese ad uncti e therapies are specific to each patient based on the symptoms and side effects they experience with their treatment therapy:5 • Bisphosphonates (pamidronate or zoledronate) or denosumab for bone health • Drug treatment for high calcium le els • Plasmapheresis for hyper iscosity • rythropoietin for anemia • accines and treatments for infection • Blood thinners to pre ent blood clots • Drugs radiation therapy or surgery for bone pain • Liquids and possible plasmapheresis to re erse kidney damage

Newly Approved Therapies Selinexor (XPOVIO®) Selinexor (XPO IO®) manufactured by aryopharm herapeutics is an oral selecti e inhibitor of nuclear export (SIN ) that is used in combination with dexamethasone for patients with refractory disease 7 It works by binding and inhibiting the nuclear export protein XPO causing the accumulation of tumor-suppressor proteins in the cell nucleus 7 his results in increasing the cells tumorsuppressor functions which leads to selecti e apoptosis in cancer cells all while sparing the normal cells 7 he pi otal clinical study of selinexor S ORM was performed as a multicenter single-arm open-label study Selinexor was e aluated in patients with relapsed or refractory multiple myeloma who had pre iously recei ed three or more anti-myeloma treatments including an alkylating agent glucocorticoids bortezomib carfilzomib lenalidomide pomalidomide and an anti CD monoclonal antibody 7 he patients recei ed mg of selinexor in combination with mg of dexamethasone gi en on days one and three of each week 7 he appro al e cacy and safety of selinexor was based on the o erall response rate from a prespecified subgroup analysis of patients 7 reatment continued until the disease progressed or toxicity reached an unacceptable le el 7 he o erall response rate 7 was he median time to first response was four weeks and the median duration of the response was months 7

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MULTIPLE MYELOMA | Continued

(

mg for patients o er ) gi en on days one eight and his three-drug combination was gi en in -day cycles until the disease progressed or toxicity reached an unacceptable le el 9 Isatuximab-irfc s primary e cacy endpoint was progression-free sur i al (PFS) which is the amount of time the patient stays ali e without their cancer progressing 9 he isatuximab-irfc pomalidomide and dexamethasone group had a response rate of 6 and showed impro ement in PFS with a risk reduction of disease progression or death 9 Patients who recei ed pomalidomide and low-dose dexamethasone alone had a response 9 rate of he median duration of treatment was weeks for the isatuximab-irfc pomalidomide and dexamethasone group and weeks for the pomalidomide and dexamethasone group 9 9

CAR-T therapies are being investigated in clinical trials for patients with relapsed or refractory multiple myeloma and are showing positive results. This therapy functions by activating an individual’s immune system to fight against the cancer. In December selinexor was appro ed by the FDA for a new indication in combination with bortezomib and dexamethasone for the treatment of adult patients with multiple myeloma who ha e recei ed at least one prior therapy

Isatuximab-irfc (SARCLISA®) Isatuximab-irfc (SARCLISA®) manufactured by Sanofi is an IgG -deri ed monoclonal antibody that binds to CD and is expressed on the malignant multiple myeloma cells 9 Isatuximab-irfc causes apoptosis of tumor cells and acti ation of immune-effector mechanisms including antibody-dependent cell-mediated cytotoxicity (ADCC); antibody-dependent cellular phagocytosis (ADCP); and complement-dependent cytotoxicity (CDC) 9 Isatuximab-irfc also inhibits ADP-ribosyl cyclase acti ity of CD acti ates natural killer cells and suppresses CD positi e -regulatory cells 9 he e cacy and safety of Isatuximab-irfc was measured in combination with pomalidomide and low-dose dexamethasone compared to patients recei ing pomalidomide and low-dose dexamethasone alone 9 A phase three pi otal clinical trial ICARIA-MM was a multicenter multinational randomized open-label two-arm study that e aluated patients with relapsed and refractory multiple myeloma who had recei ed at least two pre ious therapies including lenalidomide and a proteasome inhibitor 9 he patients were randomized in a ratio to recei e mg kg of isatuximab-irfc ia I infusion weekly for the first cycle then e ery two weeks thereafter in combination with mg of pomalidomide taken orally on days one to each cycle and mg of dexamethasone

24 | Magellan Rx Report | Spring 2021

Belantamab mafodotin-blmf (BLENREP®) Belantamab mafodotin-blmf (BL NR P®) manufactured by GlaxoSmith line is an antibody drug con ugate (ADC) that binds to BCMA a protein that is expressed on multiple myeloma cells and normal B lymphocytes and that releases monomethyl auristatin F (MMAF) by proteolytic clea age 9 he released MMAF a microtubule inhibitor disrupts the microtubule network and results in cell-cycle arrest and apoptosis 10 he e cacy of belantamab mafodotin-blmf was studied in DR AMM- an open-label multicenter study in patients with refractory multiple myeloma who had recei ed three or more preious therapies 10 Patients recei ed mg kg or mg kg of belantamab mafodotin-blmf ia I once e ery three weeks until the disease progressed or toxicity reached an unacceptable le el 10 cacy was measured by the o erall response rate 10 he results only reflected the patients who recei ed the FDA-appro ed recommended dose of mg kg of belantamab mafodotin-blmf 10 he o erall response rate was ( CI ) 10 he median time to the first response was months and of responders had response durations of more than six months 10 Belantamab mafodotin-blmf has a black box warning of potential changes in the corneal epithelium that can result in ision alterations including se ere ision loss a corneal ulcer and symptoms such as blurred ision and dry eyes 10 Belantamab mafodotin-blmf is only a ailable through a restricted program under the FDAs Risk aluation and Mitigation Strategy (R MS) called the BL NR P R MS due to the ocular toxicity risks 10

CAR-T Therapies Chimeric antigen receptor -cell (CAR- ) therapy is a new treatment option that has demonstrated greatly impro ed remission rates in blood cancers such as B-cell acute lymphoblastic leukemia and


Idecabtagene vicleucel (ide-cel) is a CAR-T cell therapy that recognizes and binds to BCMA on the surface of multiple myeloma cells — leading to CAR-T cell proliferation, cytokine secretion, and cytolytic killing of BCMA-expressing cells.

