Magellan Rx Report - Fall 2020 by Prime/Magellan Rx

Magellan Rx Report Fall 2020

MD and SMA: Treatment Update

Oncology Update: Emerging Therapies

COVID-19: Vaccine Pipeline Update

Biosimilar Update: Landscape and Impact

Magellan Rx Report MEDICAL AND PHARMACY BENEFIT MANAGEMENT Fall 2020

Hemophilia:

Treatment Options and Gene Therapy

magellanrx.com

STEPHEN // AGE 38

LATER-ONSET SMA, TREATED WITH SPINRAZA

Individual results may vary based on several factors, including severity of disease, initiation of treatment, and duration of therapy.

In 2016, SPINRAZA became the first FDA-approved treatment for SMA and is approved in 50+ countries worldwide.1,2

3-80 DAYS

YEARS

Has treated SMA in patients 3 days* to 80 years3,4,†‡

11,000+ 3,700+ 11,000+ patients treated with SMA worldwide4§

3700+ adults with SMA treated worldwide4§

FDA=US Food and Drug Administration; SMA=spinal muscular atrophy. *Includes clinical trial patients. † Clinical studies of SPINRAZA did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger patients. Clinical studies of SPINRAZA included patients from 3 days to 16 years of age at first dose. ‡ Based on commercial patients in the US (including Puerto Rico) through June 2020. § Based on commercial patients, early access patients, and clinical trial participants through June 2020.

INDICATION SPINRAZA® (nusinersen) is indicated for the treatment of spinal muscular atrophy (SMA) in pediatric and adult patients. IMPORTANT SAFETY INFORMATION Coagulation abnormalities and thrombocytopenia, including acute severe thrombocytopenia, have been observed after administration of some antisense oligonucleotides. Patients may be at increased risk of bleeding complications. In the sham-controlled studies for patients with infantile-onset and later-onset SMA, 24 of 146 SPINRAZA-treated patients (16%) with high, normal, or unknown platelet count at baseline developed a platelet level below the lower limit of normal, compared to 10 of 72 sham-controlled patients (14%). Two SPINRAZA-treated patients developed platelet counts <50,000 cells per microliter, with the lowest level of 10,000 cells per microliter recorded on study day 28.

CAMERON // AGE 4

ASHLEY // AGE 7

EARLY-ONSET SMA, TREATED WITH SPINRAZA

LATER-ONSET SMA, TREATED WITH SPINRAZA

Individual results may vary based on several factors, including severity of disease, initiation of treatment, and duration of therapy.

Visit SPINRAZA-hcp.com to learn more about SPINRAZA, a proven treatment for patients with SMA IMPORTANT SAFETY INFORMATION (continued) Renal toxicity, including potentially fatal glomerulonephritis, has been observed after administration of some antisense oligonucleotides. SPINRAZA is present in and excreted by the kidney. In the sham-controlled studies for patients with infantile-onset and later-onset SMA, 71 of 123 SPINRAZA-treated patients (58%) had elevated urine protein, compared to 22 of 65 sham-controlled patients (34%). Laboratory testing and monitoring to assess safety should be conducted. Perform a platelet count, coagulation laboratory testing, and quantitative spot urine protein testing at baseline and prior to each dose of SPINRAZA and as clinically needed. Severe hyponatremia was reported in an infant treated with SPINRAZA requiring salt supplementation for 14 months. Cases of rash were reported in patients treated with SPINRAZA. SPINRAZA may cause a reduction in growth as measured by height when administered to infants, as suggested by observations from the controlled study. It is unknown whether any effect of SPINRAZA on growth would be reversible with cessation of treatment. The most common adverse reactions (≥20% of SPINRAZA-treated patients and ≥5% more frequently than in control patients) that occurred in the infantile-onset controlled study were lower respiratory infection and constipation. Serious adverse reactions of atelectasis were more frequent in SPINRAZA-treated patients (18%) than in control patients (10%). Because patients in this controlled study were infants, adverse reactions that are verbally reported could not be assessed. The most common adverse reactions that occurred in the later-onset controlled study were pyrexia, headache, vomiting, and back pain. Post-lumbar puncture syndrome has also been observed after the administration of SPINRAZA. Please see the brief summary of full Prescribing Information on the following pages. References: 1. FDA approves first drug for spinal muscular atrophy [press release]. Silver Spring, MD: US Food and Drug Administration; December 23, 2016. https://www.fda.gov/news-events/press-announcements/fda-approves-first-drug-spinal-muscular-atrophy. Accessed August 26, 2020. 2. Biogen announces first patient treated with higher dose of SPINRAZA® (nusinersen) in phase 2/3 DEVOTE study [press release]. Cambridge, MA: Biogen; April 2, 2020. https://investors.biogen.com/news-releases/news-release-details/biogen-announces-first-patient-treated-higher-dose-spinrazar. Accessed August 26, 2020. 3. SPINRAZA [Prescribing Information]. Cambridge, MA: Biogen. 4. Biogen, Data on file.

09/20

SPZ-US-3294 V2

225 Binney Street, Cambridge, MA 02142

SPINRAZA® (nusinersen) injection, for intrathecal use Brief Summary of Full Prescribing Information 1 INDICATIONS AND USAGE SPINRAZA is indicated for the treatment of spinal muscular atrophy (SMA) in pediatric and adult patients. 2 DOSAGE AND ADMINISTRATION 2.1 Dosing Information SPINRAZA is administered intrathecally by, or under the direction of, healthcare professionals experienced in performing lumbar punctures. Recommended Dosage The recommended dosage is 12 mg (5 mL) per administration. Initiate SPINRAZA treatment with 4 loading doses. The first three loading doses should be administered at 14-day intervals. The 4th loading dose should be administered 30 days after the 3rd dose. A maintenance dose should be administered once every 4 months thereafter. Missed Dose If a loading dose is delayed or missed, administer SPINRAZA as soon as possible, with at least 14-days between doses and continue dosing as prescribed. If a maintenance dose is delayed or missed, administer SPINRAZA as soon as possible and continue dosing every 4 months. 2.2 Important Preparation and Administration Instructions SPINRAZA is for intrathecal use only. Prepare and use SPINRAZA according to the following steps using aseptic technique. Each vial is intended for single dose only. Preparation • Store SPINRAZA in the carton in a refrigerator until time of use. • Allow the SPINRAZA vial to warm to room temperature (25ºC/77ºF) prior to administration. Do not use external heat sources. • Inspect the SPINRAZA vial for particulate matter and discoloration prior to administration. Do not administer SPINRAZA if visible particulates are observed or if the liquid in the vial is discolored. The use of external filters is not required. • Withdraw 12 mg (5 mL) of SPINRAZA from the single-dose vial into a syringe and discard unused contents of the vial. • Administer SPINRAZA within 4 hours of removal from vial. Administration • Consider sedation as indicated by the clinical condition of the patient. • Consider ultrasound or other imaging techniques to guide intrathecal administration of SPINRAZA, particularly in younger patients. • Prior to administration, remove 5 mL of cerebrospinal fluid. • Administer SPINRAZA as an intrathecal bolus injection over 1 to 3 minutes using a spinal anesthesia needle [see Dosage and Administration (2.1)]. Do not administer SPINRAZA in areas of the skin where there are signs of infection or inflammation [see Adverse Reactions (6.3)]. 2.3 Laboratory Testing and Monitoring to Assess Safety Conduct the following laboratory tests at baseline and prior to each dose of SPINRAZA and as clinically needed [see Warnings and Precautions (5.1, 5.2)]: • Platelet count • Prothrombin time; activated partial thromboplastin time • Quantitative spot urine protein testing 3 DOSAGE FORMS AND STRENGTHS Injection: 12 mg/5 mL (2.4 mg/mL) nusinersen as a clear and colorless solution in a single-dose vial. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Thrombocytopenia and Coagulation Abnormalities Coagulation abnormalities and thrombocytopenia, including acute severe thrombocytopenia, have been observed after administration of some antisense oligonucleotides. In the sham-controlled studies for patients with infantile-onset and later-onset SMA, 24 of 146 (16%) SPINRAZA-treated patients with high, normal, or unknown platelet count at baseline developed a platelet level below the lower limit of normal, compared to 10 of 72 (14%) sham-controlled patients. In the sham-controlled study in patients with later-onset SMA (Study 2), two SPINRAZA-treated patients developed platelet counts less than 50,000 cells per microliter, with a lowest level of 10,000 cells per microliter recorded on study day 28. Because of the risk of thrombocytopenia and coagulation abnormalities from SPINRAZA, patients may be at increased risk of bleeding complications. Perform a platelet count and coagulation laboratory testing at baseline and prior to each administration of SPINRAZA and as clinically needed. 5.2 Renal Toxicity Renal toxicity, including potentially fatal glomerulonephritis, has been observed after administration of some antisense oligonucleotides.

SPINRAZA is present in and excreted by the kidney [see Clinical Pharmacology (12.3)]. In the sham-controlled studies for patients with infantile-onset and later-onset SMA, 71 of 123 (58%) of SPINRAZA-treated patients had elevated urine protein, compared to 22 of 65 (34%) sham-controlled patients. Conduct quantitative spot urine protein testing (preferably using a first morning urine specimen) at baseline and prior to each dose of SPINRAZA. For urinary protein concentration greater than 0.2 g/ , consider repeat testing and further evaluation. 6 ADVERSE REACTIONS The following serious adverse reactions are described in detail in other sections of the labeling: â&#x20AC;˘ Thrombocytopenia and Coagulation Abnormalities [see Warnings and Precautions (5.1)] â&#x20AC;˘ Renal Toxicity [see Warnings and Precautions (5.2)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of SPINRAZA cannot be directly compared to rates in clinical trials of other drugs and may not reflect the rates observed in practice. In clinical studies, 346 patients (47% male, 76% Caucasian) were treated with SPINRAZA, including 314 exposed for at least 6 months, 258 exposed for at least 1 year, and 138 exposed for at least 2 years. The safety of SPINRAZA was studied in presymptomatic infants with SMA; pediatric patients (approximately 3 days to 16 years of age at first dose) with symptomatic S A in a sham-controlled trial in infants with symptomatic SMA (Study 1; n=80 for SPINRAZA, n=41 for control); in a sham-controlled trial in children with symptomatic SMA (Study 2; n=84 for SPINRAZA, n=42 for control); an open-label study in presymptomatic infants (Study 3, n=25) and other studies in symptomatic infants (n=54) and later-onset patients (n=103). In Study 1, 58 patients were exposed for at least 6 months and 28 patients were exposed for at least 12 months. In Study 2, 84 patients were exposed for at least 6 months and 82 patients were exposed for at least 12 months. Clinical Trial in Infantile-Onset SMA (Study 1) In Study 1, baseline disease characteristics were largely similar in the SPINRAZA-treated patients and sham-control patients except that SPINRAZA-treated patients at baseline had a higher percentage compared to sham-control patients of paradoxical breathing (89% vs 66%), pneumonia or respiratory symptoms (35% vs 22%), swallowing or feeding difficulties (51% vs 2 %) and requirement for respiratory support (26% vs 15%). The most common adverse reactions that occurred in at least 20% of SPINRAZA-treated patients and occurred at least 5% more frequently than in control patients were lower respiratory infection and constipation. Serious adverse reactions of atelectasis were more frequent in SPINRAZA-treated patients (18%) than in control patients (10%). Because patients in Study 1 were infants, adverse reactions that are verbally reported could not be assessed in this study. Table 1.

Adverse Reactions that Occurred in at Least 5% of SPINRAZA Patients and Occurred at Least 5% More Frequently or At Least 2 Times as Frequently Than in Control Patients with Infantile-Onset SMA (Study 1) SPINRAZA 12 mg1 N=80 %

Sham-Procedure Control N=41 %

Lower respiratory infection2

Constipation

Teething

Urinary tract infection

Upper respiratory tract congestion

Ear infection

Flatulence

Decreased weight

Adverse Reactions

1 2

Loading doses followed by 12 mg (5 mL) once every 4 months Includes adenovirus infection, bronchiolitis, bronchitis, bronchitis viral, corona virus infection, influenza, lower respiratory tract infection, lower respiratory tract infection viral, lung infection, parainfluenzae virus infection, pneumonia, pneumonia bacterial, pneumonia influenzal, pneumonia moraxella, pneumonia parainfluenzae viral, pneumonia pneumococcal, pneumonia pseudomonal, pneumonia respiratory syncytial viral, pneumonia viral, and respiratory syncytial virus bronchiolitis.

In an open-label clinical study in infants with symptomatic SMA, severe hyponatremia was reported in a patient treated with SPINRAZA requiring salt supplementation for 14 months. Cases of rash were reported in patients treated with SPINRAZA. One patient, 8 months after starting SPINRAZA treatment, developed painless red macular lesions on the forearm, leg, and foot over an 8-week period. The lesions ulcerated and scabbed over within 4 weeks, and resolved over several months. A second patient developed red macular skin lesions on the cheek and hand ten months after the start of SPINRAZA treatment, which resolved over 3 months. Both cases continued to receive SPINRAZA and had spontaneous resolution of the rash. SPINRAZA may cause a reduction in growth as measured by height when administered to infants, as suggested by observations from the controlled study. It is unknown whether any effect of SPINRAZA on growth would be reversible with cessation of treatment. Clinical Trial in Later-Onset SMA (Study 2) In Study 2, baseline disease characteristics were largely similar in the SPINRAZA-treated patients and sham-control patients except for the proportion of SPINRAZA-treated patients who had ever achieved the ability to stand without support (13% vs 29%) or walk with support (24% vs 33%). The most common adverse reactions that occurred in at least 20% of SPINRAZA-treated patients and occurred at least 5% more frequently than in control patients were pyrexia, headache, vomiting, and back pain. Table 2.

Adverse Reactions that Occurred in at Least 5% of SPINRAZA Patients and Occurred at Least 5% More Frequently or At Least 2 Times as Frequently Than in Control Patients with Later-Onset SMA (Study 2) SPINRAZA 12 mg1 N=84 %

Sham-Procedure Control N=42 %

Pyrexia

Headache

Vomiting

Back pain

Epistaxis

Fall

Respiratory tract congestion

Seasonal allergy

Adverse Reactions

Loading doses followed by 12 mg (5 mL) once every 6 months

Post-lumbar puncture syndrome has also been observed after administration of SPINRAZA. 6.2 Immunogenicity As with all oligonucleotides, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to nusinersen in the studies described below with the incidence of antibodies in other studies or to other products may be misleading. The immunogenic response to nusinersen was determined in 294 patients with post-baseline plasma samples evaluated for anti-drug antibodies (ADAs). Seventeen patients (6%) developed treatment-emergent ADAs, of which 5 were transient,12 were considered to be persistent. Persistent was defined as having one positive test followed by another one more than 100 days after the first positive test. In addition, â&#x20AC;&#x153;persistentâ&#x20AC;? is also defined as having one or more positive samples and no sample more than 100 days after the first positive sample. Transient was defined as having one or more positive results and not confirmed to be persistent. There are insufficient data to evaluate an effect of ADAs on clinical response, adverse events, or the pharmacokinetic profile of nusinersen.

6.3 Postmarketing Experience The following adverse reactions have been identified during post-approval use of SPINRAZA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Serious infections associated with lumbar puncture, such as meningitis, have been observed. Hydrocephalus, aseptic meningitis, and hypersensitivity reactions (e.g. angioedema, urticaria, rash) have also been reported. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no adequate data on the developmental risk associated with the use of SPINRAZA in pregnant women. When nusinersen was administered by subcutaneous injection to mice throughout pregnancy and lactation, developmental toxicity (long-term neurobehavioral impairment) was observed at all doses tested (see Data). In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown. Data Animal Data When nusinersen (0, 3, 10, or 25 mg/kg) was administered subcutaneously to male and female mice every other day prior to and during mating and continuing in females throughout organogenesis, no adverse effects on embryofetal development were observed. Subcutaneous administration of nusinersen (0, 6, 12.6, or 25 mg/kg) to pregnant rabbits every other day throughout organogenesis produced no evidence of embryofetal developmental toxicity. When nusinersen (1.4, 5.8, or 17.2 mg/kg) was administered to pregnant female mice by subcutaneous injection every other day throughout organogenesis and continuing once every six days throughout the lactation period, adverse neurobehavioral effects (alterations in locomotor activity, learning and memory deficits) were observed when offspring were tested after weaning or as adults. A no-effect level for neurobehavioral impairment was not established. 8.2 Lactation Risk Summary There are no data on the presence of nusinersen in human milk, the effects on the breastfed infant, or the effects of the drug on milk production. Nusinersen was detected in the milk of lactating mice when administered by subcutaneous injection. The developmental and health benefits of breastfeeding should be considered along with the motherâ&#x20AC;&#x2122;s clinical need for SPINRAZA and any potential adverse effects on the breastfed infant from SPINRAZA or from the underlying maternal condition. 8.4 Pediatric Use The safety and effectiveness of SPINRAZA in pediatric patients from newborn to 17 years have been established [see Clinical Studies (14.1)]. Juvenile Animal Toxicity Data In intrathecal toxicity studies in juvenile monkeys, administration of nusinersen (0, 0.3, 1, or 3 mg/dose for 14 weeks and 0, 0.3, 1, or 4 mg/dose for 53 weeks) resulted in brain histopathology (neuronal vacuolation and necrosis/cellular debris in the hippocampus) at the mid and high doses and acute, transient deficits in lower spinal reflexes at the high dose in each study. In addition, possible neurobehavioral deficits were observed on a learning and memory test at the high dose in the 53-week monkey study. The no-effect dose for neurohistopathology in monkeys (0.3 mg/dose) is approximately equivalent to the human dose when calculated on a yearly basis and corrected for the species difference in CSF volume. 8.5 Geriatric Use Clinical studies of SPINRAZA did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. 17 PATIENT COUNSELING INFORMATION Thrombocytopenia and Coagulation Abnormalities Inform patients and caregivers that SPINRAZA could increase the risk of bleeding. Inform patients and caregivers of the importance of obtaining blood laboratory testing at baseline and prior to each dose to monitor for signs of increased potential for bleeding. Instruct patients and caregivers to seek medical attention if unexpected bleeding occurs [see Warnings and Precautions (5.1)]. Renal Toxicity Inform patients and caregivers that SPINRAZA could cause renal toxicity. Inform patients and caregivers of the importance of obtaining urine testing at baseline and prior to each dose to monitor for signs of potential renal toxicity [see Warnings and Precautions (5.2)]. Manufactured for: Biogen Cambridge, MA 02142 SPINRAZA is a registered trademark of Biogen. ÂŠ Biogen 2016-2020

IN THIS ISSUE | Fall 2020

Managed Care Newsstand

COVID-19 Vaccine Pipeline Update

Muscular Dystrophy and Spinal Muscular Atrophy:

Method Capability Spotlight:

Hemophilia:

Biosimilar Update:

Oncology Update:

Pipeline

Virtual Market Research and Payer Insights

Treatment Update

Treatment Options and Gene Therapy

Emerging NSCLC and Breast Cancer Therapies

Published By Magellan Rx Management 15950 N. 76th St. Scottsdale, AZ 85260

Contributors Caroline Carney, M.D., M.Sc., FAPM, CPHQ

Tel: 401-344-1000 Fax: 401-619-5215

SVP, Market General Manager, MRx Specialty

magellanrx.com Editor Lindsay Speicher, J.D.

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

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

Current Landscape and Impact

CMO, Magellan Rx Management

Steve Cutts, Pharm.D.

Haita Makanji, Pharm.D.

VP, Clinical Strategy and Innovation, Specialty

Misty Greficz

Director, Marketing

Joe Tavares

SVP, Sales and Business Development, Specialty

Yousaf Ali M.D., FACR

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

Steven L. D’Amato, B.S.Pharm.

Executive Director, New England Cancer Specialists

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

Chief Medical Officer, International Myeloma Foundation

Natalie Tate, Pharm.D., MBA, BCPS Vice President, Pharmacy Management, BlueCross BlueShield of Tennessee

Steve Marciniak, R.Ph.

VP, Business Development, Magellan Method

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

Stacy Inman, Pharm.D.

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

Corrado Panno

Senior Clinical Project Manager

Carole Kallas

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

Project Manager

Brian Kinsella, Esq. The content of Magellan RxTM Report — including text, graphics, images, and information obtained from third parties, licensors, and other material (“content”) — is for informational purposes only. The content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Magellan RxTM Report does not verify any claims or other information appearing in any of the advertisements contained in the publication and cannot take responsibility for any losses or other damages incurred by readers in reliance on such content. Developed by D Custom.

Senior Legal Counsel

Lilly Ackley

VP, External Communications

Kristen Durocher

Director, External Communications

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

Chief Pharmacy Officer & VP Clinical Analytics, Strategy & Innovation, Excellus BlueCross BlueShield

Dennis Bourdette M.D., FAAN, FANA

Chair and Roy and Eulalia Swank Family Research Professor, Department of Neurology, Oregon Health & Science University

ISSN: 2159-5372

10444M

A NOTE FROM OUR CMO

Dear Managed Care Colleagues, Welcome to our fall 2020 issue of the Magellan Rx Report! This unprecedented year has challenged the industry in so many ways, from ever-evolving knowledge of COVID-19 to fast-moving interventions in response to the pandemic. PBMs, payers, and consumers have faced many hurdles in the delivery and receipt of needed treatments. Despite the disruption the pandemic has created, the U.S. Food and Drug Administration (FDA) has approved 41 novel therapies so far this year, with several more anticipated by end of year. As always, Magellan Rx Management is bringing readers up-to-date content highlighting clinical advances and trends and managed care developments. We also continue to actively monitor possible supply-line shortages that may arise due to COVID-19. Our cover story (page 20) highlights hemophilia updates, specifically around gene therapies e delve into emerging treatments and discuss managed care implications of this changing landscape. In another feature story, we inform our readers on the current state of Duchenne muscular dystrophy and spinal muscular atrophy therapies (page 10). This update outlines the challenges payers face in managing this category, as well as both newly approved and pipeline treatments.

vaccines in the pipeline, as well as our thoughts on the role of PBMs and pharmacists in delivering the vaccine. Oncology is always a high priority for our readers, and this year has brought many new approvals in the space. Focusing on breast cancer and non-small cell lung cancer, we discuss 2020 FDA approvals and pipeline treatments and explore payer challenges associated with an influx in treatment options (page 27). Other exciting content includes a biosimilars update (page 44) and a market research capability spotlight (page 42). No issue of the Magellan Rx Report would be complete without our pipeline update (page 46). To learn more about Magellan Rx Management and our support for payer initiatives of the future, please contact us at MagellanRxReport@magellanhealth.com. As always, we value any feedback you may have. I hope you enjoy the Report! Sincerely,

Caroline Carney, M.D., M.Sc., FAPM, CPHQ ief edical cer Magellan Rx Management

Perhaps the timeliest of topics, a COVID-19 pipeline update (page 37) builds on the Magellan Rx Management bonus edition of the Trend Report, which was published in the spring. This piece brings readers the most updated status of COVID-19

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MANAGED CARE NEWSSTAND CDC Issues Playbook for Vaccine Distribution On Sept. 16, the Centers for Disease Control and Prevention (CDC) issued a report to Congress and an interim playbook for jurisdiction operations on the COVID-19 vaccination program. Among the key points detailed in the playbook: •

•

The administration continues to push a decentralized approach to vaccine administration, including prioritization; provider enrollment; communications; and vaccine monitoring, tracking, and data collection. Each jurisdiction (state, territory, and local government) must develop a microplan through which to identify vaccination sites and necessary logistical considerations and lay out how sites will be onboarded into the necessary IT system.

Taskforce on Telehealth Policy Issues Final Report Twenty-three of the nation’s leading healthcare experts released their muchanticipated final report on Sept identifying challenges and opportunities for telehealth in the wake of the COVID-19 pandemic. The Taskforce on Telehealth Policy, convened by the National Committee for Quality Assurance, the Alliance for Connected Care, and the American Telemedicine Association, spent the summer building consensus among its members on a comprehensive set of findings and recommendations. The taskforce posted the full report online for public review. Among highlights of the report s ey findings and recommendations: •

•

The playbook provides states with key information and microplan recommendations as to planning and coordination, phased vaccine administration, determining critical populations, recruiting and enrolling providers, and vaccine storage and handling.

The CDC is allowing a broad range of providers to administer vaccines, including hospitals, commercial partners (e.g., large-chain pharmacies), mobile vaccination providers, occupational health settings for large employers, and in-home care provider organizations. Jurisdictions will have authority to recruit, select, and enroll providers, resulting in variability across jurisdictions.

8 | Magellan Rx Report | Fall 2020

Telehealth is the natural evolution of healthcare joining the digital age. It is essentially a setting or modality of care, rather than a type of care. As such, it should be held to the same standards and quality measures as in-person care is wherever possible and appropriate.

Full enforcement of the privacy provisions within the Health Insurance Portability and Accountability Act (HIPAA) should resume when the current public health emergency ends.

The ongoing move from fee-for-service to value-based arrangements in healthcare should enhance the ability of patients, payers, and providers to leverage the potential of telehealth.

Part I of the Medicare Advantage Advance Notice Released On Sept. 14, the Centers for Medicare and Medicaid Services (CMS) issued Part I of the Medicare Advantage (MA) advance notice for calendar year (CY) 2022, which focuses on the Part C CMS-Hierarchical Condition Categories (HCC) risk adjustment model and the use of encounter data. Given the uncertainty the COVID-19 pandemic has created, CMS issued Part I earlier than usual to provide plans with advance notice of proposed policy changes. •

Part C Risk Adjustment Model: For 2022, CMS is proposing to fully phase in the 2020 CMS-HCC model, as required by the 21st Century Cures Act. Per the act, the 2020 model adds “payment conditions,” which are variables that count conditions in the risk adjustment model. It also includes payments for additional conditions for mental health, substance use disorder, and chronic kidney disease. This represents a change from the blend for 2021 of 75% of the risk score calculated using the 2020 CMS-HCC model and 25% of the risk score calculated using the older 2017 CMS-HCC model, according to a press release.

•

Encounter Data: The proposed full phase-in of the 2020 CMS-HCC model is designed to calculate risk scores using diagnoses from encounter data submissions. The Part C risk score used for payment in 2022 would rely entirely on encounter data as the source of MA diagnoses. Also, for 2022, CMS is proposing to discontinue

Early data suggests that telehealth has substituted for a good deal of inperson care during the pandemic without increasing overall costs and that it can also relieve travel burdens, risks, and care delays; improve behavioral care access; and reduce missed appointments, costly transfers to hospitals and emergency departments, and hospital readmissions. Policyma ers must expand efforts to ensure access to broadband and technology infrastructure to promote equity and not exacerbate care disparities as healthcare digitally transforms.

•

the policy (used for 2019, 2020, and 2021) of supplementing diagnoses from encounter data with diagnoses from inpatient records submitted to CMS’ Risk Adjustment Processing System for calculating beneficiary ris scores, according to the press release.

Part II of the MA Advance Notice Now at OMB In September, CMS issued Part I of the MA Advance Notice for CY 2022. The notice is being published in two parts due to requirements in the 21st Century Cures Act that mandate certain changes to Part C risk adjustment and a 60-day comment period for these changes. The Advance

President Donald Trump issued an executive order Sept. 13 directing Health and Human Services Secretary Alex Azar to implement payment models that apply ‘most-favorednation’ pricing for speci ed t pes of drugs under Medicare Parts B and D.

Rate otice Part II is now at the O ce of Management and Budget (OMB) and is expected to be released sometime this fall. A standard 30-day comment period is anticipated.

Among key payment and policy changes within the proposed rule: •

CMS added several category-one permanent telehealth codes, including codes for visit complexity, evaluation and management (E&M) add-on, prolonged E&M services, home visit E&M services, group psychotherapy, neurobehavioral status exams, assessment and care planning for the cognitively impaired, and domiciliary services.

•

CMS added several temporary codes for the remainder of a year in which the public health emergency continues, including codes for domiciliary and home visits, emergency department visits, nursing facility discharges, and psychological and neuropsychological testing.

•

CMS is requesting feedback on several other codes that could be considered for either category one or category three inclusion.

•

CMS did not expand or continue audio-only services. Instead, CMS is seeking input on how to make virtual check-in codes more capable for audio interactions.

Trump Issues ‘Most-FavoredNation’ Executive Order President Donald Trump issued an executive order Sept. 13 directing Health and Human Services (HHS) Secretary Alex Azar to implement payment models that apply “most-favored-nation” pricing for specified types of drugs under Medicare Parts B and D. This new executive order replaces and expands upon an earlier never-released executive order with the same name. Trump held back the order in an alleged attempt to negotiate a better deal with pharmaceutical companies. CMS previously attempted to address Part B drug costs, publishing in October 2018 an advanced notice of proposed rulemaking (ANPRM) spelling out an earlier proposal for a payment model for Medicare Part B drugs. CMS has yet to issue a formal notice of proposed rulemaking (NPRM), though one has been under review at the OMB since June 2019. Medicare Part D is not included in the ANPRM or the NPRM listing under review.

CMS Issues CY 2021 Physician Fee Schedule Proposed Rule CMS issued the proposed CY 2021 Physician Fee Schedule (PFS) rule, which updates payment rates and policies under Medicare Part B. Because of COVID-19, there will be a -day delay in the effective date of the final rule instead of the standard 60-day delay.

CMS is proposing to implement Section 2003 of the SUPPORT Act, which requires that prescriptions for Medicare Part D and Medicare Prescription Drug Plan-covered controlled substances be transmitted by a healthcare practitioner electronically in accordance with an electronic prescription drug program. However, this implementation is subject to any exceptions, which HHS may specify. CMS proposes that the provision would not be effective until an 1, 2022, rather than the Jan. 1, 2021, statutory effective date

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Muscular Dystrophy and Spinal Muscular Atrophy: Treatment Update New gene therapies could give patients life-enhancing and -lengthening treatment options — a first in this space Muscular dystrophy is a muscle disease caused by a genetic mutation and characterized by progressive muscle weakness and loss of muscle mass, which leads to decreased mobility.1 The several types of muscular dystrophy are categorized by the specific muscle groups affected and further classified by genotypes and phenotypes Signs and symptoms appear at different ages and vary in severity 2 Although muscular dystrophy can be hereditary some patients may be the first in their family to have the disease 2 The most common types of muscular dystrophy are: Erin Ventura, Pharm.D. Manager, Specialty Clinical Programs Magellan Rx Management

• • • • •

Duchenne muscular dystrophy (DMD) Becker muscular dystrophy (BMD) myotonic limb-girdle facioscapulohumeral

• • • •

congenital distal oculopharyngeal Emery-Dreifuss2

The only U.S. Food and Drug Administration (FDA)-approved therapies available are for DMD treatment. Treatment of other forms of muscular dystrophy focuses primarily on supportive care and symptomatic treatment Most commonly occurring in males DMD affects in to newborns worldwide and occurs in 400 to 600 U.S. births each year. It is caused by a mutation in the DMD gene, which results in a lack of dystrophin, a protein found in skeletal and cardiac muscle that stabilizes and protects muscle fibers Scott McLelland, Pharm.D. VP, Commercial and Specialty Programs Florida Blue

Typically, symptoms of muscle weakness are present in early childhood and progress rapidly. Children with DMD often exhibit delayed motor skills such as sitting, standing, and walking. By adolescence, most are wheelchair-dependent. Cardiomyopathy is also associated with DMD due to weakening cardiac muscles.

10 | Magellan Rx Report | Fall 2020

DMD and SMA can be diagnosed by a combination of tests, including enzyme and genetic testing, muscle biopsy, and electromyography. Spinal Muscular Atrophy (SMA) Spinal muscular atrophy (SMA) is a genetic disease caused by the loss of motor neurons due to a lack of survival motor neuron (SMN) protein, which leads to progressive skeletal muscle weakness and atrophy.4 SMA affects approximately in to people worldwide. Chromosome SMA the most common form is caused by the deletion or mutation of the survival motor neuron-1 gene (SMN1); it results in a lack of SMN protein needed for survival of motor neurons in the spinal cord and lower brain stem.4 Most people also have the survival motor neuron 2 (SMN2) gene, which is a duplicate of the SMN1 gene; however, only 10% of SMN2 gene transcriptions result in functional SM protein which is insu cient for spinal motor neurons’ survival.6 he different SMA phenotypes are categorized by age of onset, severity, and prognosis.6 The severity of SMA can be related to the number of SMN2 gene copies, with fewer copies resulting in more severe disease.6 Types of SMA: • SMA type 0 is characterized by decreased fetal movement during pregnancy, severe weakness and hypotonia at birth, and death occurring by 6 months of age. • SMA type 1 presents at birth or by 6 months of age. Patients with type 1 SMA typically have generalized weakness, feeding di culties and respiratory distress he life expectancy for a type 1 SMA patient is typically less than two years. • SMA type 2 presents between to months of age with primarily proximal weakness involving the lower limbs. The life expectancy of patients with type 2 SMA varies from childhood to adulthood based on severity. • SMA type 3 presents between months of age and adulthood Individuals with type can stand and wal unassisted but progression of wea ness may cause increased di culty with these activities over time Most patients with type SMA have a normal life expectancy.

• SMA type 4 is the least common and most mild form and typically onsets after age ype SMA patients have a normal life expectancy.

Diagnosis DMD and SMA can be diagnosed by a combination of tests, including enzyme and genetic testing, muscle biopsy, and electromyography.4, 7 Of those options, genetic testing is the most accurate and least-invasive diagnostic alternative.4, 7

Current Treatment Options for DMD Treatment for DMD includes generic corticosteroids and EMFLAZA® (deflazacort) to help maintain strength and slow disease progression. Angiotensin-converting enzyme (ACE) inhibitors and beta blockers are used for patients with cardiac damage from their disease.9 he FDA approved EXO D S ™ (eteplirsen) in 10, 11 and V O D S (golodirsen) in In August Viltepso™ (viltolarsen) received FDA approval. These therapies are approved for patients with specific mutations of the dystrophin gene 10, 11

e a acort

)

Deflazacort (EMFLAZA®) is a corticosteroid intended for patients 2 years of age and older for the treatment of DMD. A phase three trial compared muscle strength improvement following treatment with deflazacort mg/ g/day deflazacort mg/ g/day or prednisone mg/ g/day versus a placebo All treatment groups saw significant muscle strength improvement after wee s compared with the placebo group he most notable difference was that patients ta ing prednisone gained significantly more weight in comparison with both deflazacort groups and the placebo group The adverse events that occurred most frequently in all treatment groups were consistent with the typical adverse events occurring with corticosteroid therapies.

teplir en

Eteplirsen (EXO D S ™) is an antisense oligonucleotide indicated for the treatment of DMD in patients with a confirmed mutation in the DMD gene amenable to exon s ipping 10 A trial assessing the e cacy of eteplirsen included male children with DMD ranging in age from to Enrolled patients had confirmed DMD gene deletions correctable by s ipping exon and were able to walk 200 to 400 meters during the six-minute walk test (6MWT). Patients were randomized to wee ly IV infusions of or mg/ g/wee of eteplirsen or a placebo for wee s reatment was

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MUSCULAR DYSTROPHY AND SPINAL MUSCULAR ATROPHY | Continued

open-label after wee when placebo patients switched to or mg/ g of eteplirsen E cacy was based on the percentage of dystrophin-positive fibers and the M results Biopsies performed at wee in the mg/ g eteplirsen group found that dystrophin-positive fibers increased to of normal while the placebo group had no increase (p ) Biopsies performed at wee found that dystrophin-positive fibers increased to and of normal in the and mg/ g eteplirsen groups respectively. Ambulatory patients treated with eteplirsen had -meter improvement on the M compared with placebo (p )

Golo ir en olodirsen (V O D S ) is an antisense oligonucleotide indicated for the treatment of DMD in patients with a confirmed mutation in the DMD gene amenable to exon s ipping 11 A two-part trial evaluated the e cacy of golodirsen Part one consisted of 12 patients randomized to receive either golodirsen (n= ) or a placebo (n= ) Part two consisted of all patients from part one and additional patients; all patients in part two received treatment with mg/ g of golodirsen Safety findings were consistent with those previously observed in pediatric patients with DMD he e cacy outcome assessed was the change in the mean percent normal dystrophin protein level from baseline At wee dystrophin protein expression significantly increased by about 16-fold from baseline, and the mean percent

12 | Magellan Rx Report | Fall 2020

normal dystrophin protein level was 1.019% (range, 0.09% to )

iltolar en

iltep o

Approved in August, viltolarsen is an antisense oligonucleotide indicated for the treatment of DMD in patients with a confirmed mutation in the DMD gene amenable to exon s ipping Findings from a 16-participant phase two clinical trial (of ages 4 to 9) showed significant drug-induced dystrophin production in both viltolarsen-dose cohorts, with 94% of patients achieving dystrophin levels greater than of normal and achieving levels greater than of normal he therapy was generally well tolerated; no treatment-emergent adverse events required dose reduction, treatment discontinuation, or interruption. The FDA granted accelerated approval, with a requirement that NS Pharma conduct a clinical trial to confirm clinical benefit showing that treatment with viltolarsen improves a patientâ&#x20AC;&#x2122;s stand time.

Current Treatment Options for SMA Prior to 2016, the only treatments available for patients with SMA were supportive therapies, such as nutritional and respiratory assistance, physical therapy, and assistive equipment such as braces, walkers, and wheelchairs. In December 2016, the FDA approved SPINRAZAÂŽ (nusinersen), an SMN2-directed antisense oligonucleotide.19

In May 2019, the FDA approved ZOLGENSMA® (onasemnogene abeparvovec-xioi) as the first gene replacement therapy for SMA treatment Most recently in August the FDA approved Evrysdi™ (risdiplam). These agents are indicated to treat all SMA types.20

iner en

)

Nusinersen (SPINRAZA®) is an SMN2-directed antisense oligonucleotide indicated for the treatment of SMA in pediatric and adult patients.19 wo clinical trials assessed the e cacy of nusinersen One trial contained patients with infantile-onset SMA, and the other included patients with late-onset SMA.19 The trial for infantile-onset SMA was terminated early after an interim analysis revealed a motor-milestone response in of infants ( ) in the treatment group compared with 0 of 27 patients in the control group ( p<0.001).19, 21 he final analysis revealed that the percentage of patients with a motor-milestone response in the nusinersen group was significantly higher in comparison to the control group ( versus ) 19, 21 The likelihood of event-free survival and overall survival were also higher in the nusinersen group compared with the control group. 19, 21 The late-onset SMA trial had a primary endpoint of the least-squares mean change from baseline in the Hammersmith Functional Motor Scale-Expanded (HFMSE) score at months of treatment 19, 22 This trial was also terminated early after positive findings during the interim analysis.19, 22 The interim analysis revealed a least-squares mean increase in the HFMSE score from baseline to month in the nusinersen group by 4 points and a decrease by -1.9 points in the control group which correlates to a difference of points between groups ( confidence interval to ;p ) 19, 22 he final analysis results were similar with of the children in

the nusinersen group achieving an increase from baseline to month in the HFMSE score of at least points (p ) compared with 26% in the control group.19, 22 In both trials, the incidence of adverse events was similar in the nusinersen group compared with the control group.19, 21, 22

na e nogene a eparvovec ioi

)

Onasemnogene abeparvovec-xioi (ZOLGENSMA®) is an adenoassociated viral-vector gene therapy indicated for the treatment of SMA in patients less than 2 years old with bi-allelic mutations in the SMN1 gene.20 wo trials assessed the e cacy of onasemnogene abeparvovec-xioi.19 One trial has been completed, while the other is ongoing.20 he completed trial included patients of whom received a high dose ( vg/ g) and three of whom received a low dose ( vg/ g) At 24 months after treatment, none of the patients in the low-dose treatment group met physical milestones of sitting without support, standing, or walking, and one patient required permanent ventilation. In the high-dose group, of patients ( ) had the ability to sit unsupported for seconds, and two patients (16.7%) could stand and walk unassisted. The ongoing trial includes 21 patients who received a dose of onasemnogene abeparvovec-xioi ( vg/ g) 20 Interim results of this trial demonstrate that of patients did not require permanent ventilation by 14 months of age, and 47.6% of patients were able to sit without support for more than seconds 20 Prior to treatment with onasemnogene abeparvovec-xioi, the patients meeting inclusion criteria for this trial would not be expected to reach the milestone of sitting without support and only would be likely to survive past 14 months without permanent ventilation.20

i ipla

The introduction of gene therapies has given patients novel treatment options as well as the ability to reach developmental milestones and a life expectancy that they otherwise would not be able to achieve.

In August the FDA approved risdiplam (Evrysdi™) an SM R A splice modulator, for the treatment of patients with SMA who are at least 2 months old.24 In an open-label study of 21 patients with an average age of 6.7 months, 41% of patients were able to sit independently for more than five seconds; of patients were alive without permanent ventilation after or more months of treatment.24 A second randomized, placebo-controlled study evaluated patients ranging in age from to with later-onset SMA Patients on risdiplam saw an average increase in their motor function score at the one-year mark, compared to a 0.19% decrease in patients on the placebo.24 Common side effects associated with risdiplam were fever, diarrhea, rash, mouth ulcers, joint pain, and urinary tract infections.24 Side effects were similar among patients with infantile-onset SMA and later-onset SMA. Additional side effects for the infantile-onset population were upper respiratory tract infection, pneumonia, constipation, and vomiting.24

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MUSCULAR DYSTROPHY AND SPINAL MUSCULAR ATROPHY | Continued Pipeline Table 1. DMD Drug

Company/Lead Sponsor

Drug Type

Status

Sarepta Therapeutics

antisense oligonucleotide

pending (Q2 2021)

ataluren (Translarna)

PTC Therapeutics

inhibitor of premature protein translation termination

phase three

givinostat (I F

Italfarmaco SpA

histone deacetylase (HDAC) inhibitor

phase three

edasalonexent (Edasa)

Catabasis

NF-kB inhibitor

phase three

PF-

Pfizer

gene therapy

phase three

FibroGen

anti-CTGF antibody

phase three

casimersen (SRP-

)

pamrevlumab (F -

)

Table 2. SMA Drug

Company/ Lead Sponsor

Drug Type

SMA Type

Status

branaplam (LMI070)

Novartis

SMN2 RNA splice modulator

type 1

phase one-two

SR -

Scholar Rock

latent myostatin precursor activation inhibitor

types

and

phase two

Impact on Payers and Managed Care Prior to the approval of newer treatments, DMD and SMA were largely managed with supportive care. The introduction of gene therapies has given patients novel treatment options as well as the ability to reach developmental milestones and a life expectancy that they otherwise would not be able to achieve. he sustained e cacy of gene therapies over time remains unknown, which presents a challenge to payers. As many of these agents are high-cost, it is also important for managed care organizations to consider the development of prior authorization

14 | Magellan Rx Report | Fall 2020

criteria. As more treatment options for SMA and DMD come to the market, formulary management and preferred agents may become a focus Additionally in the SMA space specifically due to different mechanisms of action without clinical evidence of benefit combination therapies may be a management concern for managed care organizations. Consideration and development of alternate payment models may also be needed due to the high costs of some agents.

References 1.

“Muscular Dystrophy.” Mayo Clinic, Mayo Foundation for Medical Education and Research an https://www mayoclinic org/ diseases-conditions/muscular-dystrophy/symptoms-causes/syc-

“What is Muscular Dystrophy?” Centers for Disease Control and Prevention, Centers for Disease Control and Prevention, 2 Dec. 2019, https://www cdc gov/ncbddd/musculardystrophy/facts html

Frank, Diane E. et al. “Increased Dystrophin Production with Golodirsen in Patients with Duchenne Muscular Dystrophy.” Neurology vol no doi: L

“Duchenne and Becker Muscular Dystrophy – Genetics Home Reference – NIH.” U.S. National Library of Medicine, National Institutes of Health Aug https://ghr nlm nih gov/condition/duchenneand-bec er-muscular-dystrophy definition

16. Clemens Paula R et al Safety olerability and E cacy of Viltolarsen in Boys with Duchenne Muscular Dystrophy Amendable to Exon Skipping: A Phase 2 Randomized Clinical Trial.” JAMA Neurology, vol. no pp doi: /jamaneurol

“Spinal Muscular Atrophy.” Muscular Dystrophy Association https:// www mda org/disease/spinal-muscular-atrophy

17. Mercuri, Eugenio et al. “Diagnosis and Management of Spinal Muscular Atrophy: Part 1: Recommendations for Diagnosis, Rehabilitation, Orthopedic and Nutritional Care.” Neuromuscular Disorders vol no pp doi: /j nmd

“Spinal Muscular Atrophy – Genetics Home Reference – NIH.” U.S. National Library of Medicine, National Institutes of Health, 17 Aug. https://ghr nlm nih gov/condition/spinal-muscular-atrophy 6.

“A Clinical Overview of Spinal Muscular Atrophy (SMA).” December https://www togetherinsma-hcp com/en us/home/diseaseeducation/spinal-muscular-atrophy html

“Duchenne Muscular Dystrophy.” Muscular Dystrophy Association, https://www mda org/disease/duchenne-muscular-dystrophy Birn rant David et al Diagnosis and Management of Duchenne Muscular Dystrophy, Part 1: Diagnosis, and Neuromuscular, Rehabilitation, Endocrine, and Gastrointestinal and Nutritional Management.” The Lancet Neurology vol no pp doi: /S ( ) -

14. Mendell erry R et al Eteplirsen for the reatment of Duchenne Muscular Dystrophy.” Annals of Neurology vol no pp doi: /ana

Birn rant David et al Diagnosis and Management of Duchenne Muscular Dystrophy, Part 2: Respiratory, Cardiac, Bone Health, and Orthopaedic Management.” The Lancet Neurology, vol. 17, no. 4, pp doi: /S ( ) -

10. Exondys Inc; uly

™ pac age insert Cambridge MA: Sarepta herapeutics

11. Vyondys pac age insert Cambridge MA: Sarepta herapeutics Inc; December 2019. 12. EMFLAZA® pac age insert South Plainfield une

: P C herapeutics Inc;

Finkel, Richard S. et al. “Diagnosis and Management of Spinal Muscular Atrophy: Part 2: Pulmonary and Acute Care; Medications, Supplements, and Immunizations; Other Organ Systems; and Ethics.” Neuromuscular Disorders vol no pp doi: /j nmd 19. Spinraza® pac age insert Cambridge MA: Biogen; une 20. Zolgensma® pac age insert Bannoc burn IL: AveXis; uly 21. Finkel, Richard S., et al. “Nusinersen versus Sham Control in Infantile-Onset Spinal Muscular Atrophy.” New England Journal of Medicine vol no pp doi: / nejmoa 22. Mercuri, Eugenio, et al. “Nusinersen versus Sham Control in LaterOnset Spinal Muscular Atrophy.” New England Journal of Medicine, vol no pp doi: / E Moa Mendell erry R et al Single-Dose ene-Replacement herapy for Spinal Muscular Atrophy.” New England Journal of Medicine vol no pp doi: / E Moa 24. “FDA Approves Oral Treatment for Spinal Muscular Atrophy.” U.S. Food and Drug Administration Aug https://www fda gov/newsevents/press-announcements/fda-approves-oral-treatment-spinalmuscular-atrophy.

riggs Robert C et al E cacy and Safety of Deflazacort vs Prednisone and Placebo for Duchenne Muscular Dystrophy.” Neurology vol no pp doi: / L

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*In clinical trials, ADVATE demonstrated the ability to help patients prevent bleeding episodes using a prophylaxis regimen. Not an actual patient. Based on units sold, as of July 2018.

†

Prophylaxis with ADVATE prevented bleeds1 • ADVATE can prevent or reduce the frequency of bleeding episodes in children and adults when used prophylactically • In a multicenter, open-label, prospective, randomized, 2-arm, controlled postmarketