Tumor Biomarkers in
Accelerated Approvals Update: Full Approval of Cancer Therapies
Breast Cancer: ESR1 Testing and Targeted Therapies
Ophthalmic Update: New Treatment Options and Management Strategies
Prostate Cancer: Treatments for Advanced Disease and Management
Myasthenia Gravis: Treatment Advances and Payer Impact
Multiple Myeloma:
CAR-T Advances and Management Impact
Oncology
Biosimilar Update: What’s New and ASP Impact
Biosimilar Update: Stakeholder Impact
Spring 2024
Oncology X Insights | Spring 2024
The same care we would want for our loved ones
At Prime Therapeutics and Magellan Rx, we are reimagining pharmacy management to provide the same care we would want for our loved ones by delivering differentiated solutions that drive affordability, improve efficiency and enhance health outcomes.
Scan the QR code below to see how we bring these words to life in our collective purpose and the why behind the work we do every day.
4 Managed Care Newsstand
6 Single-Treatment Gene Therapies: What’s New in Payer Strategies
16 Myasthenia Gravis: Treatment Advances and Payer Impact
22 Ophthalmic Update: New Treatment Options and Management Strategies
30 Tumor Biomarkers in Breast Cancer: ESR1 Testing and Targeted Therapies
34 Product Spotlight: Lecanemab-irmb (Leqembi®) for Alzheimer’s Disease
44 Biosimilar Update: What’s New and ASP Impact
47 Pipeline
Published By Magellan Rx Management | Prime Therapeutics 2900 Ames Crossing Road Eagan, MN 55121 magellanrx.com
Editor
Lindsay Speicher, J.D. Project Manager, Specialty lspeicher@magellanhealth.com lindsay.speicher@primetherapeutics.com
Advertising, Sales and Distribution
Carole Kallas carole.kallas@primetherapeutics.com
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 Rx™ 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.
Contributors
Steve Cutts, Pharm.D.
SVP, Market General Manager, MRx Specialty
Haita Makanji, Pharm.D. VP, Clinical Strategy and Innovation, Specialty
Amy E. Edquist Senior Manager, Marketing
Joe Tavares
SVP, Sales and Business Development, Specialty
Simone Ndujiuba, Pharm.D., BCOP Director, Clinical Strategy and Innovation, Oncology
Carole Kallas
Project Manager
Brian MacDonald, Pharm.D. Director, Specialty Clinical Strategy
Alina Young Associate Legal Counsel
Editorial Advisory Board
Mona M. Chitre, Pharm.D., CGP
Chief Pharmacy Officer & VP Clinical Analytics, Strategy & Innovation, Excellus BlueCross BlueShield
Dennis Bourdette, M.D., FAAN, FANA Chair and Roy and Eulalia Swank Family Research Professor, Department of Neurology, Oregon Health & Science University
Yousaf Ali, M.D., FACR
Chief, Division of Rheumatology, Mount Sinai West; Professor of Medicine, Icahn School of Medicine at Mount Sinai
Steven L. D’Amato, B.S.Pharm. Executive Director, New England Cancer Specialists
Joseph Mikhael, M.D., M.Ed., FRCPC, FACP
Chief Medical Officer, International Myeloma Foundation
Steve Marciniak, R.Ph.
Director II, Medical Benefit Drug Management, Blue Cross Blue Shield of Michigan
Saira A. Jan, M.S., Pharm.D.
Director of Pharmacy Strategy and Clinical Integration, Horizon Blue Cross Blue Shield of New Jersey
Welcome to our spring 2024 issue of the Magellan Rx Report! This year is off to an exciting start with a robust novel drug pipeline for 2024. Magellan Rx and Prime Therapeutics LLC are dedicated to bringing our readers valuable updates in managed care trends.
Our cover story (Page 6) for this issue highlights single-treatment gene therapies and value-based contracting as a management strategy. As more gene therapies enter the marketplace with high price tags, managing this category effectively is becoming increasingly critical for payers.
Another article (Page 16) focuses on updates in myasthenia gravis. With new treatment options in this space, we outline new approvals and the pipeline as well as some methods for payer management.
In our ophthalmic update (Page 22), we highlight advances in the space and effective methods for mitigating costs and strategizing for payers.
Other topics in this issue include a discussion of tumor biomarker testing for breast cancer (Page 30), a product spotlight on lecanemab (Leqembi®) for Alzheimer’s disease (Page 34) and an update on new FDA-approved biosimilar agents (Page 44). As always, we’ve rounded out the issue with our pipeline update (Page 47) and managed care newsstand (Page 4).
To learn more about 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!
Sincerely,
Mostafa Kamal Chief Executive Officer Magellan Rx Management
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.
On Jan. 18, 2024, Congress passed a new stopgap spending bill that temporarily extends federal government funding through March 1 for some agencies and March 8 for others, giving lawmakers and pharmacy benefit manager (PBM) reform advocates another six or seven weeks to hash out their different PBM reform bills for possible movement alongside a March spending bill.
The PBM bill that goes to the president’s desk is likely to be part of an omnibus package. There have been significant efforts to attach delinking and other provisions (bans on spread, full rebate pass-through, pharmacy quality metrics in Medicare, Medicare “essential pharmacy” designation) to any package; however, while some lawmakers support these measures, key Republicans oppose intrusion into private markets. PBM fatigue is developing among some members, but others are focused on the effort and frequently present new antiPBM bills to Congress.
Inflation Reduction Act (IRA)
• Low-income subsidy expansion
• Part D redesign: including Medicare’s Part D premiums, which will have a
cap on increases beginning in 2024 and a cap on annual out-of-pocket costs in Medicare Part D, IRA. The latter will remove patient responsibility for catastrophic phase starting in 2024.
• Part B biosimilar cap
• Beginning in 2024, group health plans and health insurers must expand the real-time price comparison tool they make available to beneficiaries to include all covered items, services and drugs.
• Medicaid rebates from drugmakers will no longer be capped at 100% of AMP.
• Removing the cap could result in a significant increase in Medicaid rebate liability for manufacturers, particularly for drugs with increased prices.
• For the first time, pharmacy DIR fees must be applied at the point of sale to determine a Medicare beneficiary’s copay.
In September 2023, the U.S. District Court for the District of Columbia issued a ruling vacating the Department of Health and Human Services (HHS) Notice of Benefit and Payment Parameters for 2021, which allowed insurers to exclude prescription drug copay assistance from a beneficiary’s out-of-pocket costs for branded drugs that do not have a generic equivalent. The predecessor 2020 rule pertaining to copay assistance is now in effect. According to that rule, copay accumulators are permissible for branded drugs that have a generic equivalent, if allowed by state law.
In late December 2023, the judge clarified the 2020 rule now goes into effect.
HHS appealed last year and then withdrew its appeal. HHS has stated it plans to draft a new rule on the Affordable Care Act’s (ACA’s) cost-sharing definition, which was a chief issue in the initial case. Patient advocate groups have said prohibiting copay maximizer programs is their top priority.
The Centers for Medicaid & Medicare Services (CMS), private insurers and Medicaid officials struggle with how to cover and pay for the expensive emerging therapies, including gene therapy, GLP-1s and more.
A bipartisan group of senators wants an update from the Federal Trade Commission on its probe of PBMs, according to a letter from 14 lawmakers.
On Dec. 7, 2023, the National Institute of Standards and Technology (NIST) released a draft guidance framework for Considering the Exercise of March-In Rights for public comment. Pressure is mounting — public and political — for the government to use march-in rights to lower drug costs. March-in rights are granted under the Bayh-Dole Act of 1980 and allow federal agencies that fund private research to require patent holders to grant licenses on reasonable terms to other companies to practice the patent. This right can be exercised where “action is necessary to alleviate health or safety needs which are not reasonably satisfied” or where the benefits of a federal-funded, patented
invention are not made “available to the public on reasonable terms.” No agency has ever exercised march-in rights.
NIST invites public comments on the framework, emphasizing clarity, fulfillment of march-in rights’ purpose and alignment with Bayh-Dole Act objectives.
On Dec. 14, 2023, CMS sent a letter to health plans and PBMs concerned that certain practices could jeopardize pharmacies’ financial viability, especially small and independent pharmacies. The letter also warned PBMs of plans to refrain from payment practices that disincentivize pharmacies from administering vaccines or make it difficult for patients to access contraception. Finally, it warned of possible anticompetitive effects of vertical integration on independent pharmacies.
In particular, CMS addressed the 2023 Medicare Part D final rule, which officially went into effect Jan. 1, 2024, requiring pharmacy DIR fees to be applied at the point of sale to determine a Medicare beneficiary’s copay. The final rule revised the Part D program’s definition of negotiated price to mean the lowest possible reimbursement a network pharmacy will receive in total for a covered Part D drug. Therefore, under the final rule, pharmacies will receive the lowest possible reimbursement in 2024 while PBMs continue to collect pharmacy DIR fees from 2023, which could create cash flow issues for pharmacies during transition.
CMS strongly encouraged “Part D plan sponsors and their PBMs to make necessary cash flow arrangements with network pharmacies in preparation for these upcoming changes.” Prime has worked, and will continue to work, with pharmacies
to prepare for the transition, including developing payment plans upon request.
Delinking Revenue from Unfair Gouging (Drug) Act (H.R. 6283): Regulates the commercial market and would only allow PBMs to charge a flat fee for their services by delinking the service fee from the list price of a drug. The bill had previously been introduced in the Senate as S. 2973. The DRUG Act also bans spread pricing in the commercial market and bans “patient steering,” which occurs when a PBM encourages or requires patients to use its affiliated pharmacies.
Lower Costs, More Transparency Act (H.R. 5378): Incorporates provisions by the members of the House Energy and Commerce, Ways and Means and Education and the Workforce committees; codifies the Transparency in Coverage (TiC) Rule machine-readable file provision (i.e., public reporting of rate and payment information); requires PBMs to semiannually provide employers with detailed data on prescription drug spending, including the acquisition cost of drugs, total out-of-pocket spending, formulary placement rationale and aggregate rebate information; bans spread pricing in Medicaid and strengthens requirements that PBMs and third-party administrators disclose compensation to plan fiduciaries; and confirms that existing law banning gag clauses applies to all private health plans.
Accountability Act (S. 2973): Delinks PBM compensation from prescription drug prices under Medicare Part D; bans spread pricing in Medicaid, bans steering patients to PBM-owned pharmacies for “non-limited access drugs;” requires PBMs to report pricing data to HHS; requires the
The PBM bill that goes to the president’s desk is likely to be part of an omnibus package.
HHS Secretary to institute standard Part D measures for assessing network pharmacy performance; and requires the HHS Office of Inspector General (OIG) to investigate the impact of vertical integration between Part D plans, PBMs and pharmacies.
The Better Mental Health Care, Lower-Cost Drugs, and Extenders Act of 2023 (S. 3430): Passed the Senate Finance Committee in November; codifies provisions that Part D sponsors’ contracts with pharmacies be “reasonable and relevant”; creates a new process for pharmacies to submit violations; requires plan sponsors to contract with at least 80% of “essential” retail pharmacies, community pharmacies and 50% noncommunity pharmacies; mandates National Average Drug Acquisition Cost study of rural community pharmacies and nonretail pharmacies; requires post-deductible coinsurance for select Part D drugs be based on net prices; requires HHS to report to Congress the impacts of a rule pertaining to Part D reimbursements and DIR.
Pharmacy Benefit Manager Reform Act (S. 1339): A bipartisan proposal that limits spread pricing; requires full rebate pass-throughs and broad reporting requirements for PBMs and their affiliates; mandates a specific exception process for step-therapy protocols; and mandates study of PBM fiduciary duty.
Patrick Gleason, Pharm.D., FCCP, FAMCP, BCPS AVP, Health Outcomes Prime Therapeutics LLC
Recent advancements in cell and gene therapies demonstrate great progress and promise in potentially curing life-threatening diseases and genetic conditions. There are more than 1,000 cell and gene therapy candidates in clinical trials worldwide and the U.S. Food and Drug Administration (FDA) expects to approve between 10 and 20 new cell and gene therapy treatments annually by 2025.1 An estimated 90 cell and gene therapies, which represent around $30 billion in health care spending, can potentially be approved by 2031.2
The ten current marketed single-treatment gene therapies are the most costly of all cell and gene therapies, averaging $2.4 million; etranacogene dezaparvovec (Hemgenix®) is the most expensive at $3.5 million (See Table 1). The first marketed single-treatment gene therapy products — voretigene neparvovec (Luxturna®) to treat a specific form of blindness and onasemnogene abeparvovec (Zolgensma®) to treat spinal muscular atrophy in infants — have delivered revolutionary outcomes. However, long-term durability and safety of these therapies remain questions, especially with a large upfront cost and lifelong cure incorporated into the pricing rationale.
The financial impact of voretigene neparvovec and onasemnogene abeparvovec has been manageable due to the small number of individuals receiving treatment over the past few years since the initial approvals; however, since the second half of 2022, there have been eight new single-treatment gene therapy approvals for more common conditions, such as hemophilia, Duchenne muscular dystrophy, sickle cell disease and beta thalassemia. These new approvals are accompanied by increased financial risk and an advance in gene therapy delivery technology from viral vector delivery to clustered regularly interspaced short palindromic repeats (CRISPR) editing.3
Voretigene neparvovec-rzyl (Luxturna®) Spark Therapeutics, Inc. Biallelic RPE65 mutation-associated retinal dystrophy 12/18/2017 Adenoviral $850,000
Onasemnogene abeparvovec-xioi (Zolgensma®) Novartis SMA 5/24/2019 Adenoviral $2,125,000
Betibeglogene autotemcel (Zynteglo™) Bluebird Bio Transfusion-dependent beta thalassemia 8/17/2022 Lentiviral $2,800,000
Elivaldogene autotemcel (Skysona®) Bluebird Bio Early CALD 9/16/2022 Lentiviral $3,000,000
Etranacogene dezaparvovec (Hemgenix®) CSL Behring Hemophilia B
Beremagene geperpavec (Vyjuvek®) Krystal Biotech Dystrophic epidermolysis bullosa 5/19/2023 HSV-1 $631,000
Delandistrogene moxeparvovec (Elevidys) Sarepta Therapeutics DMD 6/22/2023
Abbreviations: AADC = aromatic L-amino acid decarboxylase; CALD = cerebral adrenoleukodystrophy; CRISPR = clustered regularly interspaced short palindromic repeats; DMD = Duchenne muscular dystrophy; HSV = herpes simplex virus; MLD = metachromatic leukodystrophy; PDUFA = Prescription Drug User Fee Act, FDA provided potential approval date; RPE = retinal pigment epithelium; SCD = Sickle cell disease; SMA = spinal muscular atrophy.
The newest form of gene therapy is administered through CRISPR and CRISPR-associated protein 9 (CRISPR-Cas9) genome editing.4 This approach was adapted from a naturally occurring genome editing system that bacteria use as an immune defense.4 In CRISPR technology, this immune defense has been adapted to edit DNA, creating a small piece of RNA with a short guide sequence which attaches to a specific target sequence in a cell’s DNA as well as to the Cas9 enzyme.4 The guide RNA recognizes the intended DNA sequence, and the Cas9 enzyme cuts the DNA at the targeted location.4
Exagamglogene autotemcel (exa-cel) (Casgevy™, Vertex), approved by the FDA on Dec. 8, 2023 and indicated for sickle cell disease, is the first approved CRISPR gene editing treatment. In this therapy, the technology is used to modify patients’ blood stem cells, which are then transplanted back into the patient, where they engraft within the bone marrow and increase the production of fetal hemoglobin.5 This increased level of fetal hemoglobin works to prevent the sickling of red blood cells in patients with sickle cell disease.5 In January 2024, exa-cel received a second indication for transfusion-dependent beta thalassemia.6 As it is used for sickle cell disease, when exa-cel is used to treat beta thalassemia, the CRISPR gene editing process corrects the hemoglobin E mutation by homology-directed repair using a single-stranded DNA template, which includes the normal hemoglobin B genetic sequence.6
Exagamglogene Autotemcel (Casgevy™) & Lovotibeglogene Autotemcel (Lyfgenia™)
On Dec. 8, 2023, the FDA approved exa-cel (Casgevy, Vertex) and lovotibeglogene autotemcel (lovo-cel) (Lyfgenia, Bluebird Bio) for the treatment of sickle cell disease.5 As stated, the approval of exacel marks the first CRISPR gene editing filing to be approved by the FDA.5 Exa-cel genome editing using CRISPR/Cas9 technology modifies patients’ hematopoietic stem cells (HSC).5
Exa-cel and lovo-cel are both made from the patients’ own blood cells; the blood cells are modified and given back as a one-time, single-dose infusion as part of an HSC transplant. Before treatment, a patient’s own stem cells are collected, at which point a patient must undergo myeloablative conditioning, or high-dose chemotherapy.5 Myeloablative conditioning removes cells from the bone marrow so healthcare providers can replace them with the modified cells in exa-cel and lovo-cel. Patients treated with either of these therapies will be followed in a long-term study to evaluate each product’s safety and effectiveness.5
Approval of exa-cel was based on results from an ongoing, single-arm, multi-center trial in adult and adolescent patients
with sickle cell disease who had a history of at least two protocol-defined severe vaso-occlusive crises (VOCs) during each of the two years prior to screening.6 The primary efficacy outcome of the trial is freedom from severe VOC episodes for at least 12 consecutive months during the 24-month follow-up period.6 A total of 31 patients had sufficient follow-up time to be evaluable and 29 (93.5%) achieved this outcome.6 All patients who received treatment achieved successful gene therapy engraftment, and no patients experienced graft failure or graft rejection.6 Side effects associated with treatment with exa-cel were low levels of platelets and white blood cells, mouth sores, nausea, musculoskeletal pain, abdominal pain, vomiting, febrile neutropenia, headache and itching.5
Lovo-cel gene therapy is delivered to the cell by a lentiviral vector, unlike exa-cel, which uses CRISPR technology to modify hematopoietic stem cells. Lovo-cel works by adding a functional β-globin gene to patients’ own HSCs.7 Approval was based on an analysis of data from a single-arm, 24-month multicenter study in patients with sickle cell disease and a history of vasoocclusive events (VOEs) between the ages of 12 and 50 years old.8 Complete resolution of VOEs (VOE-CR) between six and 18 months after infusion with lovo-cel was the primary outcome.8 Of the 32 patients evaluated during this time period, 28 (88%) achieved VOE-CR.8
Side effects associated with lovo-cel included stomatitis, low levels of platelets and white and red blood cells and febrile neutropenia, consistent with chemotherapy and underlying disease.5 A black box warning is included on the label for lovo-cel with information regarding the potential risk of hematologic malignancy, which has occurred in patients treated with lovo-cel.5 Those receiving treatment with lovo-cel should have lifelong monitoring for these potential malignancies.5
In late 2022, the FDA approved etranacogene dezaparvovec (Hemgenix, CSL Behring) as the first gene therapy for the treatment of adults with hemophilia B (congenital Factor IX [FIX] deficiency) who currently use FIX prophylaxis therapy, have current or historical life-threatening hemorrhage or have repeated, serious spontaneous bleeding episodes.9 Etranacogene dezaparvovec is a one-time, adeno-associated virus vector-based gene therapy given as a single dose by IV infusion.9 It consists of a viral vector carrying a gene for clotting FIX; this gene is expressed in the liver
On Dec. 8, 2023, the FDA approved exagamglogene autotemcel (exa-cel) (Casgevy, Vertex) and lovotibeglogene autotemcel (lovo-cel) (Lyfgenia, Bluebird Bio) for the treatment of sickle cell disease.
to produce FIX protein and increase blood levels of FIX, thereby limiting bleeding episodes.9
Approval was based on the results of two studies of 57 adult men with severe or moderately severe hemophilia B. One of the studies of 54 participants showed the subjects had increases in FIX activity levels, a decreased need for routine FIX replacement prophylaxis and a 54% reduction in annualized bleeding rate (ABR) compared to baseline.10 Adverse reactions associated with etranacogene dezaparvovec included liver enzyme elevations, headache, mild-infusion-related reactions and flu-like symptoms.9
In June 2023, CSL Behring announced the first patient had received etranacogene dezaparvovec.11
In June 2023, the FDA approved valoctocogene roxaparvovec (Roctavian, BioMarin) for the treatment of adults with severe hemophilia A without pre-existing antibodies to adenoassociated virus serotype 5 detected by an FDA-approved test.12 Valoctocogene roxaparvovec, an adeno-associated virus vectorbased gene therapy, is the first gene therapy approved for the treatment of hemophilia A.12 It is a one-time gene therapy administered as a single dose via IV infusion, consisting of a viral vector carrying a gene for clotting Factor VIII (FVIII).12 A multinational study of adult men with severe hemophilia A evaluated the safety and effectiveness of the drug.13 Participants were previously treated with FVIII replacement therapy.13 A cohort of 112 patients previously treated with FVIII replacement therapy were followed for at least three years after receiving the valoctocogene roxaparvovec treatment.13 After receiving treatment, the mean ABR decreased from 5.4 bleeds per year
at baseline to 2.6 bleeds per year.13 For the gene therapy to be effective and safe, the majority of patients received corticosteroids to suppress the immune system.13
Adverse reactions associated with treatment include mild changes in liver function, headache, nausea, vomiting, fatigue, abdominal pain and infusion-related reactions.12 Treatment with valoctocogene roxaparvovec may increase FVIII activity levels above the normal limits, which could increase the risk of thromboembolic events.12 A theoretical risk of developing hepatocellular carcinoma or other cancers exists after introduction of the product’s DNA sequence.12
In August 2023, the Institute for Clinical and Economic Review (ICER) released a Final Evidence Report assessing the comparative clinical effectiveness and value of exa-cel and lovo-cel for sickle cell disease.14 The review was conducted and the report released prior to approval and availability.14 ICER concluded the current evidence is adequate to demonstrate a net health benefit for exacel and lovo-cel when compared to standard of care.14 The ICER panelists also unanimously concluded there was no adequate available evidence to distinguish net health benefit between exa-cel and lovo-cel.14 The ICER-calculated health-benefit price
benchmark (HBPB) fair price for lovo-cel and exa-cel was between $1.35 and $2.05 million.14 Subsequently, both products have been FDA-approved and marketed with exa-cel priced at $2.2 million and lovo-cel priced at $3.1 million — above the ICER HBPB fair price.14
ICER has single-treatment therapy reports with fair price benchmarks for Luxturna at $400,000, Zolgensma at $1.5 million, Roctavian at $1.9 million, Hemgenix at $2.9 million and Zynteglo at $2.4 million. Most single-treatment gene therapies are priced higher than the ICER maximum fair price. ICER found hemophilia gene therapies had substantial cost savings with projected gains in quality-adjusted life years.15 However, due to hemophilia savings of 99% from factor prophylaxis cost avoidance, which are overpriced to value at their pricing of over $300,000, ICER recommends using $150,000 a year prophylaxis factor savings on gene therapy cost offset in the model, allowing for a societal shared savings.15 This would result in a fair price of $1.96 million for Roctavian and $2.96 million for Hemgenix.15
In its hemophilia gene therapy report, ICER recommends payers work with manufacturers to develop and implement outcomesbased agreements to address uncertainty and high cost of gene therapies for hemophilia. In response, both hemophilia gene therapy manufacturers have worked with payers, including Prime Therapeutics and Magellan Rx, to offer outcomes-based warranties.16
The 10 in-market and 12 near-term pipeline single-treatment gene therapies shown in Table 1 have the potential to bring $20 per member per month cost if all 1,954 identified gene therapy candidates, among 16.3 million commercially insured members, are treated. The in-market and near-term pipeline gene therapies have the maximal potential to have treated more than 100 per million commercially insured members, or one per 10,000 in 2026.
Prime and Magellan Rx creates gene therapy-specific candidate identification algorithms through the close connectivity with the health plans they service via integrating medical claims data with pharmacy claims data and membership eligibility files. The algorithms also take into account gene therapy manufacturer information, investor reports, FDA information and gene therapy product clinical trial reports. A dedicated team of health services researcher pharmacists, epidemiologists and data scientists perform constant surveillance of gene therapies in market and in the pipeline. They meet with product manufacturers and clinical experts synthesizing the information to operationalize gene therapy candidate identification-coded algorithms, predicting potential gene therapy candidates within an insured population to estimate financial risk.
Analytics
Forecast
• FDA-approved label
• Published hemophilia studies
• Reference diagnosis and factor replacement code list
• Potential candidates/analytic attrition
• Therapy uptake/demand factor
• Market capacity
Financial Risk
To address gene therapy financial risk, an insured population must have adequate payment projection — single-treatment gene therapies require a multi-million dollar, one-time payment due upon administration.17 Payment financial risk protection is purchased by self-insured employers through their stop-loss coverage and for health plans through reinsurance.17 Stop-loss and reinsurance cap a high-cost claimant, individual member and annual health insurance cost at a fixed attachment point (e.g., $250,000 per year).17 All annual costs above the attachment point are paid by the stop-loss carrier or reinsurer.17 Stop-loss and reinsurance are purchased at a per member per month rate and cover all high claimants; they are not specific to gene therapy.17 However, stop-loss and reinsurance are designed for unknown high-cost claimants.17 Because many single-treatment gene therapies are for known individuals, stoploss and reinsurance coverage may exclude gene therapy for an individual with a known condition.17
Self-insured employers and health plans will need to carefully review their stop-loss and reinsurance policies to ensure all gene therapies are covered. If coverage is incomplete, alternative gene therapy coverage may be considered as additional gene therapyspecific insurance or capitated coverage can be purchased.
Gene therapy management planning requires establishing utilization management (UM), or medical management criteria. The UM criteria development and coverage approval should encompass a multi-disciplinary team of clinicians, including the medical
director, pharmacists, network team and specialized medical case management with protocols to ensure consistency. In the UM criteria development, an essential team includes the manufacturer trade relations negotiator, who is capable of negotiating product access discounts. Identifying a center of excellence network specializing in the ultra-rare or rare condition for which the gene therapy is indicated is another essential component. A center of excellence network can bring contracted clinical outcome performance metrics as well as potential case rate pricing and additional volume discounts. A health care consultant surveyed their health care purchaser clients in 2023 and found, surprisingly, that most respondents rely on internal networks over a center of excellence network to provide gene therapy services.18 When asked who within a plan is notified of pending gene therapy cases, 40% of respondents answered finance; pharmacists and medical management were only consulted in 20% of surveyed plans.18
A critical need exists for clear communication between key stakeholders, which may not be occurring in most health plans. Planning for gene therapies with established UM policies and a specialized gene therapy network with centers of excellence for care and best pricing are essential pillars to mitigate financial risk.
Within value-based purchasing are two distinct concepts.19 First, value-based contracting is performance-based contracting among payer, provider or manufacturer stakeholders in which reimbursement is tied to patient health measures and other real-world outcomes and costs for a defined period of time.19 Alternative payment contracting as a payment approach centers on providing predictable costs and ties payment to provider or therapy performance over a defined period of time.19 Exploring innovative payment models will be key to effectively strategizing payment in this category.20
Outcomes-based contracts are agreed upon between the product manufacturer and the payer. The manufacturer and payer may agree upon additional payments for clinical outcomes met or financial rebates for clinical outcomes not achieved. The outcomes can be measured at the individual payment or population level and can be captured in routine care or collected via claims data.
Under risk-based contracts, payment is linked to the distribution of risk for the specified treatment or medical intervention.19 This can be done by measuring financial performance, medication utilization or health outcomes.19 These contracts are similar to outcomes-based contracts in that they are advantageous when treatment outcomes are uncertain or hard to measure. However, risk-based contracts
Alternative payment models will be critical to financing these therapies and ensuring access to these therapies when appropriate.
have a greater focus on financial performance and are defined by their reliance on anticipated real-world outcomes and the expectation that treatment responses may vary.19 These contracts may include upside (additional payments if metrics or savings are achieved) or downside (penalties if metrics are not met).19
Alternative payment models include annuity payments over time, which can be combined with annuity outcomes contract terms in which payments can stop if the gene therapy fails to deliver continued effectiveness or results in negative safety outcomes. These models have been popular ideas for gene therapies; however, annuity-based installment payments have not been adopted due to challenges with ensuring the payments can be transferred from one insurer to another if the individual changes insurance. As with the operational challenges with annuities, warranties may not be
feasible for some gene therapies because the treatment costs prior to gene therapy are minimal in comparison to the gene therapy cost itself. However, when the current disease therapy costs are welldefined or the future disease costs can be identified, gene therapy warranties hold promise. Hemophilia gene therapy manufacturers CSL Behring and BioMarin offer warranties for their products, while Novartis offers an annuity payment model for Zolgensma.16 Crucial to the effectiveness of these contracts is clearly defining what it means for the treatment to work or stop working.20 In addition, partnering with a health plan or pharmacy benefit manager who has the data and can fulfill the warranty, annuity, risk-based or outcomes contract reporting terms will be critical.
Other payment approaches included price-volume and expenditure caps.20 Price-volume models decreased the price per unit as the sales of therapy increased, while with expenditure cap models, the price per unit stays the same until a spending limit is reached, after which there is no charge for additional units.18 Subscription payment models are sometimes considered a version of an expenditure model, in which payers have access to an unlimited supply of a gene therapy in exchange for a set fee. These models tend to work best when the marginal cost of production for the therapy is low, which is not yet the reality for cell and gene therapies.20
Alternative payment models will be critical to financing these therapies and ensuring access to these therapies when appropriate. Including patient interests and ensuring access considerations are also key to gene therapy payment and valuebased contracting considerations; for further details, please refer to the Prime Therapeutics and Eli Lilly White Paper.21
Following a value-based purchasing final rule by CMS, Prime and Magellan Rx, launched a multistate value-based contracting tool to help Medicaid programs access these outcomes-based agreements for cell and gene therapies. Prime and Magellan Rx has leveraged its experience and expertise in state Medicaid programs, spanning 28 states and the District of Columbia, to implement its value-based contracting product. The product ensures that the cell and gene therapy agents’ costs are linked to patient outcomes and, if outcomes are not met, manufacturers will refund part of the drugs’ cost to the state.
As these payment models and value-based contract terms are developed, utilized and assessed, ongoing concerns continue to arise, such as the burden of information tracking, regulatory barriers and pricing and reporting requirements. Manufacturers and payers alike will have to collaborate to develop creative outcomes assessment terms and payment models that will allow access while easing the financial burdens associated with these treatments.
References
1. Gottlieb, S. (2019, Jan. 15). Statement from FDA Commissioner Scott Gottlieb, M.D. and Peter Marks, M.D., Ph.D., Director of the Centers of Biologics Evaluation and Research on new policies to advance development of safe and effective cell and gene therapies. U.S. Food and Drug Administration. fda.gov/news-events/pressannouncements/statement-fda-commissioner-scott-gottlieb-mdand-peter-marks-md-phd-director-center-biologics
2. Top Payer Strategies Around Payment Models for Advanced Therapies (2022, July 27). Health Payer Intelligence. healthpayerintelligence. com/features/top-payer-strategies-around-payment-models-foradvanced-therapies.
3. Bulcha, J.T., Wang, Y., et al. (2021). Viral vector platforms within the gene therapy landscape. Signal Transduction and Targeted Therapy, 6(53). nature.com/articles/s41392-021-00487-6
4. What are genome editing and CRISPR-Cas9? MedlinePlus. Retrieved Jan. 31, 2024 from medlineplus.gov/genetics/understanding/ genomicresearch/genomeediting/
5. FDA Approves First Gene Therapies to Treat Patients with Sickle Cell Disease. (2023, Dec. 8). U.S. Food and Drug Administration. fda. gov/news-events/press-announcements/fda-approves-first-genetherapies-treat-patients-sickle-cell-disease
6. Vertex and CRISPR Therapeutics Present New Data on More Patients with Longer Follow-Up Treated with exagamglogene autotemcel (exacel) at the 2022 European Hematology Associated (EHA) Congress (2022, June 11). CRISPR Therapeutics. crisprtx.com/about-us/ press-releases-and-presentations/vertex-and-crispr-therapeuticspresent-new-data-on-more-patients-with-longer-follow-up-treatedwith-exagamglogene-autotemcel-exa-cel-at-the-2022-europeanhematology-association-eha-congress
7. bluebird bio Announces FDA Approval of LYFGENIA™ (Lovotibeglogene autotemcel) for Patients Ages 12 and Older with Sickle Cell Disease and a History of Vaso-Occlusive Events. (2023, Dec. 8). Bluebird Bio. investor.bluebirdbio.com/news-releases/ news-release-details/bluebird-bio-announces-fda-approvallyfgeniatm-lovotibeglogene
8. Waldron, J. (2023, Aug. 16). Bluebird's lovo-cel flies closer to approval as FDA rules out advisory committee meeting. Fierce Biotech. fiercebiotech.com/biotech/bluebirds-lovo-cel-flies-closerapproval-fda-rules-out-adcom-ahead-december-decision
9. FDA Approves First Gene Therapy to Treat Adults with Hemophilia B (2022, Nov. 22). U.S. Food and Drug Administration. fda.gov/newsevents/press-announcements/fda-approves-first-gene-therapytreat-adults-hemophilia-b
10. Pipe, S.W., et al. (2023) Gene Therapy with Etranacogene Dezaparvovec for Hemophilia B. New England Journal of Medicine, 388(8), 706–718. DOI: 10.1056/NEJMoa2211644
11. CSL Behring Announces the First Patient Has Received FDA-Approved HEMGENIX® (etranacogene dezaparvovec-drlb) for Hemophilia B (2023, June 20). PR Newswire. prnewswire.com/news-releases/ csl-behring-announces-the-first-patient-has-received-fdaapproved-hemgenix-etranacogene-dezaparvovec-drlb-forhemophilia-b-301854676.html
12. FDA Approves First Gene Therapy for Adults with Severe Hemophilia A (2023, June 29). U.S. Food and Drug Administration. fda.gov/newsevents/press-announcements/fda-approves-first-gene-therapyadults-severe-hemophilia.