B-cell non-Hodgkin lymphoma 11 CAR- therapies are being inestigated in clinical trials for patients with relapsed or refractory multiple myeloma and are showing positi e results 11 CAR- therapy functions by acti ating an indi idual s immune system to fight against the cancer 11 his is achie ed by remo ing the patient s -cells genetically engineering them to produce a surface-le el protein receptor with the ability to recognize and attack malignant cells and then re-infusing the -cells back into the patient 11 he most common target protein for CAR- therapy in multiple myeloma cells is B-cell maturation antigen (BCMA) 11

Pipeline Melflufen Melflufen is a peptide-drug con ugate that works by entering a cell to be broken down by aminopeptidases which releases alkylating agents and kills cells 12 Aminopeptidases are produced in excessi e amounts in cancer cells thus becoming the specific target 12 Melflufen is currently in a phase three clinical study OC AN (OP) and is being compared directly against the current standard of care in patients with relapsed or refractory multiple myeloma 12

In the pi otal phase two clinical trial HORI ON (OP- 6) melflufen was used in combination with dexamethasone in patients with relapsed or refractory multiple myeloma he o erall response rate was In patients with triple-class refractory the o erall response rate was 6

Idecabtagene vicleucel Idecabtagene icleucel (ide-cel) is a CAR- therapy that recognizes and binds to BCMA on the surface of multiple myeloma cells leading to CAR- cell proliferation cytokine secretion and cytolytic killing of BCMA-expressing cells 14 he pi otal phase two arMMa trial was an open-label single-arm multicenter multinational study that e aluated the safety and e cacy of idecabtagene icleucel in patients with refractory or relapsed multiple myeloma who had pre iously recei ed at least three treatments including treatment with an immunomodulatory agent proteasome inhibitor (PI) and a CD -directed antibody 15 Additionally of patients recei ed pre ious autologous HSC and recei ed bridging therapy prior to lymphodepleting chemotherapy (fludarabine and cyclophosphamide) 15 he primary endpoint was the o erall response rate which was Median progression-free sur i al was 6 months 15 Idecabtagene icleucel has a set FDA appro al date of March If appro ed it will be the first CAR- therapy indicated for multiple myeloma

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MULTIPLE MYELOMA | Continued

The new investigational CAR-T therapies could be groundbreaking for the patients with relapsed or refractory multiple myeloma. JNJ-4528 N is a CAR- therapy made of modified -cells that identify and eliminate cancer cells containing BCMA 6 he N phase three trial is currently ongoing he pre ious results of the phase one-b two trial CAR I UD - showed an o erall response rate of 6 of patients reached a stringent complete response at months and were ali e and progression-free at nine months 6

26 | Magellan Rx Report | Spring 2021

Impact of CAR-T and Other Managed Care Implications he fi e-year sur i al rate for multiple myeloma is Many patients do not effecti ely respond to multiple myeloma therapies or they relapse after recei ing treatment he new in estigational CAR- therapies could be groundbreaking for the patients with relapsed or refractory multiple myeloma CAR- therapy is attracti e in that it is a one-time dose though the intensity of the therapy is not to be taken lightly he huge financial burden of CAR- therapies is an important consideration for both patients and payers Managed care payers will also need to take into account certain criteria for eligibility in order to pro ide access to these medications while keeping cost-effecti eness in mind CAR- therapy such as idecabtagene icleucel if appro ed is pro ected at an annual cost of per patient hile this therapy is not a cure to multiple myeloma it could ha e a large impact for patients who ha e few or no other treatment options


References hat Is Multiple Myeloma American Cancer Society https www cancer org cancer multiple-myeloma about what-ismultiple-myeloma html

BLENREP® belantamab mafodotin-blmf riangle Park NC GlaxoSmith line; August https www accessdata fda go drugsatfda docs label 6 s lbl pdf

Understanding multiple myeloma Multiple Myeloma Research Foundation https themmrf org multiple-myeloma

Bryson Ste e New CAR -cell herapy Shows arly Promise Against Multiple Myeloma in Lab Study Myeloma Research News Feb https myelomaresearchnews com car-tcell-immunotherapy-shows-promise-against-relapsedmultiple-myeloma-early-lab-study

Multiple Myeloma Statistics Cancer Net May https www cancer net cancer-types multiple-myeloma statistics text=Multiple myeloma is not a be diagnosed with multiple myeloma Can

About melflufen (INN melphalan flufenamide) Oncopeptides https oncopeptides se en melflufen text=Melflufen (INN melphalan flufenamide) is alkylating agents into tumor cells

e Afford the Cost of Myeloma herapy Medscape une https www medscape com iewarticle

Multiple Myeloma National Comprehensi e Cancer Network https www nccn org patients guidelines content PDF myeloma-patient pdf 6

Role of ransplant International Myeloma Foundation https www myeloma org autologous-stem-celltransplant text=Autologous stem cell transplant can high Ddose chemotherapy melphalan

Slater Hannah FDA Grants Priority Re iew to Melflufen in Combination with Dexamethasone for Myeloma Cancer Network Aug https www cancernetwork com iew fda-grantspriority-re iew-to-melflufen-in-combination-with-dexamethasonefor-myeloma Idecabtagene icleucel FDA Appro al Status Drugs com https www drugs com history idecabtagene- icleucel html

with

Slater Hannah FDA Grants Priority Re iew to Idecabtagene icleucel for Multiple Myeloma Cancer Network Sept https www cancernetwork com iew fda-grants-priority-re iewto-idecabtagene- icleucel-for-multiple-myeloma

XPO IO® selinexor Newton MA aryopharm herapeutics; uly https www accessdata fda go drugsatfda docs label 6s lbl pdf FDA appro es selinexor for refractory or relapsed multiple myeloma U S Food and Drug Administration https www fda go drugs drug-appro als-and-databases fda-appro esselinexor-refractory-or-relapsed-multiple-myeloma text=On December C C the at least one prior therapy

6

anssen s BCMA CAR- herapy N Showed arly Deep and Durable Responses in Hea ily Pretreated Patients with Multiple Myeloma ohnson ohnson May https www n com anssens-bcma-car-t-therapy- n -showed-early-deep-anddurable-responses-in-hea ily-pretreated-patients-with-multiplemyeloma

SARCLISA® isatuximab-irfc Bridgewater N Sanofi-A entis; March https www accessdata fda go drugsatfda docs label 6 s lbl pdf

Visit us online at magellanrx.com/mrxreport | 27


Rare Neuromuscular Diseases

reatment and Management Strategies

ith a number of promising therapies in the pipelines across rare neuromuscular diseases there will be added challenges for payers in managing high-cost therapies

Ben Barner, Pharm.D., MBA Senior Director Pharmacy Fallon Health

Rare diseases are defined as conditions affecting fewer than indi iduals in the United States A total cost-of-illness estimate for certain rare neuromuscular diseases in the U S ranges from to billion per year 1 hese costs are expected to increase as additional no el agents for certain rare diseases enter the market Currently the drug pipeline for rare neuromuscular disorders such as Duchenne muscular dystrophy (DMD) amyotrophic lateral sclerosis (ALS) and other spinal muscular atrophies (SMA) and Huntington s disease (HD) illustrates an expanding treatment landscape 2 he treatment options across these disease states ha e historically been limited and the current pipeline is promising Howe er with no el and inno ati e therapies come payer management challenges specifically around high-cost therapies

Current Treatment Landscape DMD DMD treatment typically includes generic corticosteroids and MFLA A® (deflazacort) to help maintain strength and slow disease progression Additionally angiotensin-con erting enzyme (AC ) inhibitors and beta blockers are used for patients with cardiac damage for their disease 4 XOND S (eteplirsen) and OND S (golodirsen) were appro ed by the Food and Drug Administration (FDA) for patients with specific mutations of the dystrophin gene in 6 and In the FDA appro ed IL PSO® ( iltolarsen) for the same indication 6 Most recently in February Amondys (casimersen) was appro ed by the FDA

ALS ALS treatment aims to help control symptoms pre ent complications and impro e quality of life here are currently only two FDA-appro ed drugs indicated for the treatment of ALS Rilutek® (riluzole) and RADICA A® (edara one) hile riluzole is used widely for patients with all stages of ALS disease progression edara one is used frequently in recently diagnosed patients

28 | Magellan Rx Report | Spring 2021


prior to significant disease progression ALS is also often treated with a comprehensi e care-management team who pro ide supporti e care including physicians; pharmacists; physical occupational and or speech therapists; nutritionists; social workers; respiratory therapists; clinical psychologists; and home care and hospice nurses he collaborati e team can de elop and pro ide an indi idualized treatment plan pro ide special equipment and impro e quality of life

SMA Until recently SMA treatments were restricted to supporti e therapies; howe er since 6 treatment of the condition has expanded with three FDA appro als for all SMA types he FDA appro ed SPINRA A® (nusinersen) in 6 OLG NSMA® (onasemnogene abepar o ec-xioi) in and rysdi (risdiplam) in

HD As with the pre iously discussed disorders there is no cure for HD and treatment goals focus on managing symptoms specifically around muscle issues such as contractions di culty with oluntary mo ements and erky in oluntary mo ements or chorea 12 In the FDA appro ed Xenazine® (tetrabenazine) as the first drug specifically indicated for HD; tetrabenazine is intended to help suppress chorea but is often associated with worsening depression and other serious side effects Later in the FDA appro ed the first alternati es to tetrabenazine AUS DO® (deutetrabenazine) and INGR A® ( albenazine tosylate) for the treatment of chorea associated with HD Other treatments for HD symptoms include antipsychotic medications to manage HD-associated psychiatric symptoms like agitation and psychosis 12

Pipelines Across these rare disease states imminent pipelines promise innoati e therapies that can change the treatment of these disorders Since the current therapy options for these rare neuromuscular diseases are fairly limited new options may present an opportunity to impro e patient outcomes and quality of life See ables - for a breakdown of treatments in the pipeline for DMD ALS SMA and HD

an exciting opportunity for impro ed patient outcomes the high cost of these therapies remains a burden for both patients and payers ith a robust pipeline there will be increased prioritization around proper management of these therapies and patient populations Sales associated with rare disease treatment are estimated to increase by annually through reaching 6 billion 6 In response to the high-cost therapies already on the market for these rare neuromuscular diseases payers ha e undertaken benefit-design changes to manage both use and cost associated with treatment including formulary restriction and specialty tiers shifting from copayments to co-insurance and prior authorization In a sur ey of consultants health plans and pharmacy benefit managers when asked to identify the best approach to managing the high cost associated with rare diseases called for a more integrated approach by benefit managers around total cost of care across the healthcare continuum An additional called for limitations from institutions like the National Institute of Health and Care xcellence or the Institute for Clinical and conomic Reiew around access to such therapies based on a cost-benefit measure like cost or quality-ad usted life year Finally almost suggested more aggressi e use-management strategies in order to regularly e aluate risk ersus benefit of such therapies promoting discontinuation when possible In other treatment categories use-management strategies are appropriate and effecti e in controlling costs because multiple therapies generics or biosimilars are a ailable Howe er for many rare diseases there are limited treatment options so payers find that more aggressi e usemanagement techniques are not appropriate Payers can strategize to effecti ely manage costs associated with treating rare diseases; for example creating a rare disease specialist with experience across se eral rare diseases may be aluable in working with case managers to pre ent direct costs and guide patients to appropriate specialists 6 ith each no el rare disease treatment appro al payers may ha e to ree aluate the effect on budgets which can be challenging 6 orking collaborati ely with manufacturers to de elop inno ati e contracts may be an option to limit risk especially in the initial years after product launch 6 Mo ing forward the strategy for effecti ely managing this treatment category will likely be to seek the right payment approach that will ensure the patient has access to necessary treatments

Payer Impact and Management hile the expansion of treatment options in this space creates

isit us online at magellanrx.com/mrxreport | 29


RARE NEUROMUSCULAR DISEASES | Continued Table 1. DMD Pipeline2 Drug

Manufacturer

I F

(gi inostat)

MOA

Route of Administration

Status

Italfarmaco

HDAC inhibitor

oral

phase three

P C herapeutics

Inhibitor of premature protein translation termination

oral

phase three

FibroGen

Anti-C GF antibody

I

phase three

CAP-

Capricor herapeutics

Immunomodulator

I

phase two

BP

Re eraGen BioPharma; Santhera Pharmaceuticals

Dissociate steroid

oral

phase two

ranslarna (ataluren) FG-

(pamre lumab)

Table 2. ALS Pipeline2 Drug

Manufacturer

MOA

Route of Administration

Status

Masitinib

AB Science

Receptor tyrosine kinase inhibitor

oral

phase three

NurOwn

BrainStorm Cell herapeutics

Cellular immunotherapy

intrathecal

phase three

Arimoclomol

Orphazyme

Molecular chaperone modulator

oral

phase three

MN- 66 (ibudilast)

yorin Pharmaceuticals; MediciNo a

PD

oral

phase three

BIIB 6 (tofersen)

Biogen; Ionis Pharmaceuticals

Antisense oligonucleotide

intrathecal

phase three

Ultomiris (ra ulizumab-cw z)

Alexion Pharmaceuticals

Complement inhibitors

I

phase three

RA

(zilucoplan)

Ra Pharmaceuticals; UCB

Complement inhibitors

SQ

phase three

BH -

( erdiperstat)

Bioha en Pharmaceuticals

MPO inhibitor

oral

phase three

Mitsubishi anabe Pharma

Neuroprotecti e agent

oral

phase three

CNM-Au (Gold Nanocrystal)

Clene Nanomedicine

Immunomodulator

oral

phase three

PF- 6

Pfizer

Gene therapy

I

phase three

Pridopidine

Prilenia herapeutics

Sigma- receptor agonist

oral

phase three

GALG

Sarepta herapeutics

Gene therapy

in ectable

phase two

SG -

Solid Biosciences

Gene therapy

I

phase two

SRP-

Sarepta herapeutics

Gene therapy

I

phase two

AMX (tauroursodeoxycholic acid; sodium phenylbutyrate)

Amylyx Pharmaceuticals

Nitrogen-binding agent; bile acid

oral

phase two

M -

6 (edara one)

6

30 | Magellan Rx Report | Spring 2021

inhibitor


Table 3. SMA Pipeline2 Drug

Manufacturer

C -

(reldesemti )

SR -

(apitegromab)

MOA

Route of Administration

Status

Cytokinetics; Astellas Pharma

Fast skeletal muscular troponin acti ator

oral

phase two

Scholar Rock

Myostatin inhibitor

I

phase two

Table 4. HD Pipeline2 Drug

Manufacturer

Pridopidine

Prilenia herapeutics

INGR

A ( albenazine tosylate)

Neurocrine Biosciences

RG6

(tominersen)

Roche; Ionis Pharmaceuticals

MOA

Route of Administration

Sigma- receptor agonist MA Antisense oligonucleotide

Status

oral

phase three

oral

phase three

Intrathecal

phase three

References Finkel Richard et al Diagnosis and management of spinal muscular atrophy part Pulmonary and acute care; medications supplements and immunizations; other organ systems; and ethics Neuromuscular Disorders March https reader else ier com reader sd pii S 6 66 token= BB AD F D B C C F F6C 6 C D D6 A DF6 B D 6A A A D 6F C BA F D F BD

Henderson endy he Cost of Neuromuscular Disorders in the U S Muscular Dystrophy News oday une https musculardystrophynews com 6 cost-illnessneuromuscular-diseases-united-states IPD Analytics https

ipdanalytics com

Birnkrant Da id et al Diagnosis and management of Duchenne muscular dystrophy part diagnosis and neuromuscular rehabilitation endocrine and gastrointestinal and nutritional management he Lancet Neurology March https www thelancet com ournals laneur article PIIS ( ) fulltext

Spinraza® package insert Cambridge MA Biogen; une olgensma® package insert Bannockburn IL A eXis; uly Appro ed reatments for Huntington s Disease Huntington s Disease News https huntingtonsdiseasenews com appro edtreatments-for-huntingtons-disease

Birnkrant Da id et al Diagnosis and management of Duchenne muscular dystrophy part respiratory cardiac bone health and orthopaedic management he Lancet Neurology April https www thelancet com ournals laneur article PIIS ( ) - fulltext

ero atiana and ose Rey etrabenazine (Xenazine) An FDAAppro ed reatment Option for Huntington s Disease-Related Chorea P December https www ncbi nlm nih go pmc articles PMC 6

xondys package insert Cambridge MA Sarepta herapeutics; uly 6

FDA appro es e a s Huntington s disease drug at second attempt PM Li e April http www pmli e com pharma news fda appro es te as huntingtons disease drug at second attempt

yondys package insert Cambridge MA Sarepta herapeutics; December Amyotrophic Lateral Sclerosis (ALS) Fact Sheet National Institute of Neurological Disorders and Stroke une https www ninds nih go Disorders Patient-Caregi er- ducation Fact-Sheets Amyotrophic-Lateral-Sclerosis-ALS-Fact-Sheet text=ALS is primarily diagnosed based the presence of the disease Mercuri ugenio et al Diagnosis and management of spinal muscular atrophy part Recommendations for diagnosis rehabilitation orthopedic and nutritional care Neuromuscular Disorders Feb https www nmd- ournal com article S 6 - 66( ) - abstract

Bell acob Neurocrine s Ingrezza secures FDA appro al BioPharma Di e Apr https www biopharmadi e com news neurocrine-fda-appro al-ingrezza 6

Pathways for Paying for Rare Disease reatments ournal of Clinical Pathways https www ournalofclinicalpathways com article pathways-paying-rare-disease-treatments Sukel ayt Balancing the Costs of Rare Disease reatment Managed Healthcare xecuti e une https www managedhealthcareexecuti e com iew balancing-costs-raredisease-treatment

isit us online at magellanrx.com/mrxreport | 31


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IV Iron:

Managed Care Implications As the market for I iron grows payers can strategize to effecti ely manage outcomes spend and utilization Iron deficiency occurs when the body s need for iron is not met ia absorption from a person s diet he discrepancy between need and absorption can be attributed to a number of factors including dietary intake poor absorption or physiologic loss Anemia secondary to iron deficiency (IDA) is the most common form of anemia and is a result of inadequate iron stores for creation of healthy red blood cells IDA is typically not considered an end diagnosis and the patient s workup is incomplete until the underlying cause has been identified

Matt Corley, R.Ph. Product Development Director, Medical Pharmacy Strategy Magellan Rx Management

Patient populations at higher risk for anemia include those demonstrating symptoms of pica restless legs pregnancy oncology patients and chronic kidney patients Additionally patients should be e aluated for sources of iron deficiency to address any underlying conditions An analysis of the global burden of anemia showed that while the incidence of IDA decreased it remained the primary dri er of cases from to for irtually all study population subsets he American Family Physician published its recommendations and noted that the pre alence of IDA totals in adult men to in non-Hispanic white women and nearly in black and MexicanAmerican women

Diagnosis aluation of complete blood count (CBC) red blood cell (RBC) indices and iron studies should be performed in adults with unexplained anemia particularly those with new-onset anemia in order to e aluate for iron deficiency See able for a breakdown of lab results found within iron deficiency de elopment

Jeff Januska, Pharm.D. Director of Pharmacy Services CenCal Health

Economic Burden of Anemia he direct and indirect costs of anemia are di cult to define due to the multifactorial nature of the condition itself and the many primary conditions associated with it Looking at oncology-specific

Visit us online at magellanrx.com/mrxreport | 33


Table 1. Laboratory Findings During the Development of Iron Deficiency3 Drug

Iron deficiency without anemia

Normal

Iron deficiency with mild anemia

Hemoglobin

Normal range

Normal range

to g L)

Red blood cell size and appearance

Normal

Normal

Normal or slight hypochromia

Microcytosis and hypo-chromia

ng mL

ng mL

Serum ferritin Serum iron otal iron-binding capacity (transferrin) ransferrin saturation Reticulocyte hemoglobin Bone marrow iron stain rythrocyte zinc protoporphyrin

to 6 to

ng mL mcg dL

to 6 mcg dL

ng mL¶ 6 to

mcg dL

to

mcg dL

g dL (

to

Severe iron deficiency with severe anemia

6 mcg dL

to

6 to

g dL (6 to

g L)

mcg dL

mcg dL

mcg dL

to 6 to

pg

Adequate iron present

to

ng ml RBC

to

pg

to

Iron absent

to

pg

Iron absent

ng ml RBC

ng ml RBC

Data not a ailable Iron absent

to

ng ml RBC

*The normal range for hemoglobin varies by age and sex (adult men, 14 to 17.5 g/dL; adult women, 12.3 to 15.3 g/dL). ¶The exact value is not well established; some clinicians may use a lower value for diagnosing iron deficiency.

patients to narrow the scope a re iew of two dozen studies noted that anemia treatments associated with these patients were estimated to be between and ( 6 USD) ith the appro als of Feraheme® ( AMAG Pharmaceuticals) In ectafer® ( American Regent) and Monoferric® ( Pharmacosmos herapeutics) the treatment cost has increased he a erage wholesale acquisition cost ( AC) per treatment cycle of the three agents in the initial analysis is 6 s 6 for the treatments most recently appro ed (see able )

Therapy Options: Oral vs. IV Regardless of the presence of symptoms patients with IDA should be treated to a oid potential organ damage ischemia and progression of the anemia reatment typically continues until the underlying cause is addressed or the patient s iron stores regain adequate le els

34 Magellan Rx Report Spring

With several more recent approvals in the space, the treatment cost has increased. hether the therapy is oral or intra enous (I ) iron depends on the se erity of the anemia cost of treatment a ailability of different products and the patient s tolerance for oral iron Patients with uncomplicated IDA are generally started with oral iron More recent practice guidelines suggest that lower and less frequent dosing of oral agents such as three times weekly is associated with better outcomes and impro ed tolerability 6 Similar dosing strategies are being explored with established I agents All oral agent options are considered equally effecti e when taken as directed For patients with complex disease a history of intolerance


IV IRON | Continued

Table 2. IDA Treatment Costs Code HCPCS / CPT®

Drug Name

ASP Cost per Treatment Cycle

AWP Cost per Treatment Cycle

WAC Cost per Treatment Cycle

Daily as needed to correct deficiency

INFeD

6

Ferrlecit

6

6

enofer

6

In ectafer

66

Feraheme

No. Doses to Treat

6

6

Daily until corrected (up to )

o er

6

6

6

weekly

6

Monoferric

The combination of novel product development — particularly intravenous supplements — and increased use in oncology, renal, gastrointestinal, and gynecological conditions is expected to continue to increase the use of IV iron.

weeks

gi en - days apart

6

to oral agents poor absorption of oral agents or who are presenting in a manner that requires more urgent correction I therapy is an appropriate option Replenishing depleted iron stores with oral treatment takes at least three or more months whereas if the primary cause of deficiency is addressed iron stores can usually be replenished with a single I dose arly I iron products such as high-molecular weight iron dextran were associated with life-threatening reactions and ha e been remo ed from the U S market A ailable products are considered to be equally effecti e at replenishing iron stores he primary differentiators between I products are cost and number of administrations needed to treat (see able ) For low-molecular weight iron dextran (INFeD®) a test dose is also needed Contraindications warnings and precautions for the fi e non-dextran products are similar and include cautions for iron o erload hypotension and hypersensiti ity reactions

Visit us online at magellanrx.com/mrxreport | 35


Surveillance and Strategies ith a growing I iron market opportunities may soon arise that were not pre iously a ailable due to a lack of competition relati e consistency in spend among products and changing strategies for diagnosing and treating these patients Plans that monitor their current I iron spend utilization trends o er time and market share of the a ailable agents could de elop strategies tailored to the population they ser ice take regional idiosyncrasies into account facilitate access to preferred products and take ad antage of pricing disparities when appropriate

References assebaum Nicholas et al A systematic analysis of global anemia burden from to Blood ( )6 illip Shersten et al Iron Deficiency Anemia Am Fam Physician March ; ( ) 6 -6 Buttarello Mauro et al aluation of the hypochromic erythrocyte and reticulocyte hemoglobin content pro ided by the Sysmex X analyzer in diagnosis of iron deficiency erythropoiesis Clin Chem Lab Med December 6 Liou S et al conomic burden of haematological ad erse effects in cancer patients a systematic re iew Clin Drug In estig ; (6) - 6 Schrier Stanley So you know how to treat iron deficiency anemia Blood October 6( ) 6

Awareness he combination of no el product de elopment particularly intra enous supplements and increased use in oncology renal gastrointestinal and gynecological conditions is expected to continue to increase the use of I iron Newer products offer con enience but at a premium cost Agents appro ed since are on a erage six times more costly per treatment cycle than the products appro ed prior to Ne ertheless CMS has appreciated the clinical alue of I iron replacement and has made I iron a first-line treatment for some conditions within its Medicare program he combination of a skyrocketing cost to treat and increased relati e patient counts may cause payers to prioritize effecti e management in this space On the patient side those whose benefits include a co-share of the costs to treat can be faced with considerable financial burden

36 Magellan Rx Report Spring

Auerbach Michael and Stanley Schrier reatment of iron deficiency is getting trendy Lancet Haematol ; ( )e pub Oct Auerbach Michael and homas Deloughery Single-dose intra enous iron for iron deficiency a new paradigm Hematology Am Soc Hematol duc Program December 6 6( ) -66 Auerbach Michael and ohn Adamson How we diagnose and treat iron deficiency anemia Am Hematol 6 ( ) Abdulrehman ameel et al he safety and e cacy of ferumoxytol in the treatment of iron deficiency a systematic re iew and metaanalysis ransfusion ( ) 6 6 pub No


LOOK BEYOND THE LIMITS IN OPHTHALMOLOGY

M-US-00009911(v1.0) 2/21 Visit us online at magellanrx.com/mrxreport | 37


PI PE LI N E D RU G LIST

PIPELINE DRUG LIST

Name

Manufacturer

Clinical Use

Dosage Form

Approval Status

Expected FDA Approval

upadacitinib (RINVOQ™)

AbbVie

PA

PO

sNDA

4/1/2021

pimavanserin (NUPLAZID®)

Acadia

Dementia-related hallucinations and delusions

PO

sNDA; breakthrough therapy

4/2/2021

brincidofovir

Chimerix

Smallpox

PO

NDA; fast track; orphan drug; priority review

4/7/2021

fosdenopterin

BridgeBio Pharma

MoCD

IV

NDA; breakthrough therapy; orphan drug; priority review; rare pediatric disease

4/9/2021

pembrolizumab (KEYTRUDA®)

Merck

Esophageal cancer (locally advanced/ metastatic, 1st line, in combination with platinum- and fluoropyrimidine-based chemotherapy)

IV

sBLA; priority review

4/13/2021

estradiol/drospirenone

Mayne Pharma

Contraception

PO

NDA

4/16/2021

benzoyl peroxide

Sol-Gel Technologies

Rosacea

TD

505(b)(2) NDA

4/26/2021

lorlatinib (LORBRENA®)

Pfizer

NSCLC (1st line, ALKpositive)

PO

sNDA; orphan drug; priority review; real-time oncology program

4/27/2021

pegunigalsidase alfa

Chiesi

Fabry Disease

IV

BLA; fast track; priority review

4/27/2021

tenapanor (IBSRELA®)

Ardelyx

Hyperphosphatemia (dialysis-dependent patient)

PO

sNDA

4/29/2021

abrocitinib

Pfizer

Atopic dermatitis/ eczema

PO

NDA; breakthrough therapy; priority review

4/30/2021

Treprostinil (TYVASO®)

United Therapeutics

Interstitial lung diseaseassociated pulmonary hypertension

Inhaled

sNDA

April 2021

teriflunomide (AUBAGIO®)

Sanofi

MS (pediatric)

PO

sNDA; priority review

5/2/2021

bupivacaine/meloxicam

Heron Therapeutics

Post-surgical pain

Instillation

NDA; breakthrough therapy; fast track

5/13/2021

pegcetacoplan

Apellis Pharmaceuticals

PNH

SQ

NDA; fast track; orphan drug; priority review

5/14/2021

avalglucosidase alfa

Sanofi

Pompe disease

IV

BLA; breakthrough therapy; fast track; priority review

5/18/2021

38 | Magellan Rx Report | Spring 2021


PI PE LI N E D RU G LIST

PIPELINE DRUG LIST CONT.

Name

Manufacturer

Clinical Use

Dosage Form

Approval Status

Expected FDA Approval

nivolumab (OPDIVO®)

Bristol Myers Squibb

Esophageal/ gastroesophageal junction cancer (resected, adjuvant setting, after neoadjuvant chemoradiation therapy)

loncastuximab tesirine

ADC Therapeutics

Diffuse large B-cell lymphoma (relapsed/ refractory)

IV

sBLA; orphan drug; priority review

5/21/2021

nivolumab (OPDIVO®)

Bristol Myers Squibb

Gastric cancer (advanced/metastatic, in combination with fluoropyrimidine- and platinum-based chemotherapy)

IV

sBLA; priority review

5/25/2021

dehydrated alcohol

Eton Pharmaceuticals

Methanol poisoning

SQ

505(b)(2); orphan drug

5/27/2021

leuprolide mesylate ready-to-use, six-month depot

Foresee Pharmaceuticals

Prostate cancer

SQ

505(b)(2)

5/27/2021

belumosudil

Kadmon Corporation

Graft versus host disease (chronic)

PO

NDA; breakthrough therapy; orphan drug; priority review; Project Orbis; real-time oncology review

5/28/2021

ozanimod (ZEPOSIA®)

Bristol Myers Squibb

UC

PO

sNDA; priority review

5/28/2021

zonisamide oral suspension

Eton Pharmaceuticals

Partial seizures

PO

505(b)(2)

5/30/2021

pirfenidone (Esbriet®)

Genentech

Interstitial lung disease

PO

sNDA; breakthrough therapy; orphan drug; priority review

May 2021

ibrexafungerp

SCYNEXIS

Vulvovaginal candidiasis

PO

NDA; fast track; orphan drug; qualified infectious drug product; priority review

6/1/2021

relugolix/estradiol/norethindrone

Myovant Sciences

Uterine fibroids

PO

NDA

6/1/2021

semaglutide (Ozempic®)

Novo Nordisk

Obesity

SQ

sNDA; priority review

6/4/2021

plasminogen (human)

Liminal BioSciences

Hypoplasminogenemia

IV

BLA; fast track; orphan drug; rare pediatric disease

6/5/2021

aducanumab

Biogen/Eisai

Alzheimer’s disease

IV

BLA; fast track; priority review

6/7/2021

Elexacaftor/tezacaftor/ivacaftor (TRIKAFTA®)

Vertex Pharmaceuticals

Cystic fibrosis (ages 6 to 11, >F508del mutation)

PO

sNDA; breakthrough therapy; orphan drug; priority review

6/8/2021

umbralisib

TG Therapeutics

Follicular lymphoma (>2 prior systemic therapies)

PO

NDA; orphan drug

6/15/2021

IV

sBLA; priority review

5/20/2021

Visit us online at magellanrx.com/mrxreport | 39


PI PE LI N E D RU G LIST

PIPELINE DRUG LIST CONT.

Name

Manufacturer

Clinical Use

Dosage Form

Approval Status

Expected FDA Approval

lonapegsomatropin

Ascendis Pharma

Growth hormone deficiency (pediatric)

SQ

BLA; orphan drug

6/25/2021

upadacitinib (RINVOQ®)

AbbVie

Axial spondyloarthritis

PO

sNDA

6/25/2021

cyclosporine

Santen

Vernal keratoconjunctivitis (ages 4 to 18)

Ophthalmic

505(b)(2); orphan drug

6/26/2021

extract of pineapple proteolytic enzymes

Vericel Corporation

Burn injury

Topical

BLA; orphan drug

6/29/2021

secnidazole (Solosec®)

Lupin

Trichomoniasis

PO

sNDA

6/30/2021

dapagliflozin (FARXIGA®)

AstraZeneca

CKD (with or without T2DM)

PO

sNDA; breakthrough therapy; fast track; priority review

April-June 2021

tofacitinib (XELJANZ®; XELJANZ XR®)

Pfizer

Axial spondyloarthritis

PO; topical

sNDA

April-June 2021

tralokinumab

AstraZeneca

Atopic dermatitis/ eczema

SQ

BLA

April-June 2021

insulin aspart (biosimilar to Novo-Log®)

Mylan/Biocon Biologics

T1DM; T2DM

SQ

BLA

April-June 2021

20-valeant pneumococcal conjugate vaccine

Pfizer

Streptococcus pneumoniae vaccines (antibacterial)

IM

BLA; breakthrough therapy; fast track

June 2021

teplizumab

Provention Bio

T1DM delay/prevention

IV

BLA; breakthrough therapy; orphan drug; priority review

7/2/2021

avacopan

ChemoCentryx

ANCA-associated vasculitis

PO

NDA; orphan drug

7/7/2021

finerenone

Bayer

Diabetic neuropathy

PO

NDA; priority review

7/9/2021

15-valent pneumococcal conjugate vaccine

Merck

Invasive pneumococcal disease prevention

IM

BLA; breakthrough therapy; priority review

7/16/2021

narsoplimab

Omeros

Hematopoietic stem cell transplantassociated thrombotic microangiopathy

SQ; IV

BLA; breakthrough therapy; orphan drug; priority review

7/16/2021

odevixibat

Albireo Pharma

Progressive familial intrahepatic cholestasisrelated pruritus

PO

NDA; fast track; ophan drug; priority review

7/20/2021

retifanlimab

Incyte

Anal cancer

IV

BLA; orphan drug; priority review

7/23/2021

sulopenem etzadroxil/probenecid

Iterum Therapeutics

UTI (uncomplicated, quinolone-resistant)

PO

NDA; fast track; qualified infectious disease product; priority review

7/23/2021

bimekizumab

UCB Biopharma

Psoriasis

SQ

BLA

July 2021

40 | Magellan Rx Report | Spring 2021


PI PE LI N E D RU G LIST

Name

Manufacturer

Clinical Use

Dosage Form

Approval Status

Expected FDA Approval

mepolizumab (NUCALA®)

GlaxoSmithKline

Nasal polyposis

SQ

sBLA

July-August 2021

anifrolumab

AstraZeneca

SLE

IV

BLA; fast track

July-December 2021

benzoyl peroxide/tretinoin

Sol-Gel

Acne

Topical

NDA

08/01/2021

topiramate oral liquid

Azurity

Partial seizures

PO

NDA

08/06/2021

sotorasib

Amgen

NSCLC

PO

breakthrough therapy; fast track; orphan drug; priority review

08/16/2021

oportuzumab monatox

Sesen Bio

Bladder cancer

Intravesical

BLA; fast track; priority review

08/18/2021

vosoritide

BioMarin

Achondroplasia

SQ

Orphan drug

08/20/2021

TBE vaccine

Pfizer

TBE

IM

BLA; priority review

August 2021

treosulfan

Medac

Allogeneic hematopoietic stem cell transplant conditioning

IV; PO

orphan drug

August 2021

Abbreviations: ANCA = antineutrophil cytoplasmic antibodies; BLA = biologics license application; CKD = chronic kidney disease; IM = intramuscular; IV = intravenous; MoCD = molybdenum cofactor deficiency; MS = multiple sclerosis; NDA = new drug application; NSCLC = non-small cell lung cancer; PA = psoriatic arthritis; PNH = paroxysmal nocturnal hemoglobinuria; PO = oral; sBLA = supplemental biologics application; SLE = systemic lupus erythematosus; sNDA = supplemental new drug application; SQ = subcutaneous; TBE = tick-borne encephalitis; T1DM = type 1 diabetes mellitus; T2DM = type 2 diabetes mellitus; TD = transdermal; UC = ulcerative colitis; UTI = urinary tract infection

MRx PIPELINE

Our latest quarterly report on anticipated specialty and traditional drugs in the pipeline

A VIEW INTO UPCOMING SPECIALTY & TRADITIONAL DRUGS JANUARY 2021

magellanrx.com/pipeline

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