MRx Summer Report 2023

Enzyme Replacement Therapy: Approvals and Management

ALS: Recent Advances and Management Strategies

Bladder Cancer: Treatment Update and Managed Care Impact

Accelerated Approvals: Formulary Challenges and Payer Impact

Magellan Rx Report

Summer 2023

Gene Therapy Update: New Approvals and Payer Strategy

MEDICAL AND PHARMACY BENEFIT MANAGEMENT magellanrx.com

Published By Magellan Rx Management 4801 E. Washington St., Ste. 100 Phoenix, AZ 85034

Tel: 401-344-1000 Fax: 401-619-5215 magellanrx.com

Editor Lindsay Speicher, J.D. Project Manager, Specialty lspeicher@magellanhealth.com

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Carole Kallas

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401-344-1132

The content of Magellan Rx™ Report — including text, graphics, images, and information obtained from third parties, licensors, and other material (“content”) — is for informational purposes only. The content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Magellan 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

Carole Kallas

Project Manager

Brian MacDonald, Pharm.D.

Director, Specialty Clinical Strategy

Erin Ventura, Pharm.D. Manager, Specialty Clinical Programs

Brian Kinsella, Esq.

Senior Legal Counsel

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

Natalie Tate, Pharm.D., MBA, BCPS

VP, Pharmacy Management, BlueCross BlueShield of Tennessee

Steve Marciniak, R.Ph.

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

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

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

A NOTE FROM OUR CEO

Dear Managed Care Colleagues,

Welcome to our summer 2023 issue of the Magellan Rx Report!

So far in 2023, the FDA has approved 26 novel drugs, with many more anticipated by year’s end. Exciting advancements and innovative therapies contribute to a promising, expansive pipeline across disease categories. We are committed to bringing our audience valuable, timely highlights of managed care trends and treatment updates.

Our cover story (page 14) focuses on the exciting advances in gene therapy. We review the gene therapies recently approved by the FDA, discussing the current landscape and highlighting management strategies around these high-cost treatments. The article also outlines the pipeline in this category.

Another article focuses on updates in bladder cancer treatment. Recent approvals in the space, including the first gene therapy for bladder cancer, will shift the landscape. We outline the pipeline in this category as well as the financial and payer impact of new approvals.

In our enzyme replacement therapy (ERT) article (page 6), we highlight the recent growth in the ERT landscape. Given that this market is anticipated to grow significantly over the next decade, management strategizing will become increasingly important.

Other topics in this issue include a discussion of recent advances in the treatment of amyotrophic lateral sclerosis (page 10), a dive into the impact of the FDA accelerated approval program (page 24), and a look at results from a real-world CMS Star Rating clinical program (page 30). As always, the issue is rounded out by our pipeline update (page 34) 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

We hope you enjoy the issue; thank you for reading.

MANAGED CARE NEWSSTAND

Energy and Commerce Committee Advances Healthcare Legislation Related to Competition, Transparency, and Access to Care

The Energy and Commerce Committee recently advanced legislation focused on competition, transparency, and access to care in the healthcare industry. These include the following:

HR 2666: Medicaid VBPs for Patients (MVP) Act. Would amend Title XIX of the Social Security Act to codify value-based purchasing (VBP) agreements under the Medicaid program and legislate reforms related to price reporting under such arrangements.

HR 3284: Providers and Payers COMPETE Act. Would require the Department of Health and Human Services (HHS) Secretary to submit an annual report on the impact of certain Medicare regulations on provider and payer consolidation.

HR 3290: Fairness for Patient Medication Act. Would amend Title III of the Public Health Service Act to ensure transparency and oversight of the 340B Drug Discount Program.

HR 3561: Promoting Access to Treatments and Increasing Extremely Needed Transparency (PATIENT) Act of 2023. Was considered in the markup as a package

of bipartisan bills that would increase price and ownership transparency for hospitals, laboratories, and insurers; reduce healthcare costs; and strengthen the health workforce. Relevant provisions include:

• Price transparency requirements, including for pharmacy benefit managers (PBMs). Specifically, the act incorporates a variation of the deferred prescription drug reporting requirements from the Transparency in Coverage regulations. Issuers would be required to report the average amount paid to each participating pharmacy for each National Drug Code (NDC), net of rebates, discounts, and price concessions. These changes would help to prevent tacit collusion, a practice whereby pharmacies and pharmaceutical companies could see each other’s prices and therefore feel free not to offer price concessions less than their competitors, increasing prices over time.

• Mandatory reporting with respect to certain health-related ownership information under Medicare Part C and Part D. This would require new reporting from Medicare (MA) plans on utilization, payment amounts to providers, diagnoses for risk adjustment, and other data, separated by whether the MA plan has a common ownership interest with the provider. It would also require Part D plans to report on payment rates and DIR to pharmacies, separated by whether the plan has a common ownership with the pharmacy. PBMs in a common ownership arrangement with a Part D plan would have separate reporting requirements regarding rebates, fees, and administrative costs for that plan and other Part D clients. This would also include certain public disclosure

requirements related to reported data and additional requirements regarding Medicare-reported encounter data.

• Oversight of PBM services by plans through certain required disclosures and audit rights. The act incorporates the PBM Accountability Act, which requires PBMs and issuers to report substantial information to plan sponsors on prescription drug use, pricing, and rebates in the commercial market. Specifically, four reports are required:

1. Summary report of gross spending on prescription drugs, total rebates and renumeration, total net spending on prescription drugs, amounts paid to brokers, and gross manufacturer copayment assistance for all beneficiaries in the plan.

2. A report for every individual drug, at the NDC level, of utilization (by beneficiary, fill, and unit count),

The Energy and Commerce Committee recently advanced legislation focused on competition, transparency, and access to care in the healthcare industry.

dispensing channel, unit cost, and beneficiary out-of-pocket spending.

3. For drugs with gross spending above $10,000, a list of all other drugs in the same therapeutic class, and the rationale for formulary placement of the drug.

4. A report for each therapeutic class detailing gross spending, utilization, formulary management, and outof-pocket spending, with additional reporting for therapeutic classes with three or more drugs, including total rebates and other remuneration in the class and net spending in the class.

• Cost-sharing limits on highly rebated drugs. Incorporated by amendment and slightly modified from prior versions, this requires that for all drugs with annual rebates greater than 50% of annual gross spending in the prior year across all plans (as reported under RxDC), plans are prohibited from charging cost-sharing, including deductible payments, that exceed the previous annual net price after rebates for that specific plan, adjusted by the volume dispensed. For highly rebated drugs (across all plans) that were not covered by a particular plan’s formulary in the previous year (excluded), the plan may not negotiate any rebate from the manufacturer unless the rebate is reflected at the point of sale.

• Increased transparency in generic drug applications.

• Measures to improve transparency through requiring pass-through and to prohibit spread-pricing for payment arrangements with PBMs in Medicaid.

CMS Proposes Medicaid Prescription Drug Transparency Rule

On May 23, CMS released a proposed rule, “Medicaid Program: Misclassification of Drugs, Program Administration, and Program Integrity Updates Under the Medicaid Drug Rebate Program.” The proposed regulation would give CMS and states additional tools, such as drug price verification surveys, that would result in greater transparency into manufacturers’ drug prices. CMS also proposes to ban spread pricing by requiring that contracts between states, Medicaid managed care plans, and third-party contractors such as PBMs reflect transparent reporting of drug payment information among third-party contractors.

According to CMS, this proposal will help ensure that taxpayer dollars are actually

paying for drugs and not increased profits. The proposed rule includes provisions to ensure that states would receive the rebates to which they are entitled, since states receive a higher percentage of rebate dollars for brand-name drugs compared to generics. CMS proposes steps to further drive down prescription drug costs in Medicaid and build on the Medicare drug price negotiation provisions in the Inflation Reduction Act of 2022 and President Biden’s executive order to lower prescription drug costs for Americans.

FTC Expands Investigations of PBMs

On June 8, the Federal Trade Commission announced as part of its ongoing study on PBMs and their impact on prescription drug prices and access that it had issued a compulsory order to a third group purchasing organization (GPO) that negotiates drug rebates on behalf of PBMs. To date, the agency has sent orders to three GPOs: Emisar Pharma Services, Zinc Health Services, and Ascent Health Services, requiring them to provide information and records pertaining to their business practices.

On May 23, CMS released a proposed rule, “Medicaid Program: Misclassification of Drugs, Program Administration, and Program Integrity Updates Under the Medicaid Drug Rebate Program.”

Enzyme Replacement Therapy:

Approvals and Management

Growth of the ERT landscape is trending, and the market is anticipated to grow significantly over the next decade.

Enzyme replacement therapy (ERT) is a treatment of congenital enzyme deficiencies using purified human, animal, or recombinant enzyme preparations in patients who suffer from chronic conditions due to enzyme deficiencies or malfunction.1, 2 The replacement enzymes used for ERT are derived from genetically modified and processed human, animal, and plant cells.1, 2 ERT is most commonly administered via intravenous (IV) infusion.

Lysosomal storage diseases (LSDs) are rare, chronic, inherited diseases that are the most common conditions treated with ERT.1, 2 These diseases occur when enzymes are absent or malfunctioning inside the lysosomes, which break down proteins and other macromolecules in the body. Some LSDs treated with ERT include Fabry, Gaucher, and Pompe diseases.1, 2

Recent Approvals

Velmanase alfa-tycv (Lamzede®)

In February 2023, velmanase alfa-tycv (Lamzede®) was approved by the U.S. Food & Drug Administration (FDA) for the treatment of adults and children with non-central nervous system manifestations of α-mannosidosis, a rare genetic condition in which the body is unable to properly break down certain complex sugars in cells.3 This condition is an ultra-rare, progressive LSD caused by deficiency in the enzyme α-mannosidase.3 Velmanase alfa is a recombinant form of human α-mannosidase used to provide or supplement natural α-mannosidase and is the first ERT approved for the treatment of rare α-mannosidasis in the U.S.3

The effectiveness of velmanase alfa was evaluated in adults and pediatric patients with α-mannosidosis in a phase 3 multicenter, randomized, double-blind, placebo-controlled, parallel group study.4 Efficacy was evaluated over 52 weeks at a dose of 1 mg/kg given weekly as an IV infusion.4 Of a total of 25 enrolled patients, including 13 adults and 12 pediatric patients, 15 patients (eight adult, seven pediatric) received velmanase alfa and 10 patients (five adult, five pediatric) received placebo.4 Clinical endpoints assessed at 12 months included a 3-minute stair climbing test, 6-minute walking test, and

Stephanie Lem, Pharm.D. Associate Director, Pharmacy CenCal Health

Alina Liang, Pharm.D. Pharmacist, Resident Magellan Rx Management

forced vital capacity, all of which favored the velmanase alfa group and were supported by a reduction in serum oligosaccharide concentration.4

Adverse reactions associated with velmanase alfa include hypersensitivity reactions, including anaphylaxis; thus, appropriate medical support measures, including resuscitation equipment, should be readily available during administration.3 Additional warnings include infusion-associated reactions and risk of embryo-fetal toxicity.