13. Ozelo, M.C., et al. (2022). Valoctocogene Roxaparvovec Gene Therapy for Hemophilia A. New England Journal of Medicine, 386(11), 1013–1035. DOI: 10.1056/NEJMoa2113708
14. ICER Publishes Final Evidence Report on Gene Therapies for Sickle Cell Disease. (2023, Aug. 21). Institute for Clinical and Economic Review. icer.org/news-insights/press-releases/icer-publishes-finalevidence-report-on-gene-therapies-for-sickle-cell-disease
15. ICER Publishes Final Evidence Report on Gene Therapies for Hemophilia A and B. (2022, Dec. 22). Institute for Clinical and Economic Review. icer.org/news-insights/press-releases/icerpublishes-final-evidence-report-on-gene-therapies-for-hemophiliaa-and-b/
16. Hagen, T. Gene. (2023, Aug. 17). Therapy Performance Guarantees Will 'Improve Access.' Managed Healthcare Executive managedhealthcareexecutive.com/view/gene-therapyperformance-guarantees-will-improve-access-
17. Hixson, M., and Minkoff, N.B. (2021). The Impact of Reinsurance of Gene Therapies on Employer Financial Risk. “American Journal of Managed Care, 27(3), 112–115. DOI: 10.37765/ajmc.2021.88653
18. Paquette, M.T., and Baxter, M. (2023, January). Gene Therapy: The next big thing. Reinsurance Group of America. rgare.com/knowledgecenter/article/gene-therapy-the-next-big-thing
19. In the World of Value-Based Care, Words Matter. (2022, August). Academy of Managed Care Pharmacy. amcp.org/sites/default/ files/2022-08/VBCLexicon_0726.pdf
20. Wehrwein, P. (2023, Nov. 28). They Cost Millions. How Payers Might Manage Those Astronomical Gene Therapy Bills. Managed Healthcare Executive. managedhealthcareexecutive.com/view/theycost-millions-how-payers-might-manage-their-gene-therapy-bills
21. Advancing Patient Interests Through Value-Based Arrangement for Prescription Drugs. (2021, September). Prime Therapeutics and Eli Lilly. primetherapeutics.com/wp-content/uploads/2021/09/ document-eli-lily-white-paper-value-based-arrangements.pdf
39% 96% MEAN FACTOR IX ACTIVITY was sustained at 3 years1
MEAN ANNUAL BLEED RATE (ABR) for all bleeds during months 7 to 36 post treatment remained significantly reduced1†
DECREASE in annualized factor IX consumption1‡
ICER projected that HEMGENIX WILL BE A DOMINANT TREATMENT WITH LOWER COSTS compared with factor IX prophylaxis2
The healthcare economic information provided herein is pursuant to Section 114 of the Food and Drug Administration Modernization Act of 1997 (FDAMA) (Public Law 105-115) and Section 3037 of the 21st Century Cures Act (Public Law 114-255). It is intended for payers, formulary committees, or other similar entities with knowledge and expertise in the area of healthcare economic analysis, carrying out its responsibilities for the selection of drugs for coverage or reimbursement.
Abbreviations: FDA, US Food and Drug Administration; ICER, Institute for Clinical and Economic Review.
*Relative to the current standard of care.
†The same bleed reduction that satisfied the primary endpoint of the trial during months 7 to 18 was sustained during months 7 to 36 (mean ABR of 1.52 compared to 4.17 during the lead-in period).1
‡Mean factor IX consumption (IU/year/participant) decreased from 257,339 during the lead-in period to 10,530 at year 3.
References: 1. Pipe SW, van der Valk P, Verhamme P, et al. Long-term bleeding protection, sustained FIX activity, reduction of FIX consumption and safety of hemophilia B gene therapy: results from the HOPE-B trial 3 years after administration of a single dose of etranacogene dezaparvovec in adult patients with severe or moderately severe hemophilia B. Abstract presented at: 65th American Society of Hematology Annual Meeting; December 9-12, 2023; San Diego, CA. 2. Tice JA, Walton S, Herce-Hagiwara B, et al; Institute for Clinical and Economic Review. Gene Therapy for Hemophilia B and An Update on Gene Therapy for Hemophilia A: Effectiveness and Value. Final evidence report. December 22, 2022. Accessed March 6, 2023. https://icer.org/ wp-content/uploads/2022/12/ICER-Hemophilia-Policy-Recommendations-122222.pdf
| Magellan Rx Report | Spring 2024
Please see Important Safety Information and brief summary of Prescribing Information on the following pages and full Prescribing Information at HEMGENIX.com.
Please see Important Safety Information and brief summary of Prescribing Information on the following pages and full Prescribing Information at HEMGENIX.com.
Infusion reactions, including hypersensitivity reactions and anaphylaxis, may occur. Monitor during administration and for at least 3 hours after end of infusion. If symptoms occur, slow or interrupt administration. Re-start administration at a slower infusion once resolved.
Post-dose, monitor for elevated transaminase levels. Consider corticosteroid treatment should elevations occur. The integration of liver-targeting AAV vector DNA into the genome may carry the theoretical risk of hepatocellular carcinoma development. For patients with preexisting risk factors for hepatocellular carcinogenicity, perform regular (eg, annual) abdominal ultrasound and alpha-fetoprotein testing following administration.
Immune-mediated neutralization of the AAV5 vector capsid
Preexisting neutralizing anti-AAV antibodies may impede transgene expression at desired levels.
In addition to monitoring liver function, monitor for Factor IX activity and Factor IX inhibitors after administration.
BRIEF SUMMARY OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use HEMGENIX safely and effectively. See full prescribing information for HEMGENIX.
HEMGENIX® (etranacogene dezaparvovec-drlb) suspension, for intravenous infusion
Initial U.S. Approval: 2022
-----------------------------------INDICATIONS AND USAGE-----------------------------------
HEMGENIX is an adeno-associated virus vector-based gene therapy indicated for the treatment of adults with Hemophilia B (congenital Factor IX deficiency) who:
• Currently use Factor IX prophylaxis therapy, or
• Have current or historical life-threatening hemorrhage, or
• Have repeated, serious spontaneous bleeding episodes.
None.
--------------------------------WARNINGS AND PRECAUTIONS------------------------------
• Infusion reactions: Monitor during administration and for at least 3 hours after end of infusion. If symptoms occur, slow or interrupt administration. Re-start administration at a slower infusion once resolved.
• Hepatotoxicity: Closely monitor transaminase levels once per week for 3 months after HEMGENIX administration to mitigate the risk of potential hepatotoxicity. Continue to monitor transaminases in all patients who developed liver enzyme elevations until liver enzymes return to baseline. Consider corticosteroid treatment should elevations occur.
The most common adverse reactions (incidence ≥5%) were elevated ALT, headache, blood creatine kinase elevations, flu-like symptoms, infusion-related reactions, fatigue, nausea, malaise, and elevated AST.
HEMGENIX is an adeno-associated virus vector-based gene therapy indicated for the treatment of adults with Hemophilia B (congenital Factor IX deficiency) who:
• Currently use Factor IX prophylaxis therapy, or
• Have current or historical life-threatening hemorrhage, or
• Have repeated, serious spontaneous bleeding episodes.
HEMGENIX is for single use intravenous infusion only.
Contraindications: None.
Please see brief summary of Prescribing Information below and full Prescribing Information at HEMGENIX.com.
To report SUSPECTED ADVERSE REACTIONS, contact the CSL Behring Pharmacovigilance Department at 1-866-915-6958 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
• Hepatocellular carcinogenicity: For patients with preexisting risk factors (e.g., cirrhosis, advanced hepatic fibrosis, hepatitis B or C, non-alcoholic fatty liver disease (NAFLD), chronic alcohol consumption, non-alcoholic steatohepatitis (NASH), and advanced age), perform regular (e.g., annual) liver ultrasound and alpha-fetoprotein testing following administration.
• Monitoring Laboratory tests: Monitor for Factor IX activity and Factor IX inhibitors.
The most common adverse reactions (incidence ≥5%) were elevated ALT, headache, blood creatine kinase elevations, flu-like symptoms, infusion-related reactions, fatigue, malaise and elevated AST.
To report SUSPECTED ADVERSE REACTIONS, contact CSL Behring at 1-866-9156958 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
----------------------------------USE
No dose adjustment is required in geriatric, hepatic, or renal impaired patients.
HEMGENIX is manufactured by uniQure Inc. and distributed by CSL Behring LLC.
HEMGENIX® is a registered trademark of CSL Behring LLC.
©2023 CSL Behring LLC. USA-HGX-0433-JAN24
Based on November 2022 version
Eileen Murphy, Pharm.D. Director of Pharmacy Services Security Health Plan
Myasthenia gravis (MG) is a chronic autoimmune, neuromuscular disease that causes weakness in the skeletal muscles responsible for functions like breathing and moving parts of the body, including the arms and legs.1 Both men and women across all racial and ethnic groups are affected by MG. It can occur at any age, though it most commonly impacts young adult women under the age of 40 and older men over the age of 60.1
Muscle weakness in MG is caused by an error in the transmission of nerve impulses to muscles, which occurs when normal communication between the nerve and muscle is interrupted at the neuromuscular junction.1 When electrical signals or impulses travel down a motor nerve, the nerve endings release a neurotransmitter called acetylcholine (ACh), which binds to sites called acetylcholine receptors (AChR) on the muscle.1 In patients with MG, antibodies block, alter or destroy the receptors for ACh at the neuromuscular junction, which prevents the muscle from contracting.1 The antibodies to the AChR typically cause this, but antibodies to other proteins, such as Muscle-Specific Kinase (MuSK) protein, can impair transmission at the neuromuscular junction.1
Some evidence suggests the thymus gland, which controls immune function, may be associated with MG; this gland plays an important role in the development of the immune system because it produces T-lymphocytes, or T cells.1, 2 While the thymus gland typically grows gradually until puberty, when it gets smaller and is replaced by fat, it remains large in many adults with MG.1 These individuals typically have clusters of immune cells in their thymus gland and may develop tumors of the thymus gland, or thymomas.1, 2 The thymus gland may give incorrect instructions to developing immune cells, which causes the immune system to attack its own cells and produce AChR antibodies.1, 2
Muscle weakness that worsens after periods of activity and improves after periods of rest is characteristic of MG. MG has two classifications: ocular (oMG) and generalized (gMG). About 50% of people with MG develop ocular symptoms first, and oMG may then develop into gMG.1 In particular, muscles that control eye and eyelid movement, facial expression, chewing, talking and swallowing are most often involved in the disorder.1 Onset is typically sudden and the degree of muscle weakness involved may vary depending on the individual.1 Symptoms include weakness of the eye muscles (oMG); drooping of one or both eyelids (ptosis); blurred or double vision (diplopia); change in facial expression; difficulty swallowing; shortness of breath; impaired speech (dysarthria); and weakness in the arms, hands, legs and neck.1, 2
Around 15% to 20% of individuals with MG will experience at least one myasthenic crisis, which happens when the muscles that control breathing weaken to the point where individuals require a ventilator to help them breathe.1, 2 These crises can be triggered by infection, stress, surgery or an adverse reaction to medication.1, 2
After a physical and neurological examination, physicians may order additional tests to confirm an MG diagnosis.1, 2 A blood test may be done to check for an abnormally elevated AChR antibody level, which occurs in most individuals with MG.1 Anti-MuSK antibodies have been found in about half of individuals with MG and can also be detected with a blood test.1 In some individuals with MG, neither antibody is present. An edrophonium test is used to test ocular muscle weakness and uses edrophonium injections to briefly relieve weakness in people with MG.1 Edrophonium blocks the breakdown of ACh and temporarily increases the levels of ACh at the neuromuscular junction.1 Electrodiagnostic tests such as repetitive nerve stimulation can be used for diagnosis. Repetitive nerve stimulation repeatedly activates a person’s nerves with small pulses of electricity to tire specific muscles.1 Single fiber electromyography (EMG) detects impaired nerve-tomuscle transmission and can diagnose mild cases of MG when other tests may fail.1 Diagnostic imaging, such as computed tomography (CT) and magnetic resonance imaging (MRI), may
identify the presence of a thymoma.1 Finally, pulmonary function testing may be performed to measure breathing strength and help predict if respiration may fail and lead to a myasthenic crisis.
Diagnosis of MG is often delayed or missed for long periods of time due to the nature of the main symptom: muscle weakness.1 Since muscle weakness is a common symptom of many disorders, it can be difficult to identify MG, particularly in patients who experience mild weakness or in those whose weakness is restricted to only a few muscles.1
MG is generally treated and controlled with drug therapy to reduce and improve muscle weakness.1 Anticholinesterase medications such as pyridostigmine slow the breakdown of ACh at the neuromuscular junction and thereby improve neuromuscular transmission and increase muscle strength.1 Oral pyridostigmine is typically the initial therapy for mild to moderate MG. In severe cases, immunosuppressive therapies, which suppress the production of abnormal antibodies and improve muscle strength, may be used.1 Plasmapheresis (PLEX) and intravenous immunoglobulin (IVIg) may also be appropriate in severe MG cases, as they remove the destructive antibodies in blood plasma. However, the effectiveness of these treatments only lasts a few weeks to months.1
Monoclonal antibodies are typically used for people who do not respond to conventional immunosuppressive therapies. Monoclonal antibodies target the process by which ACh antibodies injure the neuromuscular junction. In 2017, the FDA approved eculizumab (Soliris®) for the treatment of gMG in people who test positive for the anti-AChR antibody.1
The International Consensus Guidance for MG, published in 2016, addresses symptomatic and immunosuppressive treatment, the use of IVIg and PLEX, management of impending and manifest myasthenic crisis, thymectomy, juvenile MG, MG with antiMuSK antibodies and management of MG during pregnancy.3-5 Pyridostigmine is recommended as the initial treatment in most cases of symptomatic MG. When this is ineffective, corticosteroids or immunosuppressive drugs, including azathioprine, cyclosporine, mycophenolate mofetil, methotrexate and tacrolimus, should be used.3-5 IVIg and PLEX, cyclophosphamide or rituximab may be appropriate in cases of refractory MG. In patients who have severe respiratory insufficiency or who are about to undergo surgery, IVIg and PLEX are ideally used as short-term treatments.3-5
The treatment landscape for MG is quickly shifting. A 2022 study focusing on five treatment classes encompassing 12 treatments for MG was conducted through the Department of Neurology at the Virginia Commonwealth University Health System.6 The study investigators concluded that, because treatments
targeting the underlying pathophysiological pathway are rapidly evolving, the most appropriate selection of treatments considers the mechanisms, indications, risks, benefits and costs of each treatment along with patient preference.6 Additionally, they concluded targeting different pathomechanisms of the disease simultaneously will likely lead to improved outcomes, particularly in severe cases.6
In June 2023, the FDA approved efgartigimod alfa and hyaluronidase-qvfc (Vygart® Hytrulo, Argenx) with Enhanze® for subcutaneous use to treat gMG in adult patients who are AchR antibody-positive.7 The subcutaneous product combination of efgartigimod alfa, a human IgG1 antibody fragment, and recombinant human hyaluronidase PH20 is delivered subcutaneously using Halozyme Therapuetics' Enhaze drug delivery technology.7 Recommended dosage of the product is a single injection (1,008 mg fixed dose) over 30–90 seconds administered subcutaneously by a healthcare professional once weekly for four weeks.7
The FDA approval was based on results from the phase 3 ADAPT-SC clinical trial of efgartigimod alfa and hyaluronidase-qvfc efficacy in reducing anti-AchR antibody concentrations with noninferiority compared to intravenous efgartigimod alfa-fcag (Vyvgart).7 The ADAPT-SC study was a randomized, open-label, parallelgroup, multicenter bridging study following the phase 3 ADAPT clinical trial, which established efficacy, safety and tolerability of intravenously injected efgartigimod alfa-fcag in treating gMG in 167 participants.8, 9 A total of 110 adult participants with gMG were included in ADAPT-SC, randomized 1:1 to receive multiple injections of either subcutaneous efgartigimod alfa and hyaluronidase-qvfc or intravenous efgartigimod alfa-fcag.7, 8 Those included in the study scored at least a 5 at screening and baseline on the MG Activities of Daily Living (MG-ADL) Scale, with at least 50% of total score attributable to non-ocular symptoms.7, 8
The study results showed a mean total IgG reduction of 66.4% and 62.2% from baseline at day 29 in patients treated with subcutaneous efgartigimod alfa and hyaluronidase-qvfc and intravenous efgartigimod alfa-fcag, respectively.7, 8 More than 69% of patients treated with subcutaneous efgartigimod alfa and hyaluronidase-qvfc had at least a two-point improvement in MGADL Scale score for at least four consecutive weeks, and 65.5% of those had at least a three-point improvement of the Quantitative MG (QMG) score for at least four consecutive weeks.8, 9 Additionally,
37% of patients treated with subcutaneous efgartigimod alfa and hyaluronidase-qvfc achieved minimal symptom expression (MSE) after one cycle.8, 9
The FDA approved rozanolixumab-noli (Rystiggo®, UCB, Inc.) in June 2023 for the treatment of gMG in adult patients who are AChR- or anti-MuSK antibody-positive.10, 11 Approval was based on results from the MycarinG multicenter, phase 3, randomized, double-blind, placebo-controlled study of 200 patients with the AChR or MuSK subsets of the disease.10, 11 The primary endpoint for the MycarinG study was a change in the MG-ADL score, an eight-item patient-reported scale assessing MG symptoms.12 Patients enrolled in the study were randomized 1:1:1 to receive subcutaneous infusions once a week for six weeks of either rozanolixizumab 7 mg/kg, rozanolixizumab 10 mg/kg or placebo.12 In the rozanolixizumab 7 mg/kg group and 10 mg/ kg groups, reductions in the MG-ADL score from baseline to day 43 were greater than the placebo group (-3.37, -3.40 and -0.78, respectively).12 Eighty one percent of rozanolixizumab 7 mg/kg group and 83% of the rozanolixizumab 10 mg/kg group experienced adverse events, compared to 67% of the placebo group.12 Frequently reported adverse events included headache,
diarrhea and pyrexia.12 Eight percent of the rozanolixizumab 7 mg/kg group, 10% of the rozanolixizumab 10 mg/kg and 9% of the placebo group experienced serious adverse events.12
In October 2023, the FDA approved zilucoplan (Zilbrysq®, UCB, Inc.) for the treatment of gMG in adult patients who are AChR antibody-positive, making it the first once-daily subcutaneous, targeted C5 complement inhibitor for gMG and the only oncedaily gMG-target therapy for self-administration.13 Approval was based on the phase 3 RAISE study, a randomized, double-blind, placebo-controlled study of 174 patients with AChR-positive gMG, a MG-ADL score of at least 6, and a QMG score of at least 12.14 All participants were randomly assigned 1:1 to receive subcutaneous zilucoplan 0.3 mg/kg once daily by self-injection or placebo for 12 weeks.14 Change from baseline to week 12 in MG-ADL score was the primary endpoint.14
Those treated with zilucoplan showed a greater reduction in MG-ADL score from baseline to week 12 when compared to those who received placebo (-4.39 versus -2.30, respectively).14 Of those in the zilucoplan group, 77% experienced adverse events compared to 70% of those in the placebo group. The
pozelimab (REGN3918)
batoclimab (IMVT-1401)
gefurulimab (ALXN1720)
Regeneron Pharmaceuticals IV; SC Complement inhibitors Phase 3
Immunovant; Roivant Sciences SC FcRn antagonist Phase 3
Alexion Pharmaceuticals; AstraZeneca SC Complement inhibitors Phase 3
Descartes-08 Cartesian Therapeutics Injectable CAR-T immunotherapy Phase 2
vemircopan (ALXN2050)
tolebrutinib (SAR442168)
Abbreviations:
Alexion Pharmaceuticals; AstraZeneca Oral Complement inhibitors Phase 2
most common adverse event was injection-site bruising.14 Each group had similar incidence of serious adverse events and one death occurred in each group, neither of which were considered treatment-related.14
A 2021 ICER report assessed the clinical effectiveness of both eculizumab (Soliris®) and efgartigimod (Vyvgart) for the treatment of MG.15 The ICER report noted there is moderate certainty eculizumab delivers a small net benefit over conventional therapy alone, with the possibility of a substantial net benefit.15 ICER considered efgartigimod comparable to conventional therapy alone, with the possibility of delivering a substantial net benefit in adults who are gMG positive for anti-AchR antibodies.15 No new ICER report has been published on the newly approved gMG treatments.
As the treatment landscape for MG rapidly evolves, updated clinical treatment guidelines considering costs versus benefits, risks, patient preferences and comorbidities are becoming increasingly critical.6 Emerging treatments, including targeted
Emerging treatments, including targeted treatments with new mechanisms of action with the potential to improve efficacy and tolerability, may lead to improved outcomes, especially in severe cases.
treatments with new mechanisms of action with the potential to improve efficacy and tolerability, may lead to improved outcomes, especially in severe cases.6 Guidelines addressing these new promising treatment options will help providers and payers determine the most appropriate therapy for each individual patient with MG. These guidelines are valuable to payers in determining which management options to utilize in this category and whether utilization management, prior authorization and step therapy strategies are appropriate and provide value while ensuring patients can access treatment.
References
1. National Institutes of Health. (2020, March). Myasthenia Gravis ninds.nih.gov/sites/default/files/migrate-documents/myasthenia_ gravis_e_march_2020_508c.pdf
2. Myasthenia Gravis. Johns Hopkins Medicine. Retrieved January 26, 2024, from hopkinsmedicine.org/health/conditions-and-diseases/ myasthenia-gravis
3. Gaspar, D. D. (2022, February 25). Myasthenia Gravis Guidelines. RareDiseaseAdvisor. rarediseaseadvisor.com/disease-info-pages/ myasthenia-gravis-guideline-recommendations/
4. Sanders, D. B., and Wolfe, G.I. (2016). International consensus guidance for management of myasthenia gravis: Executive summary. Neurology. pubmed.ncbi.nlm.nih.gov/27358333/
5. Narayanaswami, P, and Sanders, D.B. (2021). International Consensus Guidance for Management of Myasthenia Gravis: 2020 Update. Neurology. pubmed.ncbi.nlm.nih.gov/33144515/
6. DeHart-McCoyle, M., et al. (2023, June). New and emerging treatments for myasthenia gravis. BMJ Medicine. bmjmedicine.bmj. com/content/bmjmed/2/1/e000241.full.pdf
7. FDA Approves Vyvgart Hytrulo to Treat Patients with Anti-AChR Antibody-Positive Generalized Myasthenia Gravis. (2023, June 22). Practical Neurology. practicalneurology.com/news/fda-approvesvyvgart-hytrulo-to-treat-patients-with-anti-achr-antibody-positivegeneralized-myasthenia-gravis
8. Argenx Announces Positive Topline Phase 3 Data from ADAPTSC Study Evaluating Subcutaneous Efgartigimod for Generalized Myasthenia Gravis. (2022, March 22). Argenx. argenx.com/sites/ default/files/media-documents/argenx_ADAPT-SC_TLR_Press_ Release.pdf
9. Sacca, F., and Barnett, C. (2023). Efgartigimod improved healthrelated quality of life in generalized myasthenia gravis: results from a randomized, double-blind, placebo-controlled phase 3 study (ADAPT). Journal of Neurology, pubmed.ncbi.nlm.nih. gov/36598575/
10. Dunleavy, K. (2023, June 27). UCB finally gets a win with the FDA, scoring approval for myasthenia gravis drug Rystiggo. FiercePharma fiercepharma.com/pharma/ucb-finally-gets-win-fda-scoringapproval-myasthenia-gravis-drug-rystiggo
11. UCB announces U.S. FDA approval of RYSTIGGO® (rozanolixizumabnoli) for the treatment of adults with generalized myasthenia gravis (2023, June 27). UCB. ucb.com/stories-media/Press-Releases/ article/UCB-announces-US-FDA-approval-of-RYSTIGGORrozanolixizumab-noli-for-the-treatment-of-adults-with-generalizedmyasthenia-gravis
12. Bril, V., and Druzdz, A. (2023). Safety and efficacy of rozanolixizumab in patients with generalised myasthenia gravis (MycarinG): a randomised, double-blind, placebo-controlled, adaptive phase 3 study. Lancet Neurology. pubmed.ncbi.nlm.nih.gov/37059507/
13. UCB announces U.S. FDA approval of ZILBRYSQ® (zilucoplan) for the treatment of adults with generalized myasthenia gravis. (2023, October 27). UCB. ucb.com/stories-media/Press-Releases/article/ UCB-announces-US-FDA-approval-of-ZILBRYSQR-zilucoplan-forthe-treatment-of-adults-with-generalized-myasthenia-gravis
14. Howard, J. F., and Bresch S. (2023). Safety and efficacy of zilucoplan in patients with generalised myasthenia gravis (RAISE): a randomised, double-blind, placebo-controlled phase 3 study. Lancet Neurology. pubmed.ncbi.nlm.nih.gov/37059508/
15. Eculizumab and Efgartigimod for the Treatment of Myasthenia Gravis: Effectiveness and Value. Institute for Clinical and Economic Review (2021, October 20). Institute for Clinical and Economic Review. icer. org/wp-content/uploads/2021/03/ICER_Myasthenia-Gravis_FinalReport_Unmasked_Data.pdf
Kathryn Canaday, Pharm.D. Vice President, Pharmacy and Clinical Drug Management Medical Mutual of Ohio
Affecting approximately 15 million Americans, age-related macular degeneration (AMD) is an ophthalmic disorder that occurs when aging causes damage to the macula, leading to vision loss.1 It is the leading cause of vision loss for older adults, and common risk factors include being over the age of 55, having family history of AMD, being Caucasian and smoking.1 While AMD does not cause complete vision loss, it causes loss of central vision, making it challenging to see faces, read, drive or complete other daily activities.1
Dry AMD (dAMD), or atrophy AMD, occurs when the macula thins with age. There are three stages of dAMD (early, intermediate and late), which typically progress slowly over several years.1 Patients with early dAMD generally have no symptoms. While some patients with intermediate dAMD have no symptoms, others may notice mild blurriness or trouble seeing in low light.1 Geographic atrophy (GA) is indicative of late stage dAMD and manifests as atrophic lesions that start in the outer retina and progressively expand to cover the macula and the fovea. GA leads to irreversible vision loss over time.2 Prior to 2023, there were no approved treatments for GA or dAMD.1
The second type of AMD, wet AMD (wAMD) or neovascular AMD, is a less common form of late AMD that causes more rapid vision loss.1 While wAMD is always late stage, any stage of dAMD can develop into wAMD, which occurs when abnormal blood vessels grow in the back of the eye and damage the macula.1 Late AMD, whether wet or dry, can cause straight lines to look wavy or crooked. A blurry area near the center of vision may form and grow over time, causing colors to appear less bright and create trouble seeing in low lighting.1 There are several available treatment options for wAMD.1
The leading cause of irreversible blindness in adult Americans is diabetic retinopathy, the most common diabetic eye disease. Diabetic macular edema (DME) is a result of fluid buildup in the macula caused by diabetic retinopathy and can occur at any stage of the condition.3 An estimated 7.7 million Americans live with diabetic retinopathy, and around 750,000 of those have DME.3 Poor blood sugar control and other associated medical conditions, such as high blood pressure, increase the risk of blindness in people with diabetes.3
Retinal vein occlusion (RVO) occurs when a blood clot blocks the main vein where blood flows out of the retina. It typically only affects one eye. When blood flow is blocked, causing a lack of oxygen, the body releases vascular endothelial growth factor (VEGF) protein. Excess VEGF protein can cause macular edema.4 Vision loss in people with RVO is often caused by the development of macular edema.5 People at risk of developing RVO include adults aged 50 or older and those with high blood pressure, diabetes, glaucoma or arteriosclerosis.
In February 2023, the FDA approved the first treatment for GA secondary to AMD: pegcetacoplan (Syfovre®, Apellis Pharmaceuticals). Prior to this approval, there were no available treatments for dAMD.6 The DERBY and OAKS phase 3, multicenter, randomized, double-masked, sham-controlled trials studied and compared the efficacy of pegcetacoplan with sham injections.7 These trials evaluated injections given monthly and every other month. Results from OAKS showed monthly injections reduced lesion growth rate by 22% compared with 18% for every other
month.7 DERBY results showed monthly injections reduced lesion growth rate by 18% compared with 17% for every other month.7
The FDA approved avacincaptad pegol (Izervay®, Iveric Bio) in August 2023 for the treatment of GA second to AMD.8 Avacincaptad pegol is a complement C5 inhibitor and the second treatment approved by the FDA to treat GA.8 Notably, it is the only currently approved treatment for which trial results show a statistically significant reduction in progression of GA after 12 months.8 Safety and efficacy were evaluated in the GATHER1 and GATHER2 trials, during which patients diagnosed with GA secondary to AMD were administered 2 mg intravitreal doses of avacincaptad pegol per month.9, 10 After baseline, there were follow-ups at six and 12 months evaluating the rate of progression of GA.9, 10 In GATHER1, monthly avacincaptad pegol treatment reduced mean GA growth over 18 months by 28.1% (0.168 mm) for the 2 mg cohort and 30% for the 4 mg cohort.9 In GATHER2, the mean rate of square-root-transformed GA area growth was 0.336 mm/year with avacincaptad pegol 2 mg and 0.392 mm/year with sham, a difference in growth of 0.056 mm/year representing a 14% difference between the avacincaptad pegol 2 mg group and the sham group.10 Both trials showed a statistically significant reduction in the progression of GA when patients were treated with avacincaptad pegol compared with a placebo.9, 10
Drug Manufacturer Route of Administration Mechanism of Action Indication Status
VEGF Inhibitors
Bevacizumab-vikg (Lytenava™) Outlook Therapeutics Ophthalmic VEGF inhibitor DME; wAMD; macular edema following RVO Phase 3
OPT-302 Opthea Limited; Vegenics Intravitreal VEGF inhibitor wAMD Phase 3
Tarcocimab tedromer (KSI-301) Kodiak Sciences Intravitreal VEGF inhibitor wAMD; DME Phase 3
TAB014 TOT BIOPHARM Intravitreal VEGF inhibitor wAMD Phase 3
VEGF Biosimilars
Ranibizumab (Xlucane™) Xbrane Biopharma; Stada Arzneimittel Intravitreal VEGF inhibitor wAMD; mCNV; macular edema following RVO Pending (4/21/24)
Aflibercept (Yesafili®) Viatris; Johnson & Johnson Innovative Medicine; Biocon Intravitreal VEGF inhibitor wAMD; macular edema following RVO; DME; DR Pending
Aflibercept (FYB203) Formycon; BioEQ Ophthalmic VEGF inhibitor wAMD Pending (06/2024)
Aflibercept (ABP 938) Amgen Intravitreal VEGF inhibitor wAMD Pending (3Q 2024)
Aflibercept (SB15) Samsung Bioepis; Biogen Intravitreal VEGF inhibitor wAMD Pending (2024)
Ranibizumab (LUBT010) Lupin Pharmaceuticals Intravitreal VEGF inhibitor wAMD Phase 3
Aflibercept (SOK583A1) Sandoz; Hexal Intravitreal VEGF inhibitor wAMD Phase 3
Aflibercept (AVT06) Alvotech; Teva Pharmaceutical Industries Intravitreal VEGF inhibitor wAMD Phase 3
Aflibercept (SCD411) Sam Chun Dang Pharm Intravitreal VEGF inhibitor wAMD Phase 3
Non-VEGF
RGX-314 Regenxbio; AbbVie Ophthalmic Gene therapy wAMD Phase 3
Dexamethasone (OCS-01) Oculis Ophthalmic Corticosteroid DME Phase 3
RG6179 Genentech; Roche Intravitreal TBD Macular edema Phase 3
Dry AMD
Gildeuretinol (ALK-001) Alkeus Pharmaceuticals Oral Vitamin A analogue dAMD Phase 3
Tinlarebant (LBS-008) Belite Bio; Lin Bioscience Oral RBP4 antagonist dAMD Phase 3
Abbreviations: AMD = age-related macular degeneration; dAMD = dry age-related macular degeneration; DME = diabetic macular edema; DR = diabetic retinopathy; mCNV = myopic choroidal neovascularization; RBP4 = retinal binding protein 4; RVO = retinal vein occlusion; TBD = to be determined; VEGF = vascular endothelial growth factor; wAMD = wet age-related macular degeneration
In August 2023, the FDA approved high-dose aflibercept (Eylea HD®, Regeneron), for the treatment of several ophthalmic conditions including wAMD, DME and diabetic retinopathy.11 This new formulation of aflibercept is an 8-mg intravitreal injection compared with the 2-mg dose for the original product to be dosed at 8 mg every four weeks for three months, then 8 mg every eight to 16 weeks for wAMD or DME and every eight to 12 weeks for diabetic retinopathy.11 Approval was based on data and results from the 48-week PULSAR and PHOTON double-masked, active-controlled trials comparing safety, efficacy and clinical outcomes of high-dose aflibercept compared to aflibercept in wAMD (PULSAR) and DME (PHOTON).12, 13 High-dose aflibercept demonstrated clinically equivalent vision gains at 48 weeks with 12- and 16-week dosing regimens after only three initial monthly doses compared with an 8-week dosing regimen of aflibercept after initial monthly doses.12, 13 Of patients randomized to receive high-dose aflibercept 12- or 16-week regimens, most were able to maintain the dosing intervals through 48 weeks.12, 13
This approval follows the issuance of a complete response letter (CRL) by the FDA to Regeneron and Bayer for high-dose aflibercept; the CRL cited issues regarding manufacturing facility inspection at a third-party filler and did not cite issues with safety and efficacy data, the product, trial design, labeling or drug substance manufacturing.14
Given treatment delays can be significant and often irreversible, it will be critical for payers to ensure timely diagnosis and treatment to improve long-term outcomes and manage costs.
In October 2023, the FDA approved faricimab-svoa (Vabysmo®, Genentech) for the treatment of macular edema following RVO.15 This marks the third indication for faricimab-svoa. It had previously been approved for wAMD and DME.15 Approval was based on results from the global BALATON and COMINO phase three studies that demonstrated monthly treatment with faricimab-svoa provided early and sustained improvement in vision in people with branch and central RVO.16, 17 BALATON and COMINO are two randomly assigned, multicenter, double-masked global phase 3
The evolution of GLP-1s
Discover your individualized strategy
studies evaluating efficacy and safety of faricimab-svoa compared to aflibercept.16, 17 Patients were randomly assigned 1:1 to receive six monthly injections of either faricimab-svoa or aflibercept for the first 20 weeks, and then from weeks 24 to 72. All patients received faricimab-svoa up to every four months using a treat-and-extend approach.16, 17 Change in best-corrected visual acuity (BCVA) from baseline at 24 weeks was the primary endpoint of the studies.16, 17 In both studies, the average vision gains from baseline were similar between the two treatments.16, 17 Vision gains at 24 weeks were +16.9 eye chart letters in the faricimab-svoa arm in BALATON and COMINO and +17.5 letters and +17.3 in the aflibercept arm in BALATON and COMINO, respectively.16, 17
When it comes to managing patients with ophthalmic disorders such as AMD and DME, there are many components to consider. In the past two years, the ophthalmic disorders space has seen an increase in biosimilar approvals and launches. With 18 products in the pipeline (See Table 3) and an additional 27 products in phase 2 for ophthalmic disorders, there are several factors for payers to consider when managing this category, such as clinical components, pipeline and legislation.
Appropriate treatment depends upon several factors, including drug availability, dosing frequency and intervals, underlying
While there are several treatment options available and the space is growing, many health plans across the country continue to leverage the cost-effective bevacizumab-first strategy.
disease state management and patient response. Given the wide range of recommended maintenance dosing intervals for specific treatment options (e.g., every four to 16 weeks, etc.) and the differences in recommended dosing via clinical trials versus that observed by providers, provider engagement is crucial.18 The wide dosing range can account for significant cost differences per eye per patient (See Table 4). It is important to note the majority of patients will likely require the higher frequency of recommended dosing in initial years, contributing to larger initial costs for payers. As treatment delays can be significant and often irreversible, it will be critical for payers to ensure timely diagnosis and treatment to improve long-term outcomes and manage costs.19
Abbreviations: ASP = average sales price; DME = diabetic macular edema; FDA = Food and Drug Administration; N/A = not available; WAC = wholesale acquisition cost; wAMD = wet age-related macular degeneration
Dosing is based on package insert and the treat-and-extend approach was used where appropriate Yearly costs have been rounded and reflect per eye per patient
*Not FDA-approved; however, compounded bevacizumab is utilized off-label via dosing from clinical compendia ^based on every 8-week dosing; costs may vary with every 12 or 16-week dosing
Under the Inflation Reduction Act (IRA), the CMS can negotiate with pharmaceutical manufacturers for reduced prices with the overall goal of establishing maximum fair prices for products. Criteria for negotiations include products for which there is no generic or biosimilar competition and those that are considered high spend products (e.g., top 50 drugs in terms of total expenditure).20 The negotiated prices would be effective starting 2028 (for Part B). It is expected that ophthalmic disorder treatments will be on the list for CMS to establish a maximum fair price.20 Companies may avoid negotiation with CMS by dropping any pending litigation in 2026 or earlier and allowing biosimilar products to be launched, disqualifying their product, because only drugs without generics and/or biosimilars will be considered for this program. The launch of biosimilars may result in market share shifts away from reference product, and with multiple biosimilars in the market, it will be imperative for payers to manage strategies based on overall cost.
An analysis was conducted using data from the Magellan Rx book of business to quantify the savings associated with an Avastin-first strategy. Implementing a prior authorization for branded anti-VEGF
products that require an Avastin-first step resulted in commercial savings of $6.6 million and Medicare savings of $2.5 million.21 Interestingly, clients that adopted such a strategy showed up to 72% Avastin utilization among new starts, compared to only 28% for clients that did not require an Avastin-first step.21 Additionally, from a cost perspective, Eylea was associated with seven times the total expenditure while representing approximately 1,600 fewer patients compared to Avastin.21
While there are several treatment options available and the space is growing, many health plans across the country continue to leverage the cost-effective bevacizumab-first strategy (See Table 4). Notably, the cost for compounded bevacizumab is considerably lower than other therapies and many payers do not currently require prior authorization for compounded bevacizumab where the drug is clinically appropriate. With the recent approval and launch of several biosimilars and many others on the horizon, some payers may choose to add an additional step after bevacizumab and prioritize biosimilars based on established efficacy and lower costs compared to reference products.
References
1. Age-Related Macular Degeneration (AMD). (2021, June 22). National Eye Institute. nei.nih.gov/learn-about-eye-health/eye-conditionsand-diseases/age-related-macular-degeneration
2. Bakri, S.J., Bektas, M., et al. (2023). Geographic atrophy: Mechanism of disease, pathophysiology, and role of the complement system. Journal of Managed Care & Specialty Pharmacy, 29(5), 2–11. DOI: 10.18553/jmcp.2023.29.5-a.s2.
3. Macular Edema. (2019, July 8). National Eye Institute. nei.nih.gov/ learn-about-eye-health/eye-conditions-and-diseases/macularedema
4. Central Retinal Vein Occlusion (CRVO). (2023, Nov. 15). National Eye Institute. nei.nih.gov/learn-about-eye-health/eye-conditions-anddiseases/central-retinal-vein-occlusion-crvo
5. Rhoades, W., Dickson, D., et al. (2017) Management of macular edema due to central retinal vein occlusion – The role of aflibercept. Taiwan Journal of Ophthalmology, 7(22), 70–76. DOI: 10.4103/tjo.tjo_9_17
6. Joszt, L. (2023, Feb. 17). FDA Approves First Treatment for Geographic Atrophy. American Journal of Managed Care. ajmc.com/ view/fda-approves-first-treatment-for-geographic-atrophy
7. Goldberg, R., Heier, J.S., et al. (2022). Efficacy of intravitreal pegcetacoplan in patients with geographic atrophy (GA): 12-month results from the phase 3 OAKS and DERBY studies. Investigative Ophthalmology & Visual Science, 63(7), 1500. iovs.arvojournals.org/ article.aspx?articleid=2779604
8. Bonavitacola, J. (2023, Aug. 7). FDA Approves New Treatment for Geographic Atrophy. American Journal of Managed Care. ajmc.com/ view/fda-approves-new-treatment-for-geographic-atrophy
9. Patel, S.S., Lally D.R., et al. (2023). Avacincaptad pegol for geographic atrophy secondary to age-related macular degeneration: 18-month findings from the GATHER1 trial. Eye, 37, 3551–3557. nature.com/articles/s41433-023-02497-w
10. Khanani, A.M., Patel, S.S., et al. (2023). Efficacy and safety of avacincaptad pegol in patients with geographic atrophy (GATHER2): 12-month results from a randomised, double-masked, phase 3 trial. Lancet, 402(10411), 1449–1458. DOI: 10.1016/S01406736(23)01583-0
11. Jeremias, S. (2023, Aug. 31). FDA Approves Higher-Dose Version of Aflibercept. American Journal of Managed Care. ajmc.com/view/fdaapproves-higher-dose-version-of-aflibercept
12. Spitzer, M.S. (2023). Intravitreal aflibercept 8 mg injection in patients with neovascular age-related macular degeneration: 48-week results from the Phase 3 PULSAR trial. Investigative Ophthalmology & Visual Science, 64(8), 461. iovs.arvojournals.org/ article.aspx?articleid=2785795
13. Do, D.V. (2023). Aflibercept 8 mg for Diabetic Macular Edema: 48-week Results From the Phase 2/3 PHOTON Trial. Investigative Ophthalmology & Visual Science, 64(8), 2814. iovs.arvojournals.org/ article.aspx?articleid=2787521
14. FDA Rejects Higher Dose of Eylea. (2023, June 28). Formulary Watch. formularywatch.com/view/fda-rejects-higher-dose-of-eylea
15. Hutton, D. (2023, Oct. 27). FDA approves faricimab-svoa for the treatment of retinal vein occlusion. Ophthalmology Times ophthalmologytimes.com/view/fda-approves-faricimab-svoa-forthe-treatment-of-retinal-vein-occlusion
16. Hutton, D. (2023, Oct. 27). Positive topline phase 3 results show faricimab-svoa improved vision for people living with retinal vein occlusion. Ophthalmology Times. ophthalmologytimes.com/view/ positive-topline-phase-3-results-show-faricimab-svoa-improvedvision-for-people-living-with-retinal-vein-occlusion
17. Genentech's Vabysmo Maintained Vision Improvements With Extended Treatment Intervals Up to Four Months for People with Retinal Vein Occlusion (RVO) in Phase III Trials. (2023, Oct. 9). Genentech. gene.com/media/press-releases/15003/2023-10-09/ genentechs-vabysmo-maintained-vision-imp
18. Kenney, J. and Stephens, K.U. (2022, Feb. 23). Approaching Treatment of Wet AMD and DME With Anti-VEGF Agents. American Journal of Managed Care. ajmc.com/view/approaching-treatment-ofwet-amd-and-dme-with-anti-vegf-agents
19. Kenney, J. and Stephens, K.U. (2022, March. 9) Impact of Therapy Delays in Wet AMD and DME. American Journal of Managed Care ajmc.com/view/impact-of-therapy-delays-in-wet-amd-and-dme
20. IPD Analytics. ipdanalytics.com
21. Internal data
References: 1. Brett JO, Spring LM, Bardia A, Wander SA. ESR1 mutation as an emerging clinical biomarker in metastatic hormone receptor-positive breast cancer. Breast Cancer Res. 2021;23(1):85. 2. Dustin D, Gu G, Fuqua SAW. ESR1 mutations in breast cancer. Cancer. 2019;125(21):3714-3728. 3. ORSERDU [prescribing information]. New York, NY: Stemline Therapeutics, Inc., a Menarini Group Company; 2023.
Simone Ndujiuba, Pharm.D., BCOP
Director, Clinical Strategy and Innovation, Oncology Magellan Rx Management, a Prime Therapeutics Company
Martin Burruano, R.Ph. Vice President, Pharmacy Services
Biomarker testing is the process of identifying genes, proteins and other substances (biomarkers or tumor markers) that provide more information about a cancer diagnosis.1 Certain biomarkers affect how some treatments work or may help providers identify appropriate treatment.1
Some cancer treatments, including targeted therapies and immunotherapies, may only work for individuals with certain tumor biomarkers.1 People with cancer that has genetic changes in the epidermal growth factor receptor (EGFR) gene can receive treatments tailored to target those changes; these treatments are called EGFR inhibitors.1
Providers routinely test breast cancer tumors for three biomarkers: estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2).2 Tumors that test positive for hormone receptors (HR-positive), known as ER- and PR-positive tumors, are likely to respond to hormonal therapies, including tamoxifen or an aromatase inhibitor. HER2-positive tumors are likely to respond to anti-HER2 therapies.2
In some cases, additional biomarker testing will be conducted on breast cancer tumors.2 However, the utilization of these additional tests often depends on consideration of other factors, such as the stage of cancer, or if it is triple-negative (HR-negative and HER2-negative) or HR-positive and has grown during treatment.2 Genomic testing or profiling may be used in early-stage breast cancers to determine recurrence risk, which may impact the course of treatment.2 In advanced-stage or metastatic triple-negative breast cancer diagnoses, providers may test for PD-L1 status to determine if immunotherapy with pembrolizumab would be appropriate.2 Circulating tumor DNA (ctDNA) tests can allow providers to identify cancer recurrence prior to physical symptoms or manifestations.2 Mutation tests can be completed when tumors continue to grow despite treatment with hormonal therapy; tests for mutations on genes such as the ESR1, BRCA1/BRCA2 and PIK3CA genes can be critical in determining effective therapy for tumors with specific gene mutations.2 Some cancer antigen tests help providers assess if a cancer is growing or metastasizing.
Testing for ESR1 mutations may be appropriate and valuable in ER-positive, HER2-negative tumors following progression on endocrine therapy with or without a CDK4/6 inhibitor.
About 70% of all breast cancers are ER-positive, and many of these patients essentially become cured of the disease.3 While effective hormonal and targeted therapies are available, half of these patients will relapse or progress further to incurable metastatic disease.3 Among other potential factors leading to endocrine therapy resistance are acquisition of ESR1 fusions or activating ESR1 missense mutations.3 Preclinical and clinical studies have demonstrated that ESR1 mutations can preexist in primary tumors and can become enriched during metastasis.3 While several endocrine therapy agents are available, all HR-positive metastatic
breast cancer (mBC) will typically become resistant to these treatments.4 Specifically, ESR1 mutations represent an important mechanism of resistance to aromatase inhibitors.4
ESR1 mutations are rarely found in primary tumors; however, up to 40% of mBC cases develop ESR1 mutations after progression on initial endocrine therapy, resulting in worse outcomes.5
Testing for ESR1 mutations may be appropriate and valuable in ERpositive, HER2-negative tumors following progression on endocrine therapy with or without a CDK4/6 inhibitor. There may be value in testing at each progression on endocrine therapy.6 Patients with ESR1 mutations can be identified via a plasma specimen, or ctDNA. Liquid biopsy is the most successful method of testing for ESR1 mutations, as ctDNA can provide a more complete biomarker profile via these means; tissue biopsies are less effective and not adequate for detecting these mutations.6-8 The ESR1 mutation is found in ESR1 gene codons, including 380, 537 and 538.9 The Guardant360® technology is the first analysis tool that combines liquid biopsy and next-generation sequencing and may be a valuable option; equivalent in-house tests may be appropriate as well.9
The FDA approved elacestrant (Orserdu®, Stemline Therapeutics) in January 2023 for the treatment of postmenopausal women or adult men with ER-positive, HER2-negative, ESR1-mutated advanced or mBC with disease progression following at least one line of endocrine therapy.10 As a companion diagnostic device, the FDA approved the Guardant360 CDx® assay to identify patients with breast cancer for treatment with elacestrant.10 Elacestrant, a novel oral selective ER degrader (SERD), selectively binds to the ER in breast cancer cells, inhibiting tumor growth.4
The approval of elacestrant was based on efficacy results from the EMERALD randomized, open-label, active-controlled, multicenter trial of 478 postmenopausal women and men with ER-positive, HER2-negative advanced or mBC.11 Of those participating, 228 patients had ESR1 mutations. To participate, patients were required to have disease progression while on one or two prior lines of endocrine therapy, including one line containing a CDK4/6 inhibitor.11 Those participating were randomized 1:1 to receive elacestrant 345 mg orally once daily or the investigator’s choice of endocrine therapy (fulvestrant or an aromatase inhibitor).11 Randomization was further stratified by ESR1 mutation status, prior treatment with fulvestrant and visceral metastasis.11
A statistically significant difference in progression-free survival (PFS), the major efficacy outcome, was observed in the intentionto-treat (ITT) population and in the subgroup of patients with ESR1 mutations.11 Of those with the mutation, median PFS was 3.8 months versus 1.9 months in the elacestrant arm compared to the fulvestrant or aromatase inhibitor arm.11 Additional analyses of the results showed a median PFS of up to 8.6 months dependent on the duration of prior treatment with CDK4/6 inhibitors.12 Longer duration of prior CDK4/6 inhibitor therapy was associated with longer PFS with elacestrant.12 These results suggest potential consideration of elacestrant as a new standard of care as a monotherapy endocrine sequency option in ER-positive, HER2negative mBC after initial treatment with CDK4/6 inhibitor before moving on to combination therapies.12
Results from a 2023 survey conducted by CancerCare show that biomarker testing helped providers tailor therapy for 93% of respondent patients whose cancers were tested over the past three years. Twenty percent of cancer patients reported avoiding unnecessary chemotherapy and/or radiation, and 10% became eligible for a clinical trial.13 One-third of respondents who received biomarker testing reported the test was not covered by insurance, while some who obtained coverage reported it was initially denied and advocacy led to its coverage.13 Notably, 14 states have
Biomarker testing can be critical in ensuring providers and patients have the necessary information for informed decision-making during the treatment process.
enacted, or are working to enact, legislation mandating coverage for biomarker testing in cancer patients, with lawmakers in eight more states having introduced biomarker coverage legislation.14
Biomarker testing can be critical in ensuring providers and patients have the necessary information for informed decision-making during the treatment process. While the established breast cancer biomarkers, including ER, PR, HER2 and PD-L1, remain widely covered, coverage for further biomarker and tissue-based testing is less consistent.15 However, the increase in FDA-approved therapies with associated genomic markers may have led to parallel increases in coverage.15
Key to payer management will be effectively identifying the appropriate patient populations and ensuring access to necessary and valuable testing, linked to evidence of improved outcomes.
References
1. Biomarker Testing for Cancer Treatment. (2021, Dec. 14). National Cancer Institute. cancer.gov/about-cancer/treatment/types/ biomarker-testing-cancer-treatment#what-is-biomarker-testing-forcancer-treatment
2. DePolo, J. (2023, Dec. 19). Breast Cancer Biomarkers and Biomarker Tests. BreastCancer.Org. breastcancer.org/screening-testing/tumormarker-tests
3. Dustin, D., et al. (2020). ESR1 Mutations in Breast Cancer. Cancer, 125(21), 3714–3728. DOI: 10.1002/cncr.32345
4. Varella, L. and Massimo, C. (2023). Evaluating Elacestrant in the Management of ER-Positive, HER2-Negative Advanced Breast Cancer: Evidence to Date. OncoTargets and Therapy, 16, 189–196. DOI: 10.2147/OTT.S400563
5. Brett, J.O., et al. (2021). ESR1 mutation as an emerging clinical biomarker in metastatic hormone receptor-positive breast cancer. Breast Cancer Research, 23(1), 85. DOI: 10.1186/s13058-02101462-3
6. Russano, Marco, et al. (2020). Liquid biopsy and tumor heterogeneity in metastatic solid tumors: the potentiality of blood samples. Journal of Experimental & Clinical Cancer Research, 39(1), 95. DOI: 10.1186/s13046-020-01601-2
7. Lee, N., et al. (2020). Currently Applied Molecular Assays for Identifying ESR1 Mutations in Patients with Advanced Breast Cancer. International Journal of Molecular Sciences, 21(22), 8807. DOI: 10.3390/ijms21228807
8. Spoerke, J.M., et al. (2016). Heterogeneity and clinical significance of ESR1 mutations in ER-positive metastatic breast cancer patients receiving fulvestrant. Nature Communications, 13(7), 11579. DOI: 10.1038/ncomms11579
9. Liao, H., et al. (2020). Detection of ESR1 Mutations Based on Liquid Biopsy in Estrogen Receptor-Positive Metastatic Breast Cancer: Clinical Impacts and Prospects. Frontiers in Oncology, 10, 587671. DOI: 10.3389/fonc.2020.587671
10. FDA approves elacestrant for ER-positive, HER2-negative, ESR1mutated advanced or metastatic breast cancer. (2023, Jan. 27). U.S. Food and Drug Administration. fda.gov/drugs/resourcesinformation-approved-drugs/fda-approves-elacestrant-er-positiveher2-negative-esr1-mutated-advanced-or-metastatic-breast-cancer
11. Bidard, F.C., et al. (2022). Elacestrant (oral selective estrogen receptor degrader) Versus Standard Endocrine Therapy for Estrogen Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: Results from the Randomized Phase III EMERALD Trial. Journal of Clinical Oncology, 40, 3246–3256. DOI: 10.1200/JCO.22.00338
12. Goodman, A. (2023, Oct. 10). EMERALD Trial: Elacestrant vs Standard Endocrine Monotherapy for Advanced Breast Cancer After CDK4/6 Inhibition. The ASCO Post. ascopost.com/issues/october-10-2023supplement-breast-cancer-almanac/emerald-trial-elacestrant-vsstandard-endocrine-monotherapy-for-advanced-breast-cancerafter-cdk46-inhibition/
13. Biomarker Testing Helps Tailor Cancer Treatment, Improve Outcomes, Says New CancerCare® Survey. (2023, April 12). CancerCare. cancercare.org/press/releases/236-2023_04_12
14. Access to Biomarker Testing. (2024, Jan.). American Cancer Society Cancer Action Network. fightcancer.org/what-we-do/accessbiomarker-testing
15. Payer Coverage Policies of Tumor Biomarkers and Pharmacogenomic Testing. (2023, March). American Cancer Society Cancer Action Network. fightcancer.org/sites/default/files/acs_can_payer_ coverage_policies_of_tumor_biomarker_and_pharmacogenomic_ testing_-_advi_final.pdf
Alzheimer’s disease (AD) is an irreversible, progressive brain disease that deteriorates memory and cognition.1 This disease is the most common cause of dementia in older adults.2 Evidence suggests AD is caused by an abnormal buildup of protein around brain cells.2 Amyloid protein deposits form plaques around brain cell and tau protein deposits to form tangles within brain cells.2
Diagnosing AD can be challenging because brain changes can occur before clinical symptoms appear or are detected.3 Memory problems may be the first apparent symptoms of AD; however, the initial symptoms manifest differently in each patient.3 AD is also associated with declines in other aspects of thinking, vision and spatial issues and impaired reasoning or judgement.3 The progression of AD occurs in three phases: preclinical, mild cognitive impairment and dementia, which is then further stratified into mild, moderate and severe stages.3 Factors including age, genetics and gender can influence how quickly patients progress through the phases of disease.3
Nationwide, more than six million adults in the U.S. age 65 or older have AD.1 If population trends continue, and as the U.S. population continues to age, the number of people living with AD will increase significantly over the next decade.1 The vast majority of AD cases occur in individuals 65 or older, which is described as late-onset AD.1 Early-onset AD occurs in individuals between ages 30 and 65, but is very rare.1
After initial diagnosis, the life expectancy of individuals with AD can average four to eight years; some patients with AD may live up to 20 years after diagnosis, with more than 40% of that time spent in the severe stage.1 In the late stages of AD, symptoms such as immobility, difficulty swallowing and malnutrition become prevalent, which impact daily living, correlate with significant morbidity and decrease autonomy and quality of life.3 Because more than an estimated 11 million Americans provide unpaid care for patients with AD and associated dementia, caregiver burden in this stage is significant.3 In 2022, AD carried a cost burden of $321 billion in the U.S. in addition to an estimated $271 billion in unpaid caregiving.4
Following an accelerated approval in January 2023, the FDA granted lecanemab-irmb (Leqembi®) traditional approval for the treatment of adult patients with AD in July 2023.5 The accelerated approval in January was granted based on clinical data which demonstrated that lecanemab-irmb reduced amyloid plaques in the brain, which is likely to predict a clinical benefit to patients.6 The FDA’s post-market requirement of the accelerated approval was for the applicant to conduct a clinical trial to verify the anticipated clinical benefit of lecanemab-irmb.6 Study 301 was conducted to demonstrate clinical benefit.5
Study 301 (CLARITY AD) was a phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group study that evaluated the efficacy of lecanemab-irmb.7 A total of 1,795 patients with AD were enrolled, and treatment was initiated in patients with mild cognitive impairment or mild dementia stage of disease with a confirmed presence of amyloid beta pathology.7 Participating patients were randomized 1:1 to receive either lecanemab, at a dose of 10 mg/kg over every two weeks, or placebo.7 Results showed patients treated with lecanemab had a statistically significant and clinically meaningful reduction of
Following an accelerated approval in January 2023, the FDA granted lecanemab-irmb (Leqembi®) traditional approval for the treatment of adult patients with AD in July 2023.
decline from baseline to 18 months on the Clinical Dementia Rating Scale Sum of Boxes score when compared to placebo.7 All secondary endpoints, including AD Assessment Scale Cognitive Subscale 14 and AD Cooperative Study-Activities of Daily Living Scale for Mild Cognitive Impairment, saw statistically significant differences between treatment groups.7
The most common side effects associated with treatment with lecanemab-irmb were headache, infusion-related reactions and
amyloid-related imaging abnormalities (ARIA).5 ARIA is known to occur with the class of antibodies targeting amyloid and most commonly presents as temporary swelling in areas of the brain seen on imaging studies.5 ARIA typically resolves over time and may be accompanied by small spots of bleeding in or on the surface of the brain.5
On the heels of the full FDA approval of intravenous lecanemabirmb, Eisai Global reported data showing a subcutaneous version of the drug was comparatively effective.8 After six months of treatment, subcutaneous lecanemab removed 14% more amyloid than intravenous lecanemab and the decrease from baseline in brain amyloid was -40.3 centiloids versus -35.4 centiloids for the subcutaneous and intravenous administrations, respectively.8 Notably, blood concentration levels of the drug were 11% higher with lecanemab administered subcutaneously compared to intravenously.8 As reported by Eisai Global, rates of systemic injection- or infusion-related reactions were significantly lower with subcutaneous relative to intravenous. There was also a low
1. What is Alzheimer’s Disease? (2021, July 8). National Institute on Aging. nia.nih.gov/health/what-alzheimers-disease
2. Alzheimer’s Disease. Cleveland Clinic. Retrieved Jan. 30, 2024, from my.clevelandclinic.org/health/diseases/9164-alzheimers-disease
3. Hill, A.M. (2022). Alzheimer Disease and the Evolving Treatment Landscape. American Journal of Managed Care. ajmc.com/view/ alzheimer-disease-and-the-evolving-treatment-landscape
4. The Economic Costs of Alzheimer’s Disease. (2022, July 6). Joint Economic Committee Democrats. jec.senate.gov/public/index. cfm/democrats/issue-briefs?id=02F4CADC-954F-4E3B-8409A4213E3C0759
On the heels of the full FDA approval of intravenous lecanemab-irmb, Eisai Global reported data showing a subcutaneous version of the drug was comparatively effective.
rate of local injection site reactions, most of which were mild or moderate in severity.8 The rates and characteristics of ARIA were similar with subcutaneous and intravenous administration. For the lecanemab naive group, timing, frequency, radiographic severity and symptomatic rates were in a similar range to intravenous. ARIA-E occurred in early treatment and was mostly asymptomatic and radiographically mild to moderate in severity.8
5. FDA Converts Novel Alzheimer's Disease Treatment to Traditional Approval. (2023, July 6). U.S. Food and Drug Administration. fda.gov/ news-events/press-announcements/fda-converts-novel-alzheimersdisease-treatment-traditional-approval
6. FDA Grants Accelerated Approval for Alzheimer's Disease Treatment (2023, Jan. 6). U.S. Food and Drug Administration. fda.gov/newsevents/press-announcements/fda-grants-accelerated-approvalalzheimers-disease-treatment
7. Van Dyck, C.H., Swanson, C.J., et al. (2023). Lecanemab in Early Alzheimer's Disease. New England Journal of Medicine, 388(1), 9–21. DOI: 10.1056/NEJMoa2212948
8. Bratulic, A. (2023, Oct. 25). Eisai says sub-Q Leqembi holds up against current infused version. FirstWord Pharma. firstwordpharma. com/story/5793902
LEQEMBI® (lecanemab-irmb) is indicated for the treatment of Alzheimer’s disease. Treatment with LEQEMBI should be initiated in patients with mild cognitive impairment or mild dementia stage of disease, the population in which treatment was initiated in clinical trials.
• Monoclonal antibodies directed against aggregated forms of amyloid beta, including LEQEMBI, can cause amyloid related imaging abnormalities (ARIA), characterized as ARIA with edema (ARIA-E) and ARIA with hemosiderin deposition (ARIA-H). Incidence and timing of ARIA vary among treatments. ARIA usually occurs early in treatment and is usually asymptomatic, although serious and life-threatening events rarely can occur. Serious intracerebral hemorrhages >1 cm, some of which have been fatal, have been observed in patients treated with this class of medications.
– Apolipoprotein E ε4 (ApoE ε4) Homozygotes: Patients who are ApoE ε4 homozygotes (approximately 15% of Alzheimer’s disease patients) treated with this class of medications, including LEQEMBI, have a higher incidence of ARIA, including symptomatic, serious, and severe radiographic ARIA, compared to heterozygotes and noncarriers. Testing for ApoE ε4 status should be performed prior to initiation of treatment to inform the risk of developing ARIA. Prior to testing, prescribers should discuss with patients the risk of ARIA across genotypes and the implications of genetic testing results. Prescribers should inform patients that if genotype testing is not performed, they can still be treated with LEQEMBI; however, it cannot be determined if they are ApoE ε4 homozygotes and at higher risk for ARIA.
• Consider the benefit of LEQEMBI for the treatment of Alzheimer’s disease and potential risk of serious adverse events associated with ARIA when deciding to initiate treatment with LEQEMBI.
LEQEMBI is contraindicated in patients with serious hypersensitivity to lecanemab-irmb or to any of the excipients of LEQEMBI. Reactions have included angioedema and anaphylaxis.
• LEQEMBI can cause ARIA-E and ARIA-H. ARIA-E can be observed on MRI as brain edema or sulcal effusions, and ARIA-H as microhemorrhage and superficial siderosis. ARIA can occur spontaneously in patients with Alzheimer’s disease. ARIA-H associated with monoclonal antibodies directed against aggregated forms of beta amyloid generally occurs in association with an occurrence of ARIA-E. ARIA-H and ARIA-E can occur together.
• ARIA usually occurs early in treatment and is usually asymptomatic, although serious and life-threatening events, including seizure and status epilepticus, rarely can occur. Reported symptoms associated with ARIA may include headache, confusion, visual changes, dizziness, nausea, and gait difficulty. Focal neurologic deficits may also occur. Symptoms associated with ARIA usually resolve over time.
Please see additional Select Safety Information throughout and Brief Summary of Prescribing Information for LEQEMBI on the following pages, including Boxed WARNING.
In Clarity AD (Study 2)
The majority of patients were in the earliest symptomatic stage, MCI due to AD4,5
Study 2 Clarity AD was an 18-month, global, placebo-controlled, double-blind, parallel-group, randomized clinical trial of 1795 patients with MCI due to AD (n=528/859) or mild AD dementia (n=331/859) with confirmed Aβ pathology. Patients were randomized 1:1 to receive LEQEMBI 10 mg/kg (IV infusion) or placebo (IV infusion) once every 2 weeks1,2
The primary endpoint was change from baseline at 18 months on the cognitive and functional CDR-SB scale1
Key secondary endpoints included change from baseline at 18 months for the following measures: ADCS MCI-ADL (function), ADAS-Cog14 (cognition), and amyloid PET1
In Study 2
LEQEMBI met the primary endpoint at 18 months, demonstrating statistically significant efficacy1
CDR-SB: Change from baseline in cognition and function at 18 months
27% slowing of progression vs placebo; with increasing separation over time
LEQEMBI showed statistical significance at all time points beginning at 6 months
Continued treatment with LEQEMBI demonstrated clinically meaningful slowing of cognitive and functional decline with increasing separation vs placebo through 18 months
MCI=mild cognitive impairment.
Select Safety Information (cont’d) WARNINGS AND PRECAUTIONS (cont’d)
AMYLOID RELATED IMAGING ABNORMALITIES (cont’d)
ARIA Monitoring and Dose Management Guidelines
• Obtain recent baseline brain magnetic resonance imaging (MRI) prior to initiating treatment with LEQEMBI. Obtain an MRI prior to the 5th, 7th and 14th infusions.
• Recommendations for dosing in patients with ARIA-E and ARIA-H depend on clinical symptoms and radiographic severity. Depending on ARIA severity, use clinical judgment in considering whether to continue dosing, temporarily discontinue treatment, or permanently discontinue LEQEMBI.
• Enhanced clinical vigilance for ARIA is recommended during the first 14 weeks of treatment with LEQEMBI. If a patient experiences symptoms suggestive of ARIA, clinical evaluation should be performed, including MRI if indicated. If ARIA is observed on MRI, careful clinical evaluation should be performed prior to continuing treatment.
• There is no experience in patients who continued dosing through symptomatic ARIA-E or through asymptomatic, but radiographically severe, ARIA-E. There is limited experience in patients who continued dosing through asymptomatic but radiographically mild to moderate ARIA-E. There are limited data in dosing patients who experienced recurrent ARIA-E. Please see additional Select Safety Information throughout and Brief Summary of Prescribing Information for LEQEMBI on the following pages, including Boxed WARNING.
Key secondary endpoints (change from baseline at 18 months)1-3,6
37% slowing of functional decline (2.0) compared with placebo P<0.0001
LEQEMBI (N)= 783
Placebo (N)= 796
Function ADCS MCI-ADL
26% slowing of cognitive decline (-1.442) compared with placebo P<0.001
LEQEMBI (N)= 854
Placebo (N)= 872
Cognition ADAS-Cog14
*Aβ plaque clearance (defined as <30 CL) achieved at the population level (mean) at 12 months for patients treated with LEQEMBI.3
~56 CL
reduction compared to placebo, (LEQEMBI=22.4 CL, Placebo=78.6 CL) achieving plaque clearance* P<0.0001
LEQEMBI (N)= 354†
Placebo (N)= 344†
Amyloid beta Brain amyloid PET
†73 subjects were not included at 18 months (per statistical analysis plan) since their PET assessments were performed after receiving LEQEMBI in the Extension phase.3
Note: Based on pharmacodynamic analysis population (PET substudy population). Adjusted mean change from baseline, SE, and P-value are derived using MMRM with treatment group, visit, treatment group-by-visit interaction, clinical subgroup, use of AD symptomatic medication at baseline, ApoE ε4 carrier status, region, baseline value-by-visit interaction as fixed effects, and baseline value as covariate.3
Cognition
is a validated outcome measure that consists of the following domains2,7:
Memory (eg, recalling recent/distant events)
Orientation (eg, time, relationships, navigating familiar territory)
Judgment/problem solving
Scoring:
Each domain can be scored as 0, 0.5, 1, 2, or 3, for a total scale range from 0-182,3 Higher scores indicate more advanced AD2,3 MCI and mild AD dementia tend to score 0.5 or 1 in each domain3
Select Safety Information (cont’d)
WARNINGS AND PRECAUTIONS (cont’d)
AMYLOID RELATED IMAGING ABNORMALITIES (cont’d)
Incidence of ARIA
Community affairs (eg, ability to work, socialize, and/or shop)
Home and hobbies (eg, household tasks and activities)
Personal care (eg, dressing, washing, using bathroom)
• In Study 2, symptomatic ARIA occurred in 3% (29/898) of LEQEMBI-treated patients. Serious symptoms associated with ARIA were reported in 0.7% (6/898) of patients treated with LEQEMBI. Clinical symptoms associated with ARIA resolved in 79% (23/29) of patients during the period of observation.
• Including asymptomatic radiographic events, ARIA was observed in LEQEMBI: 21% (191/898); placebo: 9% (84/897). ARIA-E was observed in LEQEMBI: 13% (113/898); placebo: 2% (15/897). ARIA-H was observed in LEQEMBI: 17% (152/898); placebo: 9% (80/897). There was no increase in isolated ARIA-H for LEQEMBI vs placebo.
• In Study 2, 16% (141/898) of patients in the LEQEMBI arm were ApoE ε4 homozygotes, 53% (479/898) were heterozygotes, and 31% (278/898) were noncarriers.
• The incidence of ARIA was higher in ApoE ε4 homozygotes (LEQEMBI: 45%; placebo: 22%) than in heterozygotes (LEQEMBI: 19%; placebo: 9%) and noncarriers (LEQEMBI: 13%; placebo: 4%). Among patients treated with LEQEMBI, symptomatic ARIA-E occurred in 9% of ApoE ε4 homozygotes compared with 2% of heterozygotes and 1% of noncarriers. Serious events of ARIA occurred in 3% of ApoE ε4 homozygotes, and approximately 1% of heterozygotes and noncarriers.
• The recommendations on management of ARIA do not differ between ApoE ε4 carriers and noncarriers.
• The majority of ARIA-E radiographic events occurred early in treatment (within the first 7 doses), although ARIA can occur at any time and patients can have more than 1 episode. The maximum radiographic severity of ARIA-E in patients treated with LEQEMBI® was mild in 4% (37/898), moderate in 7% (66/898), and severe in 1% (9/898). Resolution on MRI occurred in 52% of ARIA-E patients by 12 weeks, 81% by 17 weeks, and 100% overall after detection. The maximum radiographic severity of ARIA-H microhemorrhage in LEQEMBI-treated patients was mild in 9% (79/898), moderate in 2% (19/898), and severe in 3% (28/898) of patients; superficial siderosis was mild in 4% (38/898), moderate in 1% (8/898), and severe in 0.4% (4/898). Among LEQEMBI-treated patients, the rate of severe radiographic ARIA-E was highest in ApoE ε4 homozygotes 5% (7/141), compared to heterozygotes 0.4% (2/479) or noncarriers 0% (0/278). Among LEQEMBI-treated patients, the rate of severe radiographic ARIA-H was highest in ApoE ε4 homozygotes 13.5% (19/141), compared to heterozygotes 2.1% (10/479) or noncarriers 1.1% (3/278).
Intracerebral Hemorrhage
• Intracerebral hemorrhage >1 cm in diameter was reported in 0.7% (6/898) of patients in Study 2 after treatment with LEQEMBI compared to 0.1% (1/897) on placebo. Fatal events of intracerebral hemorrhage in patients taking LEQEMBI have been reported.
Concomitant Antithrombotic Medication:
• In Study 2, baseline use of antithrombotic medication (aspirin, other antiplatelets, or anticoagulants) was allowed if the patient was on a stable dose. The majority of exposures to antithrombotic medications were to aspirin. Antithrombotic medications did not increase the risk of ARIA with LEQEMBI. The incidence of intracerebral hemorrhage was 0.9% (3/328 patients) in patients taking LEQEMBI with a concomitant antithrombotic medication at the time of the event compared to 0.6% (3/545 patients) in those who did not receive an antithrombotic. Patients taking LEQEMBI with an anticoagulant alone or combined with an antiplatelet medication or aspirin had an incidence of intracerebral hemorrhage of 2.5% (2/79 patients) compared to none in patients who received placebo.
• Because intracerebral hemorrhages >1 cm in diameter have been observed in patients taking LEQEMBI, additional caution should be exercised when considering the administration of anticoagulants or a thrombolytic agent (e.g., tissue plasminogen activator) to a patient already being treated with LEQEMBI.
• Patients were excluded from enrollment in Study 2 for findings on neuroimaging that indicated an increased risk for intracerebral hemorrhage. These included findings suggestive of cerebral amyloid angiopathy (prior cerebral hemorrhage >1 cm in greatest diameter, >4 microhemorrhages, superficial siderosis, vasogenic edema) or other lesions (aneurysm, vascular malformation) that could potentially increase the risk of intracerebral hemorrhage. The presence of an ApoE ε4 allele is also associated with cerebral amyloid angiopathy, which has an increased risk for intracerebral hemorrhage. Caution should be exercised when considering the use of LEQEMBI in patients with factors that indicate an increased risk for intracerebral hemorrhage and in particular for patients who need to be on anticoagulant therapy.
Hypersensitivity reactions, including angioedema, bronchospasm, and anaphylaxis, have occurred in LEQEMBI-treated patients. Promptly discontinue the infusion upon the first observation of any signs or symptoms consistent with a hypersensitivity reaction, and initiate appropriate therapy.
• In Study 2, infusion-related reactions were observed in LEQEMBI: 26% (237/898); placebo: 7% (66/897), and the majority of cases in LEQEMBI-treated patients (75%, 178/237) occurred with the first infusion. Infusion-related reactions were mostly mild (69%) or moderate (28%) in severity. Infusion-related reactions resulted in discontinuations in 1% (12/898) of LEQEMBI-treated patients. Symptoms of infusion-related reactions included fever and flu-like symptoms (chills, generalized aches, feeling shaky, and joint pain), nausea, vomiting, hypotension, hypertension, and oxygen desaturation.
• In the event of an infusion-related reaction, the infusion rate may be reduced, or the infusion may be discontinued, and appropriate therapy initiated as clinically indicated. Prophylactic treatment with antihistamines, acetaminophen, nonsteroidal anti-inflammatory drugs, or corticosteroids prior to future infusions may be considered.
• In Study 2, the most common adverse reaction leading to discontinuation of LEQEMBI was ARIA-H microhemorrhages that led to discontinuation in 2% (15/898) of patients treated with LEQEMBI compared to <1% (1/897) of patients on placebo.
• In Study 2, the most common adverse reactions reported in ≥5% of patients treated with LEQEMBI (N=898) and ≥2% higher than placebo (N=897) were infusion-related reactions (LEQEMBI: 26%; placebo: 7%), ARIA-H (LEQEMBI: 14%; placebo: 8%), ARIA-E (LEQEMBI: 13%; placebo: 2%), headache (LEQEMBI: 11%; placebo: 8%), superficial siderosis of central nervous system (LEQEMBI: 6%; placebo: 3%), rash (LEQEMBI: 6%; placebo: 4%), and nausea/vomiting (LEQEMBI: 6%; placebo: 4%).
Please see additional Select Safety Information throughout and Brief Summary of Prescribing Information for LEQEMBI on the following pages, including Boxed WARNING.
Aß=amyloid beta; ADAS-Cog14=Alzheimer’s Disease Assessment Scale-Cognitive Subscale 14-item version; ADCS MCI-ADL=Alzheimer’s Disease Cooperative Study-Activities of Daily Living Scale for Mild Cognitive Impairment; ApoE ε4=apolipoprotein E ε4; ARIA-E=amyloid-related imaging abnormality-edema; ARIA-H=amyloid-related imaging abnormality-hemosiderin deposition; CDR-SB=Clinical Dementia Rating-Sum of Boxes; CL=Centiloids; IV=intravenous; MMRM=Mixed Models for Repeated Measures; PET=positron emission tomography; SE=standard error.
References: 1. LEQEMBI (lecanemab-irmb) injection, for intravenous use [package insert]. Nutley, NJ: Eisai Inc. 2. van Dyck CH, Swanson CJ, Aisen P, et al. Lecanemab in early Alzheimer’s disease. N Engl J Med. 2023;388(1):9-21. 3. Iwatsubo T, Irizarry M, van Dyck C, Sabbagh M, Bateman RJ, Cohen S. Clarity AD: a phase 3 placebo-controlled, double-blind, parallel-group, 18-month study evaluating lecanemab in early Alzheimer’s disease. Presented at: CTAD Conference; November 29-December 2, 2022; San Francisco, CA. 4. Alzheimer’s Association. 2023 Alzheimer’s disease facts and figures. Alzheimer’s Dement 2023;18:1-122. 5. Data on file. Clarity CSR. BAN2401-G000-301. Eisai Inc., Nutley, NJ. 6. Data on file. QOL Clarity AD. BAN2401-G000-301. Eisai Inc., Nutley, NJ. 7. Morris JC. The Clinical Dementia Rating (CDR): current version and scoring rules. Neurology. 1993;43:2412-2414.
property of their respective owners.
LEQE-US2960 11/2023
The following is a Brief Summary; refer to full Prescribing Information for complete product information.
Monoclonal antibodies directed against aggregated forms of beta amyloid, including LEQEMBI, can cause amyloid related imaging abnormalities (ARIA), characterized as ARIA with edema (ARIA-E) and ARIA with hemosiderin deposition (ARIA-H). Incidence and timing of ARIA vary among treatments. ARIA usually occurs early in treatment and is usually asymptomatic, although serious and life-threatening events rarely can occur. Serious intracerebral hemorrhages, some of which have been fatal, have been observed in patients treated with this class of medications [see Warnings and Precautions (5.1), Adverse Reactions (6.1)]
ApoE ε4 Homozygotes
Patients who are apolipoprotein E ε4 (ApoE ε4) homozygotes (approximately 15% of Alzheimer’s disease patients) treated with this class of medications, including LEQEMBI, have a higher incidence of ARIA, including symptomatic, serious, and severe radiographic ARIA, compared to heterozygotes and noncarriers. Testing for ApoE ε4 status should be performed prior to initiation of treatment to inform the risk of developing ARIA. Prior to testing, prescribers should discuss with patients the risk of ARIA across genotypes and the implications of genetic testing results. Prescribers should inform patients that if genotype testing is not performed they can still be treated with LEQEMBI; however, it cannot be determined if they are ApoE ε4 homozygotes and at higher risk for ARIA [see Warnings and Precautions (5.1)]
Consider the benefit of LEQEMBI for the treatment of Alzheimer’s disease and potential risk of serious adverse events associated with ARIA when deciding to initiate treatment with LEQEMBI [see Warnings and Precautions (5.1)]
1 INDICATIONS AND USAGE
LEQEMBI is indicated for the treatment of Alzheimer’s disease. Treatment with LEQEMBI should be initiated in patients with mild cognitive impairment or mild dementia stage of disease, the population in which treatment was initiated in clinical trials.
2 DOSAGE AND ADMINISTRATION
2.1 Patient Selection
Confirm the presence of amyloid beta pathology prior to initiating treatment
2.2 Dosing Instructions
The recommended dosage of LEQEMBI is 10 mg/kg that must be diluted then administered as an intravenous infusion over approximately one hour, once every two weeks.
If an infusion is missed, administer the next dose as soon as possible.
2.3 Monitoring and Dosing Interruption for Amyloid Related Imaging Abnormalities
LEQEMBI can cause amyloid related imaging abnormalities-edema (ARIA-E) and -hemosiderin deposition (ARIA-H) [see Warnings and Precautions (5.1)]
Monitoring for ARIA
Obtain a recent baseline brain magnetic resonance imaging (MRI) prior to initiating treatment with LEQEMBI. Obtain an MRI prior to the 5th, 7th, and 14th infusions. If a patient experiences symptoms suggestive of ARIA, clinical evaluation should be performed, including an MRI if indicated.
Recommendations for Dosing Interruptions in Patients with ARIA
ARIA-E
The recommendations for dosing interruptions for patients with ARIA-E are provided in Table 1.
Table 1: Dosing Recommendations for Patients with ARIA-E
Clinical Symptom
Severity1 ARIA-E Severity on MRI2 Mild Moderate Severe
Asymptomatic May continue dosing Suspend dosing3 Suspend dosing3
Mild May continue dosing based on clinical judgment
Suspend dosing3
Moderate or Severe Suspend dosing3
1 Clinical Symptom Severity Categories:
Mild: discomfort noticed, but no disruption of normal daily activity.
Moderate: discomfort sufficient to reduce or affect normal daily activity.
Severe: incapacitating, with inability to work or to perform normal daily activity.
2 See Table 3 for MRI severity [Warnings and Precautions (5.1)]
3 Suspend until MRI demonstrates radiographic resolution and symptoms, if present, resolve; consider a follow-up MRI to assess for resolution 2 to 4 months after initial identification. Resumption of dosing should be guided by clinical judgment
ARIA-H
The recommendations for dosing interruptions for patients with ARIA-H are provided in Table 2.
Clinical Symptom
Severity ARIA-H Severity on MRI1
Mild Moderate Severe
Asymptomatic May continue dosing Suspend dosing2 Suspend dosing3
Symptomatic Suspend dosing2 Suspend dosing2
1 See Table 3 for MRI severity [Warnings and Precautions (5.1)]
2 Suspend until MRI demonstrates radiographic stabilization and symptoms, if present, resolve; resumption of dosing should be guided by clinical judgment; consider a follow-up MRI to assess for stabilization 2 to 4 months after initial identification.
3 Suspend until MRI demonstrates radiographic stabilization and symptoms, if present, resolve; use clinical judgment in considering whether to continue treatment or permanently discontinue LEQEMBI.
In patients who develop intracerebral hemorrhage greater than 1 cm in diameter during treatment with LEQEMBI, suspend dosing until MRI demonstrates radiographic stabilization and symptoms, if present, resolve. Use clinical judgment in considering whether to continue treatment after radiographic stabilization and resolution of symptoms or permanently discontinue LEQEMBI.
3 DOSAGE FORMS AND STRENGTHS
LEQEMBI is a clear to opalescent and colorless to pale yellow solution, available as:
• Injection: 500 mg/5 mL (100 mg/mL) in a single-dose vial
• Injection: 200 mg/2 mL (100 mg/mL) in a single-dose vial
4 CONTRAINDICATIONS
LEQEMBI is contraindicated in patients with serious hypersensitivity to lecanemabirmb or to any of the excipients of LEQEMBI. Reactions have included angioedema and anaphylaxis [see Warnings and Precautions (5.2)]
5 WARNINGS AND PRECAUTIONS
5.1 Amyloid Related Imaging Abnormalities
Monoclonal antibodies directed against aggregated forms of beta amyloid, including LEQEMBI, can cause amyloid related imaging abnormalities (ARIA), characterized as ARIA with edema (ARIA-E), which can be observed on MRI as brain edema or sulcal effusions, and ARIA with hemosiderin deposition (ARIA-H), which includes microhemorrhage and superficial siderosis. ARIA can occur spontaneously in patients with Alzheimer’s disease. ARIA-H associated with monoclonal antibodies directed against aggregated forms of beta amyloid generally occurs in association with an occurrence of ARIA-E. ARIA-H of any cause and ARIA-E can occur together. ARIA usually occurs early in treatment and is usually asymptomatic, although serious and life-threatening events, including seizure and status epilepticus, rarely can occur. When present, reported symptoms associated with ARIA may include headache, confusion, visual changes, dizziness, nausea, and gait difficulty. Focal neurologic deficits may also occur. Symptoms associated with ARIA usually resolve over time. The risk of ARIA, including symptomatic and serious ARIA, is increased in apolipoprotein E ε4 (ApoE ε4) homozygotes. In addition to ARIA, intracerebral hemorrhages greater than 1 cm in diameter have occurred in patients treated with LEQEMBI.
Consider the benefit of LEQEMBI for the treatment of Alzheimer’s disease and potential risk of serious adverse events associated with ARIA when deciding to initiate treatment with LEQEMBI.
Incidence of ARIA
Symptomatic ARIA occurred in 3% (29/898) of patients treated with LEQEMBI in Study 2. Serious symptoms associated with ARIA were reported in 0.7% (6/898) of patients treated with LEQEMBI. Clinical symptoms associated with ARIA resolved in 79% (23/29) of patients during the period of observation. Similar findings were observed in Study 1.
Including asymptomatic radiographic events, ARIA was observed in 21% (191/898) of patients treated with LEQEMBI, compared to 9% (84/897) of patients on placebo in Study 2.
ARIA-E was observed in 13% (113/898) of patients treated with LEQEMBI compared with 2% (15/897) of patients on placebo. ARIA-H was observed in 17% (152/898) of patients treated with LEQEMBI compared with 9% (80/897) of patients on placebo. There was no increase in isolated ARIA-H (i.e., ARIA-H in patients who did not also experience ARIA-E) for LEQEMBI compared to placebo.
ApoE ε4 Carrier Status and Risk of ARIA
Approximately 15% of Alzheimer’s disease patients are ApoE ε4 homozygotes. In Study 2, 16% (141/898) of patients in the LEQEMBI arm were ApoE ε4 homozygotes, 53% (479/898) were heterozygotes, and 31% (278/898) were noncarriers. The incidence of ARIA was higher in ApoE ε4 homozygotes (45% on LEQEMBI vs. 22% on placebo) than in heterozygotes (19% on LEQEMBI vs 9% on placebo) and noncarriers (13% on LEQEMBI vs 4% on placebo). Among patients treated with LEQEMBI, symptomatic ARIA-E occurred in 9% of ApoE ε4 homozygotes compared with 2% of heterozygotes and 1% noncarriers. Serious events of ARIA occurred in 3% of ApoE ε4 homozygotes, and approximately 1% of heterozygotes and noncarriers. The recommendations on management of ARIA do not differ between ApoE ε4 carriers and noncarriers [see Dosage and Administration (2.3)]. Testing for ApoE ε4 status should be performed prior to initiation of treatment to inform the risk of developing ARIA. Prior to testing, prescribers should discuss with patients the risk of ARIA across genotypes and the implications of genetic testing results. Prescribers should inform patients that if genotype testing is not performed they can still be treated with LEQEMBI; however, it cannot be determined if they are ApoE ε4 homozygotes and at higher risk for ARIA. An FDA-authorized test for the detection of ApoE ε4 alleles to identify patients at risk of ARIA if treated with LEQEMBI is not currently available. Currently available tests used to identify ApoE ε4 alleles may vary in accuracy and design.
Radiographic Findings
The radiographic severity of ARIA associated with LEQEMBI was classified by the criteria shown in Table 3.
Table 3: ARIA MRI Classification Criteria
ARIA Type Radiographic Severity
Mild
ARIA-E FLAIR hyperintensity confined to sulcus and/or cortex/ subcortex white matter in one location <5 cm
ModerateSevere
FLAIR
hyperintensity
5 to 10 cm in single greatest dimension, or more than 1 site of involvement, each measuring <10 cm
ARIA-H microhemorrhage ≤ 4 new incident microhemorrhages
ARIA-H superficial siderosis 1 focal area of superficial siderosis
5 to 9 new incident microhemorrhages
2 focal areas of superficial siderosis
FLAIR hyperintensity
>10 cm with associated gyral swelling and sulcal effacement. One or more separate/ independent sites of involvement may be noted
10 or more new incident microhemorrhages
>2 areas of superficial siderosis
The majority of ARIA-E radiographic events occurred early in treatment (within the first 7 doses), although ARIA can occur at any time and patients can have more than 1 episode. The maximum radiographic severity of ARIA-E in patients treated with LEQEMBI was mild in 4% (37/898) of patients, moderate in 7% (66/898) of patients, and severe in 1% (9/898) of patients. Resolution on MRI occurred in 52% of ARIA-E patients by 12 weeks, 81% by 17 weeks, and 100% overall after detection. The maximum radiographic severity of ARIA-H microhemorrhage in patients treated with LEQEMBI was mild in 9% (79/898), moderate in 2% (19/898), and severe in 3% (28/898) of patients; superficial siderosis was mild in 4% (38/898), moderate in 1% (8/898), and severe in 0.4% (4/898). Among patients treated with LEQEMBI, the rate of severe radiographic ARIA-E was highest in ApoE ε4 homozygotes 5% (7/141), compared to heterozygotes 0.4% (2/479) or noncarriers 0% (0/278). Among patients treated with LEQEMBI, the rate of severe radiographic ARIA-H was highest in ApoE ε4 homozygotes 13.5% (19/141), compared to heterozygotes 2.1% (10/479) or noncarriers 1.1% (3/278).
Intracerebral Hemorrhage
Intracerebral hemorrhage greater than 1 cm in diameter was reported in 0.7% (6/898) of patients in Study 2 after treatment with LEQEMBI compared to 0.1% (1/897) on placebo. Fatal events of intracerebral hemorrhage in patients taking LEQEMBI have been observed.
Concomitant Antithrombotic Medication
In Study 2, baseline use of antithrombotic medication (aspirin, other antiplatelets, or anticoagulants) was allowed if the patient was on a stable dose. The majority of exposures to antithrombotic medications were to aspirin. Antithrombotic medications did not increase the risk of ARIA with LEQEMBI. The incidence of intracerebral hemorrhage was 0.9% (3/328 patients) in patients taking LEQEMBI with a concomitant antithrombotic medication at the time of the event compared to 0.6% (3/545 patients) in those who did not receive an antithrombotic. Patients taking LEQEMBI with an anticoagulant alone or combined with an antiplatelet medication or aspirin had an incidence of intracerebral hemorrhage of 2.5% (2/79 patients) compared to none in patients who received placebo.
Because intracerebral hemorrhages greater than 1 cm in diameter have been observed in patients taking LEQEMBI, additional caution should be exercised when considering the administration of anticoagulants or a thrombolytic agent (e.g., tissue plasminogen activator) to a patient already being treated with LEQEMBI.
Other Risk Factors for Intracerebral Hemorrhage
Patients were excluded from enrollment in Study 2 for findings on neuroimaging that indicated an increased risk for intracerebral hemorrhage. These included findings suggestive of cerebral amyloid angiopathy (prior cerebral hemorrhage greater than 1 cm in greatest diameter, more than 4 microhemorrhages, superficial siderosis, vasogenic edema) or other lesions (aneurysm, vascular malformation) that could potentially increase the risk of intracerebral hemorrhage.
The presence of an ApoE ε4 allele is also associated with cerebral amyloid angiopathy, which has an increased risk for intracerebral hemorrhage.
Caution should be exercised when considering the use of LEQEMBI in patients with factors that indicate an increased risk for intracerebral hemorrhage and in particular for patients who need to be on anticoagulant therapy.
Recommendations for dosing in patients with ARIA-E depend on clinical symptoms and radiographic severity [see Dosage and Administration (2.3)]. Recommendations for dosing in patients with ARIA-H depend on the type of ARIA-H and radiographic severity [see Dosage and Administration (2.3)]. Use clinical judgment in considering whether to continue dosing in patients with recurrent ARIA-E.
Baseline brain MRI and periodic monitoring with MRI are recommended [see Dosage and Administration (2.3)]. Enhanced clinical vigilance for ARIA is recommended during the first 14 weeks of treatment with LEQEMBI. If a patient experiences symptoms suggestive of ARIA, clinical evaluation should be performed, including MRI if indicated. If ARIA is observed on MRI, careful clinical evaluation should be performed prior to continuing treatment.
There is no experience in patients who continued dosing through symptomatic ARIA-E, or through asymptomatic but radiographically severe ARIA-E. There is limited experience in patients who continued dosing through asymptomatic but radiographically mild to moderate ARIA-E. There are limited data in dosing patients who experienced recurrent ARIA-E.
The Alzheimer’s Network for Treatment and Diagnostics (ALZ-NET) is a voluntary provider-enrolled patient registry that collects information on treatments for Alzheimer’s disease, including LEQEMBI. Providers may obtain information about the registry at www.alz-net.org or contact alz-net@acr.org.
5.2
Hypersensitivity reactions, including angioedema, bronchospasm, and anaphylaxis, have occurred in patients who were treated with LEQEMBI. Promptly discontinue the infusion upon the first observation of any signs or symptoms consistent with a hypersensitivity reaction, and initiate appropriate therapy. LEQEMBI is contraindicated in patients with a history of serious hypersensitivity to lecanemab-irmb or to any of the excipients of LEQEMBI.
In Study 2, infusion-related reactions were observed in 26% (237/898) of patients treated with LEQEMBI compared to 7% (66/897) of patients on placebo; and the majority (75%, 178/237) occurred with the first infusion. Infusion-related reactions were mostly mild (69%) or moderate (28%) in severity. Infusion-related reactions resulted in discontinuations in 1% (12/898) of patients treated with LEQEMBI.
Symptoms of infusion-related reactions include fever and flu-like symptoms (chills, generalized aches, feeling shaky, and joint pain), nausea, vomiting, hypotension, hypertension, and oxygen desaturation.
After the first infusion in Study 1, 38% of patients treated with LEQEMBI had transient decreased lymphocyte counts to less than 0.9 x109/L compared to 2% in patients on placebo, and 22% of patients treated with LEQEMBI had transient increased neutrophil counts to greater than 7.9 x109/L compared to 1% of patients on placebo. Lymphocyte and neutrophil counts were not obtained after the first infusion in Study 2. In the event of an infusion-related reaction, the infusion rate may be reduced, or the infusion may be discontinued, and appropriate therapy initiated as clinically indicated. Prophylactic treatment with antihistamines, acetaminophen, nonsteroidal antiinflammatory drugs, or corticosteroids prior to future infusions may be considered.
6 ADVERSE REACTIONS
The following clinically significant adverse reactions are described elsewhere in the labeling:
• Amyloid Related Imaging Abnormalities [see Warnings and Precautions (5.1)]
• Hypersensitivity Reactions [see Warnings and Precautions (5.2)]
• Infusion-Related Reactions [see Warnings and Precautions (5.3)]
6.1 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 safety of LEQEMBI has been evaluated in 2090 patients who received at least one dose of LEQEMBI. In Studies 1 and 2 in patients with Alzheimer’s disease, 1059 patients received LEQEMBI 10 mg/kg every two weeks. Of these 1059 patients, 50% were female, 79% were White, 15% were Asian, 12% were of Hispanic or Latino ethnicity, and 2% were Black. The mean age at study entry was 72 years (range from 50 to 90 years).
In the combined double-blind, placebo-controlled period and long-term extension period of Studies 1 and 2, 1604 patients received LEQEMBI for at least 6 months, 1261 patients for at least 12 months, and 965 patients for 18 months.
In the double-blind, placebo-controlled period in Study 2, patients stopped study treatment because of an adverse reaction in 7% of patients treated with LEQEMBI, compared to 3% of patients on placebo.
In Study 2, the most common adverse reaction leading to discontinuation of LEQEMBI was ARIA-H microhemorrhages that led to discontinuation in 2% (15/898) of patients treated with LEQEMBI compared to <1% (1/897) of patients on placebo. Adverse reactions reported in Study 2 are shown in Table 4.
Table 4: Adverse Reactions Reported in at Least 5% of Patients Treated With LEQEMBI 10 mg/kg Every Two Weeks and at Least 2% Higher than Placebo in Study 2
1 Rash includes acne, erythema, infusion site rash, injection site rash, rash, rash erythematous, rash pruritic, skin reactions, and urticaria.
Less Common Adverse Reactions
Atrial fibrillation occurred in 3% of patients treated with LEQEMBI compared to 2% in patients on placebo. In Study 1, lymphopenia or decreased lymphocyte count were reported in 4% of patients treated with LEQEMBI after the first dose, compared to less than 1% of patients on placebo [see Warnings and Precautions (5.3)]; lymphocytes were not measured after the first dose in Study 2.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Risk Summary
There are no adequate data on LEQEMBI use in pregnant women to evaluate for a drug associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. No animal studies have been conducted to assess the potential reproductive or developmental toxicity of LEQEMBI.
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 15 to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.
8.2 Lactation
Risk Summary
There are no data on the presence of lecanemab-irmb in human milk, the effects on the breastfed infant, or the effects of the drug on milk production. Published data from other monoclonal antibodies generally indicate low passage of monoclonal antibodies into human milk and limited systemic exposure in the breastfed infant. The effects of this limited exposure are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for LEQEMBI and any potential adverse effects on the breastfed infant from LEQEMBI or from the underlying maternal condition.
8.4 Pediatric Use
Safety and effectiveness of LEQEMBI in pediatric patients have not been established.
8.5 Geriatric Use
In Studies 1 and 2, the age of patients exposed to LEQEMBI 10 mg/kg every two weeks (n=1059) ranged from 50 to 90 years, with a mean age of 72 years; 81% were 65 years and older, and 39% were 75 years and older. No overall differences in safety or effectiveness of LEQEMBI have been observed between patients 65 years of age and older and younger adult patients.
17 PATIENT COUNSELING INFORMATION
Advise the patient and/or caregiver to read the FDA-approved patient labeling (Medication Guide).
Amyloid Related Imaging Abnormalities
Inform patients that LEQEMBI may cause Amyloid Related Imaging Abnormalities or “ARIA”. ARIA most commonly presents as a temporary swelling in areas of the brain that usually resolves over time. Some people may also have small spots of bleeding in or on the surface of the brain. Inform patients that most people with swelling in areas of the brain do not experience symptoms, however, some people may experience symptoms such as headache, confusion, dizziness, vision changes, nausea, aphasia, weakness, or seizure. Instruct patients to notify their healthcare provider if these symptoms occur. Inform patients that events of intracerebral hemorrhage greater than 1 cm in diameter have been reported infrequently in patients taking LEQEMBI, and that the use of anticoagulant or thrombolytic medications while taking LEQEMBI may increase the risk of bleeding in the brain. Notify patients that their healthcare provider will perform MRI scans to monitor for ARIA [see Warnings and Precautions (5.1)]
Inform patients that although ARIA can occur in any patient treated with LEQEMBI, there is an increased risk in patients who are ApoE ε4 homozygotes and that testing for ApoE ε4 status should be performed prior to initiation of treatment to inform the risk of developing ARIA. Prior to testing, discuss with patients the risk of ARIA across genotypes and the implications of genetic testing results. Inform patients that if testing is not performed, it cannot be determined if they are ApoE ε4 homozygotes and at a higher risk for ARIA.
Patient Registry
Advise patients that the Alzheimer’s Network for Treatment and Diagnostics (ALZ-NET) is a voluntary provider-enrolled patient registry that collects information on treatments for Alzheimer’s disease, including LEQEMBI. Encourage patients to participate in the ALZ-NET registry [see Warnings and Precautions (5.1)]
Hypersensitivity Reactions
Inform patients that hypersensitivity reactions, including angioedema and anaphylaxis have occurred in patients who were treated with LEQEMBI. Advise patients to seek immediate medical attention if they experience any symptoms of serious or severe hypersensitivity reactions [see Warnings and Precautions (5.2)]
Infusion-Related Reactions
Advise patients of the potential risk of infusion-related reactions, which can include flu-like symptoms, nausea, vomiting, and changes in blood pressure, the majority of which occur with the first infusion [see Warnings and Precautions (5.3)]
In 2023, the FDA approved nine new biosimilar agents with approximately 93 more expected to receive approval or launch in the next five years. Biosimilars can drive utilization and savings, especially as less expensive biosimilars play a critical role in managing drug spend. Table 5 outlines recent and upcoming biosimilar approvals and launches.
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As new biosimilars are introduced to the market, there is an inevitable impact on average sales price (ASP) across originator products. Biosimilar launches at large have resulted in an ASP decline of 41% on average after the first biosimilar launch. These trends are expected to continue downward as more biosimilar options are approved and launch on the market.
This decline in ASPs will likely result in cost savings. According to the 2023 Magellan Rx Medical Pharmacy Trend Report, biosimilars continued to mitigate costs in high-spend market baskets across all classes. This report also showed Medicaid per member per month (PMPM) trend decreased modestly based on decreased ASP rates due to biosimilar competition within the autoimmune disorder class. Specifically, across the highest spend autoimmune categories, biosimilars have had major cost impact. The introduction of infliximab biosimilars has contributed to cost per claim decreases across all lines of business, playing a larger
role in the negative PMPM trend for Medicare and Medicaid. The Remicade® reference commercial market share and cost have continued to drop with a shift in utilization to biosimilars Inflectra® and Renflexis® in 2022, and while the reference retained the majority utilization, biosimilar Entyvio® started to contend.
Per the report, most payers reported preferring oncology biosimilars over reference products to drive savings, and half of payers required step therapy for new utilizers, while another one-third required biosimilar use for all utilizers. The PMPM for long-acting CSF class continued a downward trend across lines of business, largely resulting from increased biosimilar utilization for all lines of business. The PMPM trend in this class is expected to further decline as ASPs erode; the Udenyca OnBody® approval is expected to contribute to this trend.
Biosimilars continue to change the treatment and management landscape with more approvals and launches to come. Planning around biosimilar strategy will be critical to proper management.
References
1. Joszt, L. (2023, July 13). Price Discounts Have Driven Higher Biosimilar Usage, Especially in Oncology. American Journal of Managed Care. ajmc.com/view/price-discounts-have-driven-higherbiosimilar-usage-especially-in-oncology
2. Medical Pharmacy Trend Report. (2023). Prime Therapeutics | Magellan Rx Management. issuu.com/magellanrx/docs/medicalpharmacy-trend-report-2023?fr=sYmEzZTY2MjgzNzc
Insulin
(biosimilar to Eli Lilly’s Humalog®)
Nivolumab (Opdivo®) Bristol Myers Squibb
Urothelial carcinoma (unresectable or metastatic, first-line, in combination with cisplatin-based chemotherapy)
Insulin
(biosimilar to Sanofi’s Lantus®)
Ranibizumab (biosimilar to Genentech’s Lucentis®)
Diabetic retinopathy; DME; myopic choroidal neovascularization; macular edema following RVO; wAMD
Boehringer
Interstitial
syncytial virus-lower respiratory tract disease prevention (ages > 60 years)
Intravitreal BLA
sNDA; Breakthrough Therapy March–April 2024
Rituximab (biosimilar to Genentech’s Rituxan®)
Dr. Reddy’s Laboratories
Chronic lymphocytic leukemia; granulomatosis with polyangiitis/ microscopic polyangiitis; NHL; mature B-cell NHL/mature B-cell acute leukemia; pemphigus vulgaris; RA
Naloxone (powder-based technology) Orexo Opioid overdose Intranasal 505(b)(2) NDA 7/15/2024
Vonoprazan (Takecab®) Phathom Pharmaceuticals GERD (non-erosive) Oral sNDA 7/19/2024
Vedolizumab (Entyvio®)
Takeda Pharmaceuticals Crohn’s disease (SC maintenance following IV induction) SC sBLA
July 2024
Aflibercept (biosimilar to Regeneron’s Eylea®) Amgen DME; diabetic retinopathy; macular edema following RVO; wAMD Intravitreal BLA July–August 2024
Fam-trastuzumab deruxtecan-nxki (Enhertu®) Daiichi Sankyo Breast cancer (HER2+, third-line) IV sBLA: Breakthrough Therapy; Fast Track July–December 2024
Abbreviations: BLA = Biologics License Application; CIDP = chronic inflammatory demyelinating polyneuropathy; DME = diabetic macular edema; GERD = gastroesophageal reflux disease; JIA = juvenile idiopathic arthritis; IM = intramuscular; IV = intravenous; MM = multiple myeloma; NDA = new drug application; NHL = non-Hodgkin’s lymphoma; NSCLC = non-small cell lung cancer; RA = rheumatoid arthritis; R/R = relapsing and remitting; RTOR = real-time oncology review; RVO = retinal vein occlusion; sBLA = supplemental Biologics License Application; SC = subcutaneous; sNDA = supplemental new drug application; T1DM = type 1 diabetes mellitus; T2DM = type 2 diabetes mellitus; UC = ulcerative colitis; wAMD = wet age-related macular degeneration