Pegunigalsidase alfa-iwxi (ELFABRIO)

The FDA approved pegunigalsidase alfa-iwxi (ELFABRIO) in May 2023 for the treatment of adults with Fabry disease.5 This is an alternate treatment with a unique mechanism of action for this rare disease patient population.5 Pegunigalsidase alfa is a PEGylated ERT comprised of recombinant human α-Galactosidase-A enzyme, expressed in plant-cell culture designed for elongated half-life.5

Approval was based on findings from three phase 3 trials: BALANCE, BRIDGE, and BRIGHT, along with a phase 1/2 trial.5 The combined trials involved more than 140 individuals with Fabry disease with up to 7.5 years of follow-up treatment. Results showed efficacy in both ERT-naïve and ERT-experienced patients.5

The open-label, single-arm, phase 3 BRIDGE trial assessed the safety and efficacy of treatment in adults with Fabry, aged 24 to 60 years, who previously received a stable dose of agalsidase alfa for at least two years.6 Patients showed substantial improvement in renal function as measured by mean annualized estimated Glomerular Filtration Rate (eGFR slope) in patients who were switched from agalsidase alfa to pegunigalsidase alfa.6 BRIDGE results showed mean annualized eGFR slope of the study participants improved from -5.90 ml/min/1.73m2/year to -1.19 mL/min/1.73m2/year on agalsidase alfa to pegunigalsidase alfa, respectively.

A 12-month, open-label, switch-over BRIGHT study of 30 patients with Fabry disease treated previously with an ERT such as agalsidase alfa or agalsidase beta assessed patients after receiving treatment with pegunigalsidase alfa 2 mg/kg every four weeks; no patients developed treatment-induced anti-drug antibodies and no Fabry clinical events were reported.6 During the study, plasma lso-Gb3 concentrations remained stable during the study with a mean change of 3.01 nM from baseline to week 52.6 Mean absolute change of eGFR values remained stable during the treatment period.6

Pegunigalsidase alfa comes with a safety label stating clinicians should consider pretreating Fabry with antihistamines, antipyretics, and/or corticosteroids before administration and that patients should immediately discontinue treatment if a severe hypersensitivity reaction or severe infusion-associated reaction occurs.5

Avalglucosidase alfa-ngpt (NEXVIAZYME®)

The FDA previously approved avalglucosidase alfa-ngpt (NEXVIAZYME®) for the treatment of late-onset Pompe disease in patients 1 and older in August 2021. Avalglucosidase alfa is an IV ERT that helps reduce glycogen accumulation.7 A study of 100 patients demonstrated effectiveness; patients were randomized to receive avalglucosidase alfa or another FDA-approved ERT for Pompe disease.8 Avalglucosidase alfa treatment was associated

Lysosomal storage diseases (LSDs) are rare, chronic, inherited diseases that are the most common conditions treated with ERT.

ENZYME REPLACEMENT THERAPY |

Abbreviations: ASD = autism spectrum disorder; CDI = clostridium difficile infection; ENPP1 = ectonucleotide

enzyme replacement therapy;

= Graft versus host disease; IL-18 = interleukin 18; IV = intravenous; SQ = subcutaneous

with improved lung function similar to the improvement seen with the other therapy.8 Long-term extension results from the phase 3 COMET study showed, after nearly two years, that treatments with avalglucosidase alfa in both primary and extension periods led to a 2.65-point improvement in forced vital capacity compared to baseline.9 Patients treated with avalglucosidase alfa during primary and extension periods showed an average increase of 18.6 meters in walking disease measured by a six-minute walking test compared with distance at baseline.9

Avalglucosidase alfa is currently being investigated as an alternative treatment option for infantile-onset Pompe disease (IOPD).9 The phase 3 Baby-COMET trial started in September 2021 in participants under six months with a primary endpoint of proportion of participants who are alive and free of invasive ventilation at week 52.9

Side effects associated with avalglucosidase alfa include headache, fatigue, diarrhea, nausea, joint pain, dizziness, muscle pain, itching, vomiting, difficulty breathing, skin redness, paresthesia, and skin welts, while more serious reactions include hypersensitivity.7

Management Opportunities

Growth of the ERT landscape is trending, and the market is anticipated to grow significantly over the next decade.10 A rise in prevalence and diagnoses of rare LSDs will drive much of this growth.10 As this market continues to grow and more treatment options become available for these rare LSDs, payer focus on management will become increasingly important. Management strategies that aim to allow access to the patient population that will benefit most from these therapies will be key to managing costs and improving outcomes.

References

1. “What is Enzyme Replacement Therapy and How Does It Work?” Infusion Associates, https://infusionassociates.com/what-is-enzymereplacement-therapy.

2. “Enzyme Replacement Therapy.” LiverTox: Clinical and Research Information on Drug-Induced Liver Injury, 10 Mar. 2016, https://www. ncbi.nlm.nih.gov/books/NBK548796.

3. “FDA approves first enzyme replacement therapy for rare alphamannosidosis.” U.S. Food & Drug Administration, 17 Feb. 2023, https://www.fda.gov/drugs/news-events-human-drugs/fda-approvesfirst-enzyme-replacement-therapy-rare-alpha-mannosidosis.

4. Borgwardt, Line, et al. “Efficacy and safety of Velmanase alfa in the treatment of patients with alpha-mannosidosis: results from the core and extension phase analysis of a phase III multicentre, double-blind, randomised, placebo-controlled trial.” Journal of Inherited Metabolic Disease, 2018, https://www.ncbi.nlm.nih.gov/ pmc/articles/PMC6326984.

5. Meglio, Marco. “FDA Approves Enzyme Replacement Therapy

Pegunigalsidase Alfa for Fabry Disease.” NeurologyLive, 10 May 2023, https://www.neurologylive.com/view/fda-approves-enzymereplacement-therapy-pegunigalsidase-alfa-for-fabry.

6. Meglio, Marco. “Pegunigalsidase Alfa Demonstrates Efficacy in Phase 3 Fabry Disease Study.” NeurologyLive, 3 Mar. 2021, https:// www.neurologylive.com/view/pegunigalsidase-alfa-demonstratesefficacy-phase-3-fabry-disease.

7. “FDA Approves New Treatment for Pompe Disease.” U.S. Food & Drug Administration, 6 Aug. 2021, https://www.fda.gov/news-events/pressannouncements/fda-approves-new-treatment-pompe-disease.

8. Diaz-Manera, Jordi, et al. “Safety and efficacy of avalglucosidase alfa versus alglucosidase alfa in patients with late-onset Pompe disease (COMET): a phase 3, randomised, multicentre trial.” Lancet Neurology, Dec. 2021, https://pubmed.ncbi.nlm.nih.gov/34800399/.

9. “Nexviazyme® (avalglucosidase alfa) shows sustained improvements in respiratory function and mobility in patients with Pompe disease.” Sanofi, 8 Feb. 2022, https://www.sanofi.com/en/media-room/press-releas es/2022/2022-02-08-14-00-00-2380936.

10. Smita, N., et al. “Enzyme Replacement Therapy Market by Product, Disease, and End User: Global Opportunity Analysis and Industry Forecast, 2021-2030.” Enzyme Replacement Therapy Market, Sept. 2021, https://www.alliedmarketresearch.com/enzyme-replacementtherapy-market-A10949.

Amyotrophic Lateral Sclerosis (ALS): Recent Advances and Management Strategies

The approval of new treatment options for ALS means that payer strategy will become more important to proper management.

A progressive, disabling, and fatal neurodegenerative disorder, amyotrophic lateral sclerosis (ALS) affects motor neurons in the brain and spinal cord that control voluntary muscle movement in the body.1,2 Up to 30,000 adults in the U.S. are living with ALS, with an estimated 5,000 new cases diagnosed yearly.1 ALS is most common in adults over age 60.1 ALS is diagnosed based on a review of symptom history coupled with a physical exam; often, a series of tests are utilized to rule out other diseases with similar symptom presentation.2 While the cause of ALS is unknown, some studies suggest genetics and environmental factors may contribute.2

John Joffer, Pharm.D. Vice President, Pharmacy Services PacificSource

Early stage ALS manifests as muscle twitching and cramping, loss of muscle control and muscle weakness and fatigue; it affects muscles such as the arms, legs, shoulders, neck, and diaphragm. As a result, patients with ALS are initially likely to trip and fall, drop things, have slurred or thick speech, and have difficulty projecting their voice.2 As ALS progresses, the severity of symptoms increases and patients go on to experience shortness of breath, difficulty breathing, difficulty chewing and swallowing, and paralysis.2 Disease progression is measured using the ALS Functioning Rating Scale (ALSFRS-R); a substantial decline in functioning is reflected by point decreases in the ALSFRS-R.4

In the U.S., total costs associated with ALS are $212 million to $1.4 billion per year, including direct and indirect costs to this population.5 The average anticipated cost of care per patient varies in the U.S. from $16,000 to $200,000, depending on the stage of the disease.3

Current Treatment Landscape

The first treatment available indicated for ALS, riluzole (RILUTEK®), was approved by the U.S. Food & Drug Administration (FDA) in 1995.6 The second FDA-approved drug for ALS, edaravone (RADICAVA®), was approved in 2017.7 The American Academy of Neurology (AAN) Treatment Guidelines from 2009, which have been most recently reaffirmed in February 2023, recommend riluzole for the treatment of ALS. The guidelines are silent on more recently approved treatments, including edaravone, taurursodiol, and tofersen.8 As the treatment landscape continues to expand, updated guidelines and real-world evidence will be critical in providing clear guidance around appropriate management and consensus-driven place in therapy for these treatments.

Recent Approvals

Edaravone (RADICAVA ORS®)

The FDA approved an oral suspension form of edaravone (RADICAVA ORS®, Mitsubishi Tanabe Pharma) in May 2022 for the treatment of ALS.9 Edaravone was originally approved in 2017 as an intravenous (IV) infusion after efficacy for the treatment of ALS was demonstrated in a six-month clinical trial. The effectiveness and approval of the oral suspension was then based on the study results showing comparable levels of oral edaravone in the bloodstream to levels from the IV formulation.9 Common side effects associated with edaravone are bruising, problems walking, headaches, and possibly fatigue.9

Sodium phenylbutyrate; taurursodiol (RELYVRIO®)

In September 2022, the FDA approved sodium phenylbutyrate/ taurursodiol (RELYVRIO®, Amylyx Pharmaceuticals) to treat ALS through priority review and orphan drug pathways.10 Sodium phenylbutyrate/taurursodiol can be taken orally before a snack or meal and also administered via feeding tube; before administration, one packet should be combined in 8 ounces of room temperature water.10 The recommended dose is one packet daily for the first three weeks followed by one packet twice daily thereafter.10

Efficacy was evaluated and demonstrated in a 24-week, multicenter, randomized, double-blind, placebo-controlled, parallel group study that included 137 adult patients with ALS who were randomized to receive either sodium phenylbutyrate/ taurursodiol or placebo.11 Patients treated with sodium phenylbutyrate/taurursodiol were shown to experience a slower rate of decline in the study’s clinical assessment of daily

functioning compared to those receiving a placebo;11 a post hoc, long-term analysis demonstrated longer overall survival in patients who originally received sodium phenylbutyrate/ taurursodiol versus placebo.12 Adverse reactions associated with treatment were diarrhea, abdominal pain, nausea, and upper respiratory tract infection.10 Notably, taurursodiol, a bile acid, may cause worsening diarrhea in patients with disorders that interfere with bile acid circulation.10

Tofersen (QALSODY®)

The FDA approved tofersen (QALSODY®, Biogen) in April 2023 for the treatment of ALS. The recommended dose of tofersen is 100 mg administered intrathecally by a healthcare professional.13 Three initial doses are administered at 14-day intervals, followed by a maintenance dose every 28 days.13 Approval was based on results from a 28-week, randomized, double-blind, placebo-controlled clinical study in 147 patients with weakness attributed to ALS and a confirmed superoxide dismutase 1 gene (SOD1)-mutation.14 In this study, 108 patients were randomized to receive treatment with either tofersen or placebo for 24 weeks.14 Treatment with tofersen was associated with nominally significant reductions in plasma neurofilament light (NfL) concentration at week 28 compared to treatment with placebo.14 The FDA determined that the results are reasonably likely to predict a clinical benefit in patients.

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Tofersen was approved under the accelerated approval pathway. To further support clinical benefit, there is an active phase 3 randomized, double-blind, placebo-controlled trial in individuals who are carriers of the SOD1 genetic mutation who do not yet have symptoms.13 This study will assess and compare the development of ALS symptoms in individuals treated with tofersen and placebo.13 Treatment with tofersen was associated with side effects including pain, fatigue, arthralgia, increased cerebrospinal fluid, white blood cells, and myalgia.13

ICER Review

An Institute of Clinical and Economic Review (ICER) report from September 2022 included an analysis on the cost of ALS therapies, specifically edaravone and sodium phenylbutyrate/taurursodiol.15 The report noted that edaravone provided an added 0.04 qualityadjusted life years (QALYs) and 0.05 equal value life years gained (evLYG) compared with standard care.15 Edaravone was deemed not cost-effective at its list price of $171,000 per year. It was also noted that patients gained 0.14 QALYs and 0.31 evLYGs with sodium phenylbutyrate/taurursodiol added to standard care of therapies; however, this therapy was also found to be not cost-effective at the placeholder price used for the analysis ($169,000 per year).15 The list price of sodium phenylbutyrate/taurursodiol, now available, is $158,000 per year.15 An ICER determination of cost effectiveness at this list price has not yet been published.

Managed Care Impact

Management of ALS requires multidisciplinary teams comprised of a combination of healthcare professionals: physicians, pharmacists, physical, occupational and speech therapists,

nutritionists, social workers, respiratory therapists, clinical psychologists, and home care and hospice nurses.2 Proper treatment may include medication paired with physical therapy, speech therapy, nutritional support, and respiratory support. Since ALS management is patient-specific, a patient’s treatment team can be crucial in tailoring an individualized treatment plan.2 Coordination between managed care organizations and the care team will be key to appropriate management, optimizing outcomes, and potentially delaying disease progression.16

With the approval of new treatment options for ALS, payer strategy around this category will become more important to proper management. Payers may benefit from strategizing how they can best manage the space while ensuring patients have access to the most appropriate therapy, particularly now that there are several available options. Utilization management by managed care organizations and payers as well as support for the multidisciplinary care teams may lead to improved outcomes and better cost management.16

Payers may benefit from strategizing how they can best manage the space while ensuring patients have access to the most appropriate therapy, particularly now that there are several available options.

References

1. “ALS – amyotrophic lateral sclerosis.” Johns Hopkins Medicine, https://www.hopkinsmedicine.org/neurology_neurosurgery/ centers_clinics/als/conditions/als_amyotrophic_lateral_sclerosis. html.

2. “Amyotrophic Lateral Sclerosis (ALS) Fact Sheet.” National Institute of Neurological Disorders and Stroke, 22 Jun. 2020, https://www. ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/ Amyotrophic-Lateral-Sclerosis-ALS-Fact-Sheet.

3. Santaniello, B. “ALS Managed Care Considerations.” American Journal of Managed Care. https://www.ajmc.com/view/als-managedcare-considerations.

4. Berry, James D., et al. “The Combined Assessment of Function and Survival (CAFS): A new endpoint for ALS clinical trials.” Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 23 Oct 2012, https://www.tandfonline.com/doi/full/10.3109/21678421.2012.7 62930

5. Berry, James D., et al. “Epidemiology and economic burden of amyotrophic lateral sclerosis in the United States: a literature review.” Amyotrophic Lateral Sclerosis Frontotemporal Degeneration, 7 Feb. 2023, https://pubmed.ncbi.nlm.nih.gov/36748473.

6. Miller, R.G., et al. “Clinical trials of riluzole in patients with ALS. ALS/ riluzole study group – II.” Neurology, 1996, https://pubmed.ncbi. nlm.nih.gov/8858057/.

7. “FDA approves drug to treat ALS.” U.S. Food & Drug Administration, 5 May 2017, https://www.fda.gov/news-events/pressannouncements/fda-approves-drug-treat-als.

8. “AAN Summary of Evidence-based Guideline for CLINICIANS: The care of the patient with amyotrophic lateral sclerosis: Drug, nutritional and respiratory therapies.” American Academy of Neurology, 11 Jan. 2020, https://www.aan.com/Guidelines/home/ GuidelineDetail/370.

9. “FDA Approves Oral Form for the treatment of adults with amyotrophic lateral sclerosis (ALS).” U.S. Food & Drug Administration, 12 May 2022, https://www.fda.gov/drugs/news-events-humandrugs/fda-approves-oral-form-treatment-adults-amyotrophiclateral-sclerosis-als.

10. “FDA Approves New Treatment Option for Patients with ALS.” U.S. Food & Drug Administration, 29 Sept. 2022, https://www.fda.gov/ news-events/press-announcements/fda-approves-new-treatmentoption-patients-als.

11. Paganoni, Sabrina, et al. “Trial of Sodium PhenylbutyrateTaurursodiol for Amyotrophic Lateral Sclerosis.” The New England Journal of Medicine, 3 Sept. 2020, https://pubmed.ncbi.nlm.nih. gov/32877582/.

12. Paganoni, Sabrina, et al. “Survival analyses from the CENTAUR trial in amyotrophic lateral sclerosis: Evaluating the impact of treatment crossover on outcomes.” Muscle Nerve, Aug. 2022, https://pubmed. ncbi.nlm.nih.gov/35508892/.

13. “FDA approves treatment of amyotrophic lateral sclerosis associated with a mutation in the SOD1 gene.” U.S. Food & Drug Administration, 25 Apr. 2023, https://www.fda.gov/drugs/newsevents-human-drugs/fda-approves-treatment-amyotrophic-lateralsclerosis-associated-mutation-sod1-gene.

14. Miller, Timothy M., et al. “Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS.” The New England Journal of Medicine, 22 Sept. 2022, https://www.nejm.org/doi/10.1056/NEJMoa2204705.

15. “ICER Publishes Final Evidence Report and Policy Recommendations on Treatments for Amyotrophic Lateral Sclerosis.” Institute for Clinical and Economic Review, 13 Sept. 2022, https://icer.org/news-insights/ press-releases/icer-publishes-final-evidence-report-and-policyrecommendations-on-treatments-foramyotrophic-lateral-sclerosis/.

16. Wong, Winston. “The Role of Managed Care Professionals in Improving Care for Patients with ALS.” American Journal of Managed Care, 17 Aug. 2020, https://www.ajmc.com/view/the-role-ofmanaged-care-professionals-in-improving-care-for-patients-with-als.

Gene Therapy Update: New Approvals and Payer Strategy

Potentially 90 new gene and cellular therapies could be approved by 2031, representing $30 billion in healthcare spending.

Gene therapy works via agents that can replace a disease-causing gene with a functioning copy of the gene, deactivate a disease-causing gene that is malfunctioning, or introduce a new or modified gene to help treat the disease.1

Since the first U.S. Food & Drug Administration (FDA) approval of a gene therapy, KYMRIAH®, in 2017, an increasing number of gene therapies have been approved and become available. These gene therapies have been approved for a range of indications including spinal muscular atrophy, beta thalassemia, cerebral adrenoleukodystrophy, hemophilia B, inherited retinal disease, and non-muscle invasive bladder cancer.1

Amber Zuber, Pharm.D. AVP Pharmacy & Member Services

The landscape of available gene therapies as well as approved indications is expected to continue expanding. Up to 90 new gene and cellular therapies could be approved by 2031, representing $30 billion in healthcare spending.2

Recent Approvals

Etranacogene

dezaparvovec (HEMGENIX®)

In November 2022, the FDA approved etranacogene dezaparvovec (HEMGENIX®) for the treatment of adults with hemophilia B (congenital Factor IX deficiency) who currently use factor IX (FIX) prophylaxis therapy, who have current or historical life-threatening hemorrhage, or who have repeated serious spontaneous bleeding episodes. The FDA application received priority review, orphan, and breakthrough therapy designations.3

Etranacogene dezaparvovec is an adeno-associated virus vectorbased, one-time gene therapy given as a single dose by IV infusion.3 In a study of 54 adult men with severe or moderately severe hemophilia B, subjects who received the treatment showed increased FIX activity levels, a decreased need for routine FIX replacement prophylaxis, and a 54% reduction in annualized bleeding rate compared to baseline.4

Adverse reactions associated with etranacogene dezaparvovec included liver enzyme elevations, headache, mild infusionrelated reactions, and flu-like symptoms.3

In December 2022, the Institute for Clinical and Economic Review (ICER) released a report assessing the comparative clinical effectiveness and value of etranacogene dezaparvovec for hemophilia B.5 The report concluded that there is a moderate certainty of a small or substantial health benefit with high certainty of at least a small net health benefit for etranacogene dezparvovec compared with FIX prophylaxis.5

Nadofaragene firadenovec-vncg (ADSTILADRIN®)

The FDA approved nadofaragene firadenovec-vncg (ADSTILADRIN®) in December 2022 for the treatment of adult patients with high-risk Bacillus Calmette-Guérin unresponsive non-muscle invasive bladder cancer with carcinoma in situ

with or without papillary tumors.6 Efficacy was evaluated in a multicenter, single-arm trial, Study CS-003, with 157 patients with high-risk non-muscle invasive bladder cancer; 98 participants had Bacillus Calmette-Guérin — unresponsive carcinoma in situ evaluable for response.7 In the study, participants were administered nadofaragene firadenovec-vncg 75 mL intravesical instillation once every three months for up to 12 months, until unacceptable toxicity, or recurrent high-grade non-muscle invasive bladder cancer.7 Efficacy outcome measures were complete response (CR) and duration of response.7 The rate of CR was 51% and median duration of response was 9.7 months, with 46% of responding patients remaining in CR for at least one year.7

Common adverse reactions associated with nadofaragene firadenovec-vncg include increased glucose, triglycerides, and creatinine; decreased phosphate; instillation site discharge; fatigue; bladder spasm; micturition urgency; hematuria; chills; dysuria; and pyrexia.6

Beremagene Geperpavec (VYJUVEK®)

Beremagene geperpavec (VYJUVEK®) was approved by the FDA in May 2023 for the treatment of wounds in patients 6 months and older with dystrophic epidermolysis bullosa (DEB) with mutations in the collagen type VII alpha 1 chain (CO7A1) gene.8 This represents the first approved gene therapy for DEB, a genetic disorder that affects connective tissue in the skin and nails.8 Beremagene geperpavec is a genetically modified herpes-simplex virus used to deliver normal copies of the COL7A1 gene to the wounds.8 The treatment is mixed into an excipient gel prior to topical application and is administered topically by a healthcare professional once a week.8

Approval was based on a randomized, double-blinded, placebo-controlled study involving a total of 31 subjects with DEB, including 30 subjects with recessive DEB (RDEB) and one with dominant DEB (DDEB). 9 Two DEB wounds of comparable size on each patient were identified and randomized to receive either topical administration of beremagene geperpavec or placebo weekly. 9 Efficacy was established by improved wound healing, or the difference in the proportion of confirmed complete wound closure between those treated with beremagene geperpavec and those treated with placebo at 24 weeks. 9 Of wounds treated with beremagene geperpavec, 65% completely closed while only 26% of the placebo-treated wounds completely closed. 9 Common adverse reactions associated with beremagene geperpavec are itching, chills, redness, rash, cough, and runny nose. 8

Up to 90 new gene and cellular therapies could be approved by 2031, representing $30 billion in healthcare spending.

Delandistrogene moxeparvovec (ELEVIDYS®)

In June 2023, the FDA approved delandistrogene moxeparvovec-rokl (ELEVIDYS®, Sarepta Therapeutics) via accelerated approval pathway; this is the first gene therapy to treat Duchenne muscular dystrophy (DMD).10 The therapy is approved for the treatment of ambulatory pediatric patients aged 4 through 5 years with DMD who have a confirmed mutation in the DMD gene.10 Approval was supported empirical and biologic evidence as well as efficacy data from two clinical studies (SRP-9001-102 and SRP-9001-103) and safety data from SRP 9001-101.10 A confirmatory, global, randomized, doubleblind, placebo-controlled phase 3 trial, EMBARK, is fully enrolled with top-line results anticipated late in 2023.10 Adverse reactions associated with delandistrogene moxeparvovec-rokl were vomiting, nausea, liver function test increased, pyrexia, and thrombocytopenia.10

Valoctocogene roxaparvovec (ROCTAVIAN®)

The FDA approved the first gene therapy for adults with severe hemophilia A, valoctocogene roxaparvovec (ROCTAVIAN®, BioMarin Pharmaceutical Inc.) in June 2023.11 Valoctocogene roxaparvovec is an adeno-associated virus vector-based gene therapy, now approved for the treatment of adults with severe hemophilia A without pre-existing antibodies to adeno-associated virus serotype 5 detected by an FDA-approved test.11 A multinational study in adult men 18 to 70 years of age with severe hemophilia A

evaluated safety and effectiveness.12 Participants were previously treated with Factor VIII replacement therapy and effectiveness was established based on results from a cohort of 112 patients followed up for at least three years after treatment with the gene therapy.12 Mean annualized bleeding rate decreased from 5.4 bleeds per year at baseline to 2.6 bleeds per year following infusion.12 A majority of patients who received valoctocogene roxaparvovec received corticosteroids as an immune system suppressant for the gene therapy to be effective and safe.12 The treatment response may decrease over time.11 Common adverse reactions associated with treatment were mild changes in liver function, headache, nausea, vomiting, fatigue, abdominal pain and infusion-related reactions.11

Payer Management

As the gene therapy landscape continues to expand with more options and approved indications, payer management of the space will become increasingly important considering the high price tag associated with these treatments. A May 2023 survey of benefit leaders at employers and health plans from the Pharmaceutical Strategy Group outlined findings and concerns regarding gene therapy and specialty drug benefit design.13 About half of the payers reported gene therapy affordability as a major challenge in the next few years and 25% anticipated a major challenge from the drugs.13 Only 25% of payers surveyed reported using value-based contracts for specialty drugs with only 5% of employers reporting the same.13 About 14% of employers and 7% of payers use alternative payment models, like grant and manufacturer patient programs, to pay for specialty drugs.13 Site of care carboplatin programs are utilized by half of payers and a quarter of employers surveyed, in an effort to reduce specialty drug costs.13 The top challenge concerning specialty drug cost for health plans was cost parity across medical and pharmacy benefits and, for employers, was affordability for members.13 Despite concerns around the financial burden and cost associated with these therapies, there is consensus that ensuring access to potentially life-saving therapies for the appropriate patient population is important.2

In February 2023, the U.S. Department of Health and Human Services (HHS) announced a new payment and service delivery model for testing by the Center for Medicare & Medicaid Innovation (CMS Innovation Center).14 Under the voluntary Cell and Gene Therapy Access Model, state Medicaid agencies would have the option to direct CMS to coordinate and administer multistate, outcomes-based agreements with manufacturers for certain cell and gene therapies, giving CMS the responsibility of implementing, monitoring, reconciling, and evaluating the financial and clinical outcomes.14 The objective of the model would be to allow CMS to pool bargaining power to obtain discounted pricing,

tie the cost of cell and gene therapies to outcomes, and shift the burden of administering complex outcomes-based agreements from state Medicaid agencies to CMS.9 The model development is slated to begin this year with a launch as early as 2026.14

Overall, alternative payment models may prove critical in financing and allowing access to gene therapies where appropriate. These models, including outcomes- or milestone-based agreements,

Pipeline Rare Diseases

lovotibeglogene autotemcel (Lovo-cel)

mortgage-like mechanisms, subscription payment models, risk pools, and orphan reinsurer benefit managers, can help finance high-cost gene therapies. There are ongoing concerns around current reimbursement models, such as the burden of information tracking, regulatory barriers, and pricing and reporting requirements. Thus, collaborative development of creative payment models by all stakeholders will be key to effectively manage these treatments, allow access, and ease the financial burdens.

bluebird bio IV SCD pending (1H 2024)

exagamglogene autotemcel (Exa-cel) CRISPR Therapeutics; Vertex IV beta thalassemia; SCD phase 3

giroctocogene fitelparvovec (SB-525) Sangamo Therapeutics; Pfizer IV hemophilia A phase 3

fidanacogene elaparvovec (PF-06838435) Spark Therapeutics; Pfizer IV

debcoemagene autoficel (D-Fi)

EB-101

fordadistrogene movaparvovec (PF-06939926)

Hemophilia B phase 3

Castle Creek Biosciences; Fibrocell Technologies injectable epidermolysis bullosa phase 3

Abeona Therapeutics other epidermolysis bullosa phase 3

Pfizer IV DMD phase 3

timrepigene emparvovec (AAV2-REP1) Nightstar Therapeutics; Biogen intravitreal choroideremia phase 3

olenasufligene relduparvovec (LYS-SAF302)

Lysogene other mucopolysaccharidosis type IIIA phase 3

lenadogene nolparvovec (GS010) GenSight Biologics ophthalmic LHON phase 3

simoladagene autotemcel (OTL-101) Orchard Therapeutics injectable SCID phase 3

onasemnogene abeparvovec (Zolgensma IT)

Novartis Gene Therapies intrathecal SMA phase 3

OTL-103 Orchard Therapeutics; GSK IV WAS phase 3

pariglasgene brecaparvovec (DTX401)

UX701

botaretigene sparoparvovec (AAV-RPGR)

Ultragenyx IV Von Glerke disease phase 3

Ultragenyx IV Wilson’s disease phase 3

MeiraGTx; Janssen other retinitis pigmentosa phase 3

afidarsagene autotemcel (OTL-200) Orchard Therapeutics; GSK IV metachromatic leukodystrophy phase 3

laruparetigene zosaparvovec (AGTC-501)

avalotcagene ontaparvovec (DTX301)

Common diseases

alferminogene tadenovec (Generx)

RGX-314

LBP-EC01

donaperminogene seltoplasmid (Engensis)

Applied Genetic Technologies injectable retinitis pigmentosa phase 3

Ultragenyx IV urea cycle disorders phase 3

Angionetics; Gene Biotherapeutics other angina pectoris phase 3

Regenxbio; AbbVie ophthalmic wAMD phase 3

Locus Biosciences oral

UTI caused by certain organisms phase 3

ViroMed; Helixmith intramuscular chronic diabetic foot ulcers; diabetic neuropathy phase 3

Abbreviations: DMD = Duchenne muscular dystrophy; IV = intravenous; LHON = Leber hereditary optic neuropathy; SCD = Sickle cell disease; SCID = severe combined immunodeficiency; SMA = spinal muscular atrophy; UTI = urinary tract infection; wAMD = wet age-related macular degeneration; WAS = Wiskott Aldrich syndrome

References

1. “What is Gene Therapy?” U.S. Food & Drug Administration, 25 Jul. 2018, https://www.fda.gov/vaccines-blood-biologics/cellular-genetherapy-products/what-gene-therapy.

2. “Top Payer Strategies Around Payment Models for Advanced Therapies.” Health Payer Intelligence, 27 Jul. 2022, https:// healthpayerintelligence.com/features/top-payer-strategies-aroundpayment-models-for-advanced-therapies.

3. “FDA Approves First Gene Therapy to Treat Adults with Hemophilia

B.” U.S. Food & Drug Administration, 22 Nov. 2022, https://www.fda. gov/news-events/press-announcements/fda-approves-first-genetherapy-treat-adults-hemophilia-b.

4. Pipe, Steven W., et al. “Adults with Severe or Moderately Severe Hemophilia B Receiving Etranacogene Dezaparvovec in the HOPE-B Phase 3 Clinical Trial Continue to Experience a Stable Increase in Mean Factor IX Activity Levels and Durable Hemostatic Protection after 24 Months’ Follow-up.” Blood, 15 Nov. 2022, https://ashpublications.org/ blood/article/140/Supplement%201/4910/490589/Adults-withSevere-or-Moderately-Severe-Hemophilia.

5. “ICER Publishes Final Evidence Report on Gene Therapies for Hemophilia A and B.” Institute for Clinical and Economic Review, 22 Dec. 2022, https://icer.org/news-insights/press-releases/icer-publishesfinal-evidence-report-on-gene-therapies-for-hemophilia-a-and-b/.

6. “FDA D.I.S.C.O. Burst Edition: FDA Approval of Adstiladrin (nadofaragene firadenovec-vncg) for patients with high-risk Bacillus Calmette-Guérin unresponsive non-muscle invasive bladder cancer with carcinoma in situ with or without papillary tumors.” U.S. Food & Drug Administration, 20 Jan. 2023, https://www.fda.gov/drugs/resources-informationapproved-drugs/fda-disco-burst-edition-fda-approval-adstiladrinnadofaragene-firadenovec-vncg-patients-high-risk.

7. Boorjian, Stephen A., et al. “Intravesical nadofaragene firadenovec gene therapy for BCG-unresponsive non-muscle-invasive bladder cancer: a single-arm, open-label, repeat-dose clinical trial.” The Lancet Oncology, Jan. 2021, https://pubmed.ncbi.nlm.nih. gov/33253641/.

8. “FDA Approves First Topical Gene Therapy for Treatment of Wounds in Patients with Dystrophic Epidermolysis Bullosa.” U.S. Food & Drug Administration, 19 May 2023, https://www.fda.gov/news-events/pressannouncements/fda-approves-first-topical-gene-therapy-treatmentwounds-patients-dystrophic-epidermolysis-bullosa.

9. Guide, Shireen V., et al. “Trial of Beremagene Geperpavec (B-VEC) for Dystrophic Epidermolysis Bullosa.” The New England Journal of Medicine, 15 Dec. 2022, https://pubmed.ncbi.nlm.nih. gov/36516090/.

10. “Sarepta Therapeutics Announces FDA Approval of ELEVIDYS, the First Gene Therapy to Treat Duchenne Muscular Dystrophy.” Sarepta Therapeutics, 22 June 2023, https://investorrelations.sarepta. com/news-releases/news-release-details/sarepta-therapeuticsannounces-fda-approval-elevidys-first-gene.

11. “FDA Approves First Gene Therapy for Adults with Severe Hemophilia A.” U.S. Food & Drug Administration, 29 June 2023, https://www.fda.gov/news-events/press-announcements/fdaapproves-first-gene-therapy-adults-severe-hemophilia.

12. Ozelo, Margareth C., et al. “Valoctocogene Roxaparvovec Gene Therapy for Hemophilia A.” he New England Journal of Medicine, 17 Mar 2022, https://www.nejm.org/doi/full/10.1056/ NEJMoa2113708

13. Wilson, Rylee. “Payers are concerned about gene-therapy drug costs: 5 things to know.” Becker’s Payer Issues, 5 May 2023, https:// www.beckerspayer.com/payer/payers-are-concerned-about-genetherapy-drug-costs-5-things-to-know.html.

14. “New U.S. Drug Pricing Models Target Cell and Gene Therapies, Accelerated Approval Drugs, and Generics.” Sidley, 23 Feb. 2023, https://www.sidley.com/en/insights/newsupdates/2023/02/ new-us-drug-pricing-models-target-cell-and-gene-therapiesaccelerated-approval-drugs-and-generics.

Bladder Cancer: Treatment Update and Managed Care Impact

With the introduction of the first gene therapy for bladder cancer and its associated high costs, management criteria around the specific patient population and indications will be key.

An estimated 82,290 adults in the U.S. will be diagnosed with bladder cancer in 2023.1 Urothelial carcinoma (UC) is the most common form of bladder cancer, accounting for about 95% of all bladder cancer cases.2 The rate of bladder cancer steadily declined an estimated 2% yearly from 2015 to 2019. About 90% of people with bladder cancer are over age 55, and the average age of those diagnosed is 73. It is the fourth most common cancer in men but is less common in women.3

Andrew J. Colby, R.Ph., MBA VP, Enterprise Pharmacy Solutions

Estimates state that about 16,710 deaths from bladder cancer will occur in the U.S. in 2023.1 While the death rate for bladder cancer decreased by over 2% annually in recent years, bladder cancer is the eighth most common cause of cancer death among men in the U.S.1 The five-year relative survival rate for bladder cancer is 77%, though this depends on various factors, including the cancer’s stage, the patient’s age and general health, and the effectiveness of the treatment plan.1 In cases where the bladder cancer has not spread beyond the inner layer of the bladder wall, about half of diagnoses, the five-year survival rate is 96%.1 The survival rate decreases as the cancer metastasizes to surrounding tissue and other organs.1

Treatment Landscape

Drug therapy for bladder cancer will vary depending on the stage and type of disease, but may include chemotherapy, immunotherapy, targeted therapy, or gene therapy. Common systemic chemotherapy regimens for bladder cancer include: cisplatin and gemcitabine, carboplatin and gemcitabine, MVAC (combination of methotrexate, vinblastine, doxorubicin, and cisplatin), dose-dense-MVAC, docetaxel or paclitaxel, and pemetrexed.4

Local or systemic immunotherapy may be used to treat bladder cancer. The most common local immunotherapy for

bladder cancer is Bacillus Calmette-Guérin (BCG).4 Systemic immunotherapies used to treat bladder cancer include avelumab, nivolumab, and pembrolizumab. With proper genomic testing to identify genetic factors and biomarkers in a patient’s tumor, a healthcare provider may find that targeted therapy is the most appropriate course of care.4

Erdafitinib, enfortumab vedotin-ejfv, and sacituzumab govitecan are targeted therapies for specific types and stages of UC.4 For example, the first targeted therapy, erdafitinib (BALVERSA®), was approved by the U.S. Food & Drug Administration (FDA) in 2019 to treat adult patients with locally advanced or metastatic UC with particular FGFR3 or FGFR2 genetic changes and has a specific FDA-approved companion test to identify appropriate patients.5

Recent Approvals

Enfortumab vedotin-ejfv (PADCEV®) + Pembrolizumab (KEYTRUDA®)

The FDA granted accelerated approval to enfortumab vedotin-ejfv (PADCEV®) with pembrolizumab (KEYTRUDA®) in April 2023 for patients with locally advanced or metastatic UC who are ineligible for cisplatin-containing chemotherapy.6 A multi-cohort study (dose escalation cohort, Cohort A, Cohort K), EV-103/KEYNOTE-869 evaluated efficacy.7 Single-arm cohorts — dose escalation cohort

PHARMACY FRIENDS

With proper genomic testing to identify genetic factors and biomarkers in a patient’s tumor, a healthcare provider may find that targeted therapy is the most appropriate course of care.

and Cohort A — treated patients with enfortumab vedotin-ejfv plus pembrolizumab, while Cohort K patients were randomized to either the combination or to enfortumab vedotin-ejfv alone.7 Participants were patients who had not received prior systemic therapy for locally advanced or metastatic disease and were ineligible for cisplatin-containing chemotherapy.7

Of 121 patients who received enfortumab vedotin-ejfv plus pembrolizumab, 68% had a confirmed objective response, including 12% that had complete responses.7 Median duration of response for the dose escalation cohort and Cohort A was 22 months and for Cohort K was not reached.7 Adverse reactions associated with treatment occurring in more than 20% of patients, including laboratory abnormalities, included increased glucose, aspartate aminotransferase, creatinine, alanine aminotransferase, lipase, and calcium; decreased hemoglobin, lymphocytes, sodium, albumin, phosphate, weight, appetite, potassium, neutrophils; peripheral neuropathy; fatigue; rash; diarrhea; pruritus; nausea; dysgeusia; urinary tract infection; constipation; peripheral edema; dry eye; dizziness; arthralgia; and dry skin.6

Enfortumab vedotin-ejfv was previously approved by the FDA in 2021 for adult patients with locally advanced or metastatic UC who had previously received a PD-1 or PD-L1 inhibitor and platinum containing chemotherapy or who are ineligible for cisplatin-containing chemotherapy and had previously received one or more prior lines of therapy.8

Nadofaragene firadenovec-vncg (ADSTILADRIN®)

In December 2022, the FDA approved nadofaragene firadenovecvncg (ADSTILADRIN®) for the treatment of adult patients with high-risk BCG-unresponsive non-muscle-invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors.9 Nadofaragene firadenovec-vncg is a non-replicating adenoviral vector-based gene therapy.9

Safety and effectiveness of the gene therapy was demonstrated in a multicenter clinical study that included 157 patients with high-risk BCG-unresponsive NMIBC; 98 of those patients had BCG-unresponsive CIS with or without papillary tumors and could be evaluated for response.10 Nadofaragene firadenovec-vncg was administered into the bladder via a urinary catheter once every three months for up to 12 months or until unacceptable toxicity or recurrent high-grade NMIBC.10

Of the patients using nadofaragene firadenovec, 51% achieved a complete response, defined as the disappearance of all signs of cancer as seen on cystoscopy, biopsied tissue, and urine.10 Median duration of response was 9.7 months, and 46% of responding patients remained in complete response for at least one year.10 Adverse reactions associated with treatment included bladder discharge, fatigue, bladder spasm, urinary urgency, hematuria, chills, fever, and painful urination.9 The drug is expected to launch later in 2023.

ICER Review

A 2022 Institute of Clinical and Economic Review (ICER) report assessed the cost-effectiveness of nadofaragene firadenovec and pembrolizumab in BCG-unresponsive NMIBC.11 The report concluded that, using a placeholder price, nadofaragene firadenovec was cost-effective in the non-CIS population, but not in the CIS population.11 ICER noted the health-benefit price benchmark for nadofaragene firadenovec is $158,600 to $262,000 per year. 11 Further, pembrolizumab, at the current list price, was not cost-effective in the CIS population.11 Ultimately, ICER noted that the cost per quality-adjusted life-year gained and threshold price estimates can be used in pricing and reimbursement negotiations.11

Management Strategies

Over the years, multiple immune checkpoint inhibitors (ICIs) have received approval as single agents or following chemotherapy in early and late-stage UC.12 Without definitive cost-effectiveness data, payers are concerned about the added spend for this therapy class.12 As ICIs tend to have high costs, payers may seek pricing discounts or other management strategies.12 Although UC accounts for only 4% of new cancer cases in the U.S. and the number of metastatic UC (mUC) cases is even smaller, higher cost treatments tend to be a concern for payers.12 The population of cisplatin-ineligible mUC patients only account for about half of the mUC cases and may require different treatment and management for improved outcomes; due to the small size of this subset of the UC population, these patients may not be a high priority in terms of payer management.12 However, as the long-term outcomes of ICIs and treatments for mUC continue to be examined, payers may continue to consider and evaluate appropriate access and management of this category.

A 2020 study of Medicare claims assessed the lifetime economic burden of UC.12 Results showed that stage III UC had the highest cost

per patient, driven by intensive care with multi-modal management, including cystectomy and multi-drug chemotherapy.13 Stage IV UC had the lowest cost per patient, which could be due to the less intense therapy.13 However, across all stages, hospitalizations contributed the greatest spend to the lifetime cost.13 Access to and utilization of treatments that may decrease hospitalizations — in frequency and duration — may play a role in lowering costs.13

With the introduction of the first gene therapy for bladder cancer and its associated high costs, management tools will prove critical in ensuring appropriate access and managing costs. Particularly, criteria around the specific patient population and indications will be key. In a 2022 survey of commercial payers, commercial payers with 79% of beneficiaries said they expected to manage nadofaragene firadenovec to label soon after launch.14 Factors noted by respondents were the gene therapy’s “potential to be better than standard of care” and the high unmet need in the population with the approved indication.14 Management strategies of interest to payers for this therapy were step therapy requirements or quantity limits.14 Prior authorization and other utilization management strategies may be appropriate measures for payers to ensure patients with appropriate diagnoses who are ineligible for other care regimens are able to access proper treatment.

With introduction of the first gene therapy for bladder cancer and its associated high costs, management tools will prove critical in ensuring appropriate access and managing costs.

References

1. “Bladder Cancer: Statistics,” Cancer.Net, Mar. 2023, https://www. cancer.net/cancer-types/bladder-cancer/statistics.

2. Markman, Maurie. “Bladder cancer types.” Cancer Treatment Centers of America, May 18, 2022, https://www.cancercenter.com/cancertypes/bladder-cancer/types.

3. “Key Statistics for Bladder Cancer,” American Cancer Society, 13 Jan. 2023, https://www.cancer.org/cancer/types/bladder-cancer/about/ key-statistics.html.

4. “Bladder Cancer: Types of Treatment.” American Society of Clinical Oncology, Dec. 2021, https://www.cancer.net/cancer-types/bladdercancer/types-treatment#gene-therapy.

5. “FDA approves first targeted therapy for metastatic bladder cancer.” U.S. Food & Drug Administration, 12 Apr. 2019, https://fda.gov/newsevents/press-announcements/fda-approves-first-targeted-therapymetastatic-bladder-cancer.

6. “FDA D.I.S.C.O. Burst Edition: FDA approval of Padcev (enfortumab vedotin-ejfv) with Keytruda (pembrolizumab) for locally advanced or metastatic urothelial carcinoma,” U.S. Food & Drug Administration, 3 May 2023, https://www.fda.gov/drugs/resources-informationapproved-drugs/fda-disco-burst-edition-fda-approval-padcevenfortumab-vedotin-ejfv-keytruda-pembrolizumab-locally.

7. Holmes, Christopher J., et al. “Enfortumab Vedotin Plus Pembrolizumab in Previously Untreated Advanced Urothelial Cancer,” Journal of Clinical Oncology, 1 Jan. 2023, https://ascopubs. org/doi/10.1200/JCO.22.01643.

8. “FDA grants regular approval to enfortumab vedotin-ejfv for locally advanced or metastatic urothelial cancer.” U.S. Food & Drug Administration, 9 Jul. 2021, https://www.fda.gov/drugs/resourcesinformation-approved-drugs/fda-grants-regular-approval-enfortumabvedotin-ejfv-locally-advanced-or-metastatic-urothelial-cancer.

9. “FDA Approves First Gene Therapy for the Treatment of HighRisk, Non-Muscle Invasive Bladder Cancer,” U.S. Food & Drug Administration, 16 Dec. 2022, https://www.fda.gov/news-events/ press-announcements/fda-approves-first-gene-therapy-treatmenthigh-risk-non-muscle-invasive-bladder-cancer.

10. Boorjian, Stephen A., et al. “Intravesical nadofaragene firadenovec gene therapy for BCG-unresponsive non-muscle-invasive bladder cancer: a single-arm, open-label, repeat-dose clinical trial.” The Lancet Oncology, Jan. 2021, https://pubmed.ncbi.nlm.nih. gov/33253641/.

11. Joshi, Mrinmayee, et al. “Cost-Effectiveness of Nadofaragene Firadenovec and Pembrolizumab in Bacillus Calmette-Guérin Immunotherapy Unresponsive Non-Muscle Invasive Bladder Cancer.” ISPOR, 15 Dec. 2022, https://www.valueinhealthjournal. com/article/S1098-3015(22)04779-9/fulltext.

12. Walia, AS, et al. “Cost-Effectiveness of Immune Checkpoint Inhibitors in Urothelial Carcinoma-A Review.” Cancers, 24 Dec. 2021, https://pubmed.ncbi.nlm.nih.gov/35008237/.

13. Aly, A, et al. “The Real-World Lifetime Economic Burden of Urothelial Carcinoma by Stage at Diagnosis.” Journal of Clinical Pathways, May 2020, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7433100/ pdf/nihms-1607319.pdf.

14. “Oncologists Express Interest in New Bladder Cancer Gene Therapy Adstiladrin.” AISHealth, 16 Feb. 2023, https://www.mmitnetwork. com/aishealth/spotlight-on-market-access/oncologists-expressinterest-in-new-bladder-cancer-gene-therapy-adstiladrin/.

Accelerated Approvals: Formulary Challenges and Payer Impact

A historic 49 drug approvals came through the accelerated approval pathway in 2020, and the trend only continues to grow.

In 1992, the U.S. Food & Drug Administration (FDA) instituted its accelerated approval program to allow for earlier approval of drugs that treat serious conditions.1 Through the traditional FDA approval process, at a minimum, two phase 3 clinical trials are required prior to approval to demonstrate full efficacy and safety.2 The traditional pathway leads to a full approval.2

Yuqian Liu, Pharm.D. Senior Director, Specialty Clinical Solutions Magellan Rx Management

In comparison, the objective of the accelerated approval pathway is to fill an unmet medical need based on a surrogate endpoint or an intermediate clinical endpoint.2 Some surrogate endpoints include laboratory measurements, radiographic images, and physical signs. An intermediate clinical endpoint is a measure of a therapeutic effect that is considered reasonably likely to predict the clinical benefit.1 Through accelerated approval, the use of a surrogate endpoint can considerably shorten the time required prior to receiving FDA approval.1

Conditional approval is granted under the accelerated approval pathway, which means if the confirmation trial fails to demonstrate actual clinical benefit, the drug or the approved indication may be withdrawn from the market.1

There has been a significant increase in the number of accelerated approvals since the pathway was first introduced. In 2020, a historic 49 drug approvals passed through the accelerated approval pathway, and this trend continues to grow.1

The accelerated approval pathway offers advantages, including earlier access to drugs, particularly in spaces with unmet needs.3 There are also strong data to support continuity of these accelerated approval products; 76.5% of drugs approved via the accelerated pathway receive full approval.3

Pharm.D.,

Director, Clinical Strategy and Innovation, Oncology Magellan Rx Management

Despite the benefits, the accelerated approval pathway does introduce challenges, particularly in managed care evaluation of these products.4 There is limited clinical data available at the time of approval due to smaller studies and lack of long-term data. It is important to note that surrogate markers only serve as predictors and do not exemplify actual clinical benefit. These limitations can pose challenges to evaluating products and developing management strategies.

Simone Ndujiuba,

BCOP

Impact on Formulary Review Process

The data available for accelerated approval drugs are limited due to smaller size and some earlier stage clinical trials; therefore, it is harder to extrapolate the data to larger populations.4 For some products that are initially approved based on single-arm trials, especially in oncology and rare disease spaces, it is harder to compare against already available options.4 Notably, many accelerated approval products are the first treatment option for a disease; however, even in these cases, it is challenging for managed care professionals to evaluate the value and appropriateness of a new therapy against the current standard of care.4

As previously stated, surrogate endpoints as predictors for clinical benefits are not measures of clinical benefits.4 Therefore, it is difficult for a managed care pharmacist to assess the real-world

applicability of these metrics and predict the true clinical benefits of the drug. Surrogate endpoints do not provide data for long-term clinical benefit.4 In the formulary review process, cost-effectiveness modeling is becoming increasingly utilized; however, it requires accurate long-term clinical benefit information to provide value.4 With only surrogate endpoints for accelerated approval drugs, managed care organizations will not be able to strategize using cost-effectiveness modeling.4

Particularly for rare diseases, the cost of accelerated approval drugs can be high.4 Data show that after 15 years on the market, on average, a drug that won FDA accelerated approval had 15.4 times price increases compared with 12.7 times for other drugs approved via traditional pathways.4

Additionally, products that receive accelerated approval are required to confirm clinical benefits via phase 3 clinical trials.4 However, the timeline for this confirmation may vary significantly based on the disease state. The FDA does not mandate a specific deadline by or timeframe within which the trials must completed. Data show that 13% of accelerated approvals have been on the market for a median of 9.5 years without confirmatory evidence, which is a substantial period of time without having confirmation of actual clinical benefit. Aside from the 4% that were approved more recently, 54% of the accelerated approval drugs started confirmatory trials within the first year on the market, with the remaining 42% having started after at least one year on the market.5

In 2020, a historic 49 drug approvals passed through the accelerated approval pathway, and this trend continues to grow.

Another challenge is managing market withdrawal. As the number of accelerated approvals increases, the number of withdrawals has followed a similar trend. From 1992 to 2001, there were six withdrawals.6 This number increased to 12 withdrawals from 2002 to 2011. From 2012 to 2021, another 14 drugs were withdrawn.6 As the number of withdrawals increases, however, the length of time to withdrawal has shortened.6 The average time to withdrawal between 2012 and 2021 was 3.7 years with a median of 3.5 years, compared to an average of 8.9 years and a median of 10.4 years between 1992 and 2001.6 For payers, the challenge lies in the cost associated with these market withdrawals.6 The cost burden increases along with the number of approvals.6

In 2014, the U.S. Centers for Medicare & Medicaid Services (CMS) issued a National Coverage Determination (NCD) with guidelines for coverage of these products in the Medicare population.7, 8 When this NCD is invoked, CMS will only cover an accelerated approval product when it is given as part of a CMS-approved study or National Institute of Health (NIH)-supported trial.7, 8 With the approvals of products used to treat Alzheimer’s disease, CMS issued an NCD to clarify CMS coverage of these products, referring payers to the original NCD from 2014.7, 8 For the Medicaid population, there are some state-specific requirements surrounding accelerated approval drugs.7, 8 For commercial and exchange populations, formulary and management strategy is dependent on the approach of individual payers.7, 8

2022 Orphan Drugs with Accelerated Approval14

Impact on Disease Spaces

Rare Diseases

A rare disease is any disease or condition that either affects fewer than 200,000 people in the U.S. or for which there is no reasonable expectation that the cost of development and making a drug available in the U.S. will be recovered from sales in the U.S.9 Rare diseases represent about 370 diseases affecting 8.4 million patients, of which more than 50% are children.10

The Orphan Drug Act of 1983 provided financial incentives to attract industry interest through a seven-year period of market exclusivity for a drug approved to treat a rare, or orphan, disease, even if it were not under patent, and tax credits up to 50% for research and development expenses.11 Through the Act, the FDA was authorized to designate drugs and biologics for orphan status, provide grants for orphan drug testing, and offer assistance for framing study protocols.11 Orphan drug designation was provided to drugs used to treat, prevent, or diagnose an orphan disease. Orphan drugs may be approved through expedited FDA programs, including the accelerated approval pathway and phase 2 trials that may be used as pivotal trials.12 The top priorities for therapeutic development are metabolic, hematologic, immunologic, congenital, and neurologic disorders.10

pacritinib (VONJO™) adults with intermediate or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis with a platelet count below 50 x 109/L

alpelisib (VIJOICE®) treatment of PIK3CA-related overgrowth spectrum in adults and pediatric patients

tisagenlecleucel (KYMRIAH®) relapsed or refractory follicular lymphoma; CAR T-cell

futibatinib (LYTGOBI®) cholangiocarcinoma with FGFR2 mutation

selpercatinib (Retevmo™) tissue agnostic RET fusion solid tumors, RET fusion positive NSCLC

teclistamab-cqyv (TECVAYLI™) relapsed or refractory multiple myeloma

elivaldogene autotemcel (SKYSONA®) cerebral adrenoleukodystrophy (CALD) in boys ages 4-17

mirvetuximab soravtansinegynx (Elahere™) ovarian cancer

mosunetuzumab-axgb (LUNSUMIO™) relapsed or refractory follicular lymphoma in adults

adagrasib (KRAZATI®) KRAS G12C mutation NSCLC in adults

Abbreviations: CAR T-cell = chimeric antigen receptor T-cell; FGFR2 = fibroblast growth factor receptor 2; KRAS G12C = Kirsten rat sarcoma, glycine 12 to cysteine; NSCLC = non-small cell lung cancer; PIK3CA = phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit alpha; RET = rearranged during transfection

Rare diseases come with significant healthcare costs. The total cost estimate to treat 24 rare diseases is $125 billion.10 Per patient, per year costs for rare diseases range from $121,000 to $334,000 with an average cost of $266,000.10 The annual estimated overall costs to treat rare diseases in the U.S. is $2.2 trillion for an affected population of 8.4 million.10

Recently, the number of drugs for rare diseases approved under the accelerated approval program, including gene therapies, has increased.13 Due to the use of surrogate markers and small populations studied, payers face challenges in determining the true clinical value of these products, making it difficult to design coverage criteria.13 Additionally, medications with accelerated approval are now direct competitors for drugs with phase 3 clinical trial data.13 It is difficult to determine real-world outcomes and clinical value of therapy post-launch due to the small population of individuals with the rare diseases of interest.13

Oncology

The most commonly used surrogate endpoint to support accelerated approvals is objective response rate (ORR).15 Response Evaluation Criteria in Solid Tumors (RECIST) are criteria developed by the World Health Organization (WHO) to measure tumor response to therapy.15, 16 RECIST criteria were published by the WHO in 1979 to define objective response and were used until 2000.15, 16 The criteria are based on the visual assessment of tumor size in morphological images provided by computed tomography or magnetic resonance imaging.15, 16

After the introduction of molecularly targeted treatment with biologic agents, routine use of a fluorodeoxyglucose-positron emission tomography scan, and advanced MRI techniques as functional imaging ushered in the need for new perspectives in response evaluation.15, 16 New criteria are being developed to better quantify responses based on cancer type and therapy used to treat.15, 16 Specifically, immunotherapy by checkpoint inhibitors, due to differences in response patterns and progression when compared to chemotherapy and targeted agents, has led to the development of more response criteria distinctive to the tumor or therapy used to treat.15, 16

Accelerated approvals offer some benefits in the oncology space.2 Specifically, oncology products that show initial evidence for safety and effectiveness are available an average of 4.7 years faster.2 Some cancers for which accelerated approval products eventually received standard approval include metastatic breast cancer, Philadelphia chromosome positive chronic myeloid leukemia in chronic phase, metastatic non-small cell lung cancer,

and metastatic urothelial cancer.2 As of March 2023, there have been 180 accelerated approvals in the oncology space.1 Of these, 89 demonstrated actual clinical benefit through post-marketing trials, 69 are pending post-marketing trial verification, and 22 had indication or market withdrawals.1

Beginning in 2011, the FDA began the withdrawal of accelerated approvals, with the average time from approval to withdrawal being 5.5 years.1 More recently, as more drugs are approved through the accelerated approval pathway, the time to withdrawal has decreased and the number of withdrawals has increased.1 Notably, by 2022, all 22 withdrawn accelerated approvals were for cancer products due to safety concerns of failure to meet confirmatory endpoints.1 Withdrawn drugs or indications can have a clinical and financial impact on patients and payers. Notably, patient subgroups who benefitted from the therapy may potentially have no access to efficacious treatment and may be required to transition to treatment that may not offer equally efficacious outcomes. Among patient groups who did not benefit from the therapy, there may be disease progression or greater toxicity as well as financial consequence due to expenses, both direct and indirect.

One example is intravenous olaratumab, which received accelerated approval in late 2016 and was withdrawn when the confirmatory trial did not show survival benefit in the approved indication after 2.5 years.4 The drug cost $106,100 for six months of treatment, and in 2018, it generated $305 million in sales.4

Alzheimer’s Disease

Alzheimer’s disease (AD), a progressive, neurodegenerative brain disease, is the sixth-leading cause of death among Americans.17, 18 It is estimated that only 50% of patients with AD have been diagnosed and with a rapidly aging population, AD cases are expected to reach 13.8 million by 2060.17, 18

Two newly approved drugs for AD were approved through the accelerated approval pathway: aducanumab-avwa ( ADUHELM ®) in 2021 and lecanemab-irmb ( LEQEMBI ®) in 2023. 19, 20 For both therapies, there is no safety or effectiveness if started in earlier or later stages than was examined in the studies. Additional studies demonstrating clinical efficacy of patient outcomes and cost-effectiveness will be integral to determine the place in AD management for both of these agents.

The Institute for Clinical and Economic Review (ICER) concluded the suggested cost-effective annual list price range from $8,500 to $20,600; both aducanumab and lecanemab are priced above the ICER range.17 The 2022 CMS NCD policy of aducanumab and any future FDA-approved monoclonal anti-amyloid antibodies, restricts coverage to patients enrolled in CMS-approved or National Institute of Health-supported clinical trials.17 This determination was based on the requirement of clinical trial data to demonstrate clinically meaningful improvement in health

outcomes secondary to anti-amyloid monoclonal antibodies.17 Utilization and uptake of lecanemab are expected to be low until CMS modifies the NCD, which currently limits use to the clinical trial population. This is not expected to be modified until late 2023 at the earliest.

Takeaways

Accelerated approval may become a target when states have budget windfalls. As a result of the COVID-19 pandemic-related state budget shortfalls, efforts to cut Medicaid spending have increased.21 The National Governors Association advised that Medicaid coverage of “selected fast-tracked, first-in-class drugs,” like those approved through the FDA’s accelerated approval pathway, are opportunities for cuts.21 For example, Massachusetts and Tennessee have requested federal waivers from Medicaid coverage requirements to curtail patient access to these medicines.21 Patient and provider concerns regarding limitations to access to treatment for the Medicaid population have heightened, especially for those living with serious or lifethreatening, often rare, conditions without treatment options — the population for whom the accelerated approval pathway was developed. States are seeking savings through these proposed restrictions.21 However, an analysis of Medicaid spending on accelerated approval drugs between 2007 and 2018 and their impact on the growth in Medicaid spending revealed that drugs approved under the accelerated approval consistently accounted for less than 1% of annual Medicaid spending.21 These data for the Medicaid population support continued access to accelerated approval drugs for the seriously ill.21

Despite some concerns and challenges, the director of the Center for Biologics Evaluation and Research at the FDA, Peter Marks, indicated in May 2023 a willingness to use the accelerated approval pathway for cell and gene therapies.22 Noting that confirmatory data will be required at some point, Marks discussed the willingness to use regulatory flexibility, particularly when dealing with very small populations.22 He specifically noted that there is more willingness to use the pathway because of new teeth granted by Congress last year, which allow the agency to require confirmatory trials well in progress as accelerated approval is granted.22

Determining the value of emerging novel therapeutics by payers will require clinical trial end points that demonstrate improved survival or quality of life. The continued requirement for confirmatory trials and evidence will be key to ensuring payers allow appropriate access to therapies with clinical benefit while avoiding costs where patients will not benefit.

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References

1. “Accelerated approval Program.” U.S. Food & Drug Administration, 30 May 2023, https://www.fda.gov/drugs/nda-and-bla-approvals/ accelerated-approval-program.

2. Ribeiro, Tatiane B., et al. “Comparison of FDA accelerated vs regular pathway approvals for lung cancer treatments between 2006 and 2018.” PLOS One, 2020, https://www.ncbi.nlm.nih.gov/pmc/articles/ PMC7380631/.

3. Johnson, J.R., et al. “Accelerated approval of oncology products: the food and drug administration experience.” Journal of the National Cancer Institute, 20 Apr. 2011, https://pubmed.ncbi.nlm.nih. gov/21422403/.

4. Kaltenboeck, Anna, et al. “Strengthening the Accelerated approval Pathway: An Analysis of Potential Policy Reforms and Their Impact on Uncertainty, Access, Innovation, and Cost.” Institute for Clinical and Economic Review, 26 Apr. 2021, https://icer.org/wp-content/ uploads/2021/04/Strengthening-the-Accelerated-ApprovalPathway-_-ICER-White-Paper-_-April-2021.pdf.

5. Lupkin, Sydney. “Drugmakers are slow to prove medicines that got a fast track to market really work.” National Public Radio, 22 Jul. 2022, https://www.npr.org/sections/healthshots/2022/07/22/1110830985/drugmakers-are-slow-to-provemedicines-that-got-a-fast-track-to-market-really-wo.

6. Beakes-Read, Ginny, et al. “Analysis of FDA’s Accelerated approval Program Performance December 1992-December 2021.” Therapeutic Innovation and Regulatory Science, Sep. 2022, https:// pubmed.ncbi.nlm.nih.gov/35900722/.

7. “Monoclonal Antibodies Directed Against Amyloid for the Treatment of Alzheimer’s Disease.” U.S. Centers for Medicare & Medicaid Services, 7 Apr. 2022, https://www.cms.gov/ medicare-coverage-database/view/ncacal-decision-memo. aspx?proposed=N&ncaid=305.

8. “Guidance for the Public, Industry, and CMS Staff: Coverage with Evidence Development.” U.S. Centers for Medicare & Medicaid Services, 20 Nov. 2014, https://www.cms.gov/medicare-coveragedatabase/view/medicare-coverage-document.aspx?MCDId=27.

9. “Orphan Drug Act - Relevant Excerpts.” U.S. Food & Drug Administration, Aug. 2013, https://www.fda.gov/industry/ designating-orphan-product-drugs-and-biological-products/ orphan-drug-act-relevant-excerpts.

10. Andreu, Pedro, et al. “The burden of rare diseases: an economic evaluation.” Chiesi Global Rare Diseases, 2022, https:// chiesirarediseases.com/assets/pdf/chiesiglobalrarediseases. whitepaper-feb.-2022_production-proof.pdf.

11. Swann, John. “The Story Behind the Orphan Drug Act.” U.S. Food & Drug Administration, 23 Feb. 2018, https://www.fda.gov/industry/ fdas-rare-disease-day/story-behind-orphan-drug-act.

12. Fan, Min, et al. “Postmarketing safety of orphan drugs: a longitudinal analysis of the US Food and Drug Administration database between 1999 and 2018.” Orphanet Journal of Rare Diseases, 4 Jan. 2022, https://ojrd.biomedcentral.com/articles/10.1186/s13023-02102166-9.

13. Hertler, Andrew. “Accelerated drug approvals present a mounting challenge to oncologists and raises concerns about cost effectiveness for health system finance leaders.” Healthcare Financial Management Association, 7 Jan. 2022, https://www.hfma. org/cost-effectiveness-of-health/accelerated-drug-approvalspresent-a-mounting-challenge-to-oncol/.

14. “Orphan Drug Designations and Approvals.” U.S. Food & Drug Administration, 2023, https://www.accessdata.fda.gov/scripts/ opdlisting/oopd/index.cfm.

15. Aykan, Nuri Faruk, et al. “Objective response rate assessment in oncology: Current situation and future expectations.” World Journal of Clinical Oncology, 24 Feb. 2020, https://www.ncbi.nlm.nih.gov/ pmc/articles/PMC7046919/.

16. Gyawali, Bishal, et al. “Assessment of the Clinical Benefit of Cancer Drugs Receiving Accelerated approval.” Journal of the American Medical Association Internal Medicine, 28 May 2019, https://jamanetwork.com/journals/jamainternalmedicine/ fullarticle/2733561.

17. Skaria, Anita Pothen. “The Economic and Societal Burden of Alzheimer Disease: Managed Care Considerations.” American Journal of Managed Care, 12 Sep. 2022, https://www.ajmc.com/ view/the-economic-and-societal-burden-of-alzheimer-diseasemanaged-care-considerations.

18. “Alzheimer’s Disease and Healthy Aging.” Centers for Disease Control and Prevention, accessed 23 Jan. 2023, https://www.cdc.gov/aging/ aginginfo/alzheimers.htm.

19. “FDA Grants Accelerated approval for Alzheimer’s Drug.” U.S. Food & Drug Administration, 7 Jun. 2021, https://www.fda.gov/newsevents/press-announcements/fda-grants-accelerated-approvalalzheimers-drug.

20. “FDA Grants Accelerated approval for Alzheimer’s Drug.” U.S. Food & Drug Administration, 6 Jan. 2023, https://www.fda.gov/news-events/ press-announcements/fda-grants-accelerated-approval-alzheimersdisease-treatment.

21. Thorpe, Kenneth E., and Douglas Holtz-Eakin. “Limiting Medicaid Access to Accelerated approval Drugs: Costs and Consequences.” American Journal of Managed Care, 30 Mar. 2021, https://www.ajmc. com/view/limiting-medicaid-access-to-accelerated-approval-drugscosts-and-consequences.

22. Fiore, Kristina. “FDA ‘Leans In’ to Accelerated approval for Rare Disease Drugs.” MedPageToday, 19 May 2023, https://www. medpagetoday.com/special-reports/exclusives/104594.

Medicare Star Clinical Programs

Discover a health plan’s experience with achieving significant improvement for multiple Medicare Star Rating measures.

Luke Cecil, Pharm.D. Vice President, Pharmacy

The Health Plan of West Virginia

Medicare Star Ratings continue to stress the importance of statin therapy for the treatment of cardiovascular disease and prevention of cardiovascular events. A specialized, pharmacist-led clinical program can effectively close gaps in care and improve Medicare Star Rating performance.

Scope of the Problem and Burden of Disease

Cardiovascular disease (CVD) is the leading cause of death in the U.S. and is responsible for one death every 33 seconds.1 Evidence-based recommendations for the prevention of CVD are heavily focused on mitigation of risk through the management of comorbidities such as hypertension, hyperlipidemia, and diabetes. While novel classes of pharmacotherapies including proprotein convertase subtilisin/ kexin type 9 (PCSK-9) inhibitors and adenosine triphosphate-citrate lyase (ACL) inhibitors have recently emerged for hypercholesterolemia management, HMG-CoA reductase inhibitors, or statins, remain at the forefront of primary and secondary prevention of CVD.

Quality performance is incentivized at the health plan level by rewarding top performing plans with bonus payments to enhance benefit offerings, a high performing icon and favorable plan placement on Medicare enrollment sites, and expanded, more flexible enrollment options.

Robust clinical evidence has spawned widespread adoption of guideline recommendations for statins as first-line intervention for high-risk populations, including those with diabetes and established cardiovascular disease. In addition to their cholesterollowering properties, statins have additional anti-atherosclerotic effects that reduce the risk of CV events including improved vascular endothelial function, stabilization of atherosclerotic plaques, and modulation of the inflammatory response.2

The American Heart Association reported that in 2016, CVD cost the U.S. $555 billion and estimates that by 2035, the costs will rise to $1.1 trillion.3 With rising prevalence and costs, it is imperative to close gaps in care for effective population health management. Clinical literature reports the number needed to treat (NNT) to prevent one CV event in patients with diabetes is as low as 37 and the NNT for secondary prevention of CV events in patients with established CVD is as low as 18.4, 5 Statins have longevity in reducing morbidity and mortality where indicated and the lowcost generic availability can provide a meaningful ROI.

The Centers for Medicare & Medicaid Services (CMS) have placed focused on statin quality measures in various capacities since 2012 via the Star Ratings program. The CMS Five-Star Quality Ratings system annually assigns a 1 through 5 Star Rating to all Medicare contracts at 0.5 Star intervals. The Star Ratings system is designed to provide Medicare enrollees with the necessary tools they need to select a high-performing Medicare plan. Quality performance is incentivized at the health plan level by rewarding top performing plans with bonus payments to enhance benefit

offerings, a high performing icon and favorable plan placement on Medicare enrollment sites, and expanded, more flexible enrollment options.

The Medicare 2023 Part C & D Star Ratings include three measures directly related to statin therapy. The Part C Star Ratings, Measure C16: Statin Therapy for Patients with Cardiovascular Disease (SPC), evaluates the percentage of Medicare members with established cardiovascular disease who receive treatment with moderate-high intensity statin. Part D, D12 Statin Use in Persons with Diabetes (SUPD) annually assesses the percentage of members with diabetes who receive statin therapy. Additionally, the Part D Ratings have an adherence measure (D10) that analyzes the percentage of enrollees who remain compliant to their statin medication, defined as a proportion of days covered (PDC) ≥80%.

The objective of the CMS Star Ratings is to drive improvement in clinical outcomes at scale among the Medicare population. The important role statin therapy continues to play is reinforced by CMS with three distinct Star measures focusing on the initiation of and compliance to statin therapy for long-term clinical benefit.

Statin Use in Persons with Diabetes (SUPD)

In 2021, in an effort to improve the delivery of care provided to our enrollees, The Health Plan (THP) partnered with Magellan Rx Management (MRx) to implement a clinical program tailored to the SUPD Star measure. The SUPD measure aligns with the American Diabetes Association (ADA) recommendation for statin therapy for diabetes patients ages 40-75, regardless of baseline LDL values.6

Atherosclerotic CVD (ASCVD) is the leading cause of morbidity and mortality in patients with diabetes, and the CMS Star measure aims to reduce CV risk by maximizing adoption of the evidencebased statin recommendation. At baseline, the two Medicare contracts were performing well below the national average at 75% and 80% compliance — these rates equated to a 1- and 3-Star performance for measurement year 2020.

The program launched at the end of October 2021 generated immediate momentum in our performance. For 2021, both Medicare contracts saw treatment rate improvement and closed the gap on the national average, but only earned 2-Star performance due to rising cut points. Without the year-over-year improvement, predominantly generated in the fourth quarter of 2021, both contracts were at risk for a 1-Star finish in the SUPD measure due to changes in Star thresholds.

MEDICARE STAR CLINICAL PROGRAMS |

The impact of the SUPD program was substantially realized in 2022, the first full program year. THP’s Medicare performance improved 4-5%, and 1- and 2-Star increases were achieved based on currently available cut points. Despite continually rising benchmarks, the Medicare contracts are now at 3- and 4-Star performance based on 2022 performance and current cut points, and early 2023 data project a 5-Star finish for both contracts in the second full program year.

risk for members by adhering to guideline-, evidence-based recommendations for moderate or high intensity statin.

Underlining this initiative was an understanding of the immediate and long-term benefits to members and to THP as an organization. This partnership with MRx has proven successful in the first program year with >10% improvements in treatment rates, which equates to a 3-Star improvement in one year. Both Medicare contracts realized 5-Star performance based on currently available thresholds in the first program year, ensuring that over 89% of THP members with CVD at-risk realized the benefits of statin therapy. Based on 2021 performance data, THP has moved from the bottom 10th percentile nationally into the top 10th percentile in just one program year. Early 2023 projections are set to exceed 2022 performance with the maintenance of 5-Star performance.

^Program start date 10/29/2021

Note: 2020 Star performance is based on CMS 2022 Star Technical Notes. 2021 and 2022 Star performance is based on current thresholds listed in CMS 2023 Star Technical Notes. 2023 projections are based on year-over-year improvement with Acumen data through April.

^Program start date 10/29/2021

Note: 2020 Star performance based on CMS 2022 Star Technical Notes. 2021 and 2022 Star performance is based on current thresholds listed in CMS 2023 Star Technical Notes. 2023 projections are based on year-over-year improvement with Acumen data through April.

Statin Therapy for Patients with Cardiovascular Disease (SPC)

Following the implementation and early success of the SUPD program, THP and MRx expanded the business partnership, adding a clinical program for Star Measure C16: SPC. Members with established cardiovascular disease are at extremely high risk of morbidity and mortality directly related to their chronic condition. The SPC program is designed to reduce the clinical

Medication Adherence for Cholesterol (Statins)

The resounding success in improving the initiation of statin therapy in THP members with CVD and diabetes has led to a third clinical partnership with MRx for the Star Statin adherence measure as well as adherence to diabetes and renin-angiotensinsystem (RAS) antagonists medications.

*Star performance is based on current thresholds listed in CMS 2023 Star Technical Notes.

*Star performance is based on current thresholds listed in CMS 2023 Star Technical Notes.

Non-adherence to medications is an overwhelming burden on the healthcare system. The estimated adherence rate to chronic medications in the U.S. is around 50% and leads to definitively poorer health outcomes.7 Appropriate adherence to prescribed medications effectively improves treatment success, lowers hospitalizations, and lowers overall healthcare expenditures.8

THP has been successful at initiating members on statin therapy, and focus has been shifted to proper adherence in order to optimize member outcomes. Early performance trends for both contracts indicate year-over-year improvement across all three measures with the potential for full Star improvements. Medication adherence benchmarks have risen substantially over the past few years, and a dedicated clinical program to intervene on member-specific barriers has become increasingly important. THP and MRx anticipate promising results generated in the first program year as the adherence program progresses.

Looking Ahead

The Star clinical programs have been successful and valuable for THP of West Virginia. The use of data analytics, clinical strategy, and dynamic prioritization play a crucial role in improving clinical Star measures. A holistic approach to closing the care gap by engaging members, providers, and pharmacies for each measure enables the targeted approach to moving the needle for various statin-related performance measures. Furthermore, the specialization of the team at the Star measure level is a key differentiator for success.

Given that Star Ratings continue to evolve with higher thresholds, measure refinements, and other changes, achieving 5-Star

References

1. “National Center for Health Statistics Mortality Data.” CDC WONDER, 11 Jan. 2023, https://wonder.cdc.gov/mcd.html.

2. Takata, Kohei, et al. “Stabilization of high-risk plaques.” Cardiovascular Diagnosis and Therapy, Aug. 2016, https://www.ncbi. nlm.nih.gov/pmc/articles/PMC4960066/.

3. “Cardiovascular Disease: A Costly Burden for America Projections through 2035.” American Heart Association, 2017, https://www. heart.org/-/media/Files/About-Us/Policy-Research/Fact-Sheets/ Public-Health-Advocacy-and-Research/CVD-A-Costly-Burden-forAmerica-Projections-Through-2035.pdf.

4. Colhoun, Helen M., et al. “Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomized placebo-controlled trial.” Lancet, Aug. 2004, https://pubmed.ncbi. nlm.nih.gov/15325833/.

performance continues to become increasingly challenging. Deep-domain expertise will be vital to understanding the nuances associated with each clinical Star measure and effectively maintaining high performance and quality of care.

Health Plan Overview

The Health Plan is a clinically driven, technology-enhanced, and customer-focused health maintenance organization that manages and improves the health and well-being of its members. Established in 1979, the West Virginia-based company, with offices in Wheeling, Charleston, and Morgantown, West Virginia, and Massillon, Ohio, has offered a complete line of managed care products and services designed to provide healthcare systems and clients with innovative healthcare benefits and plans at a reasonable cost across the mid-Atlantic region and nationally.

5. Egan, Brent M., et al. “2013 ACC/AHA Cholesterol Guideline and Implications for Healthy People 2020 Cardiovascular Disease Prevention Goals.” Journal of the American Heart Association, Aug. 2016, https://www.ahajournals.org/doi/10.1161/JAHA.116.003558.

6. El Sayed, Nuha A, et al. “10. Cardiovascular Disease and Risk Management: Standards of Care in Diabetes—2023.” Diabetes Care, 1 Jan. 2023, https://pubmed.ncbi.nlm.nih.gov/36507632/.

7. DiMatteo M. Robin, et al. “Patient adherence and medical treatment outcomes: a meta-analysis.” Medical Care, Sept. 2022, https:// pubmed.ncbi.nlm.nih.gov/12218770/.

8. “Medication Adherence Clinical Reference.” American College of Preventive Medicine, 2011, www.acpm.org/?MedAdherTT_ClinRef.

A holistic approach to closing the care gap by engaging members, providers, and pharmacies for each measure enables the targeted approach to moving the needle for various statin-related performance measures.

cancer (metastatic, prior chemotherapy, anti-VEGF, and antiEGFR [if RAS wild-type] therapy)

meningococcal pentavalent vaccine (PF-06886992)

encorafenib (BRAKTOVI®)

(metastatic, BRAF V600E mutation, in combination with binimetinib)

Abbreviations: AChR-Ab+ = acetylcholine receptor antibody positive; AMD = age-related macular degeneration; AML = acute myeloid leukemia; BLA = biologics license application; BMT = bone marrow transplant; CD = Crohn’s disease; CKD = chronic kidney disease; CMV = cytomegalovirus; DLBCL = diffuse large B cell lymphoma; EGFR = estimated glomerular filtration rate; ESA = erythropoiesisstimulating agent; GVHD = graft vs. host disease; HSCT = hematopoietic stem cell transplantation; IM = intramuscular; IV = intravenous; JIA = juvenile idiopathic arthritis; MDD = major depressive disorder; NDA = new drug application; NSCLC = non-small cell lung cancer; PsA = psoriatic arthritis; PSO = psoriasis; PPD = postpartum depression; RA = rheumatoid arthritis; RPD = rare pediatric disease; R/R = relapsed-refractory; RSV = respiratory syncytial virus; RTOR = real-time oncology review; sBLA = supplemental biologics license application; SC = subcutaneous; SCLC = small cell lung cancer; sNDA = supplemental new drug application; UC = ulcerative colitis; VEGF = vascular endothelial growth factor

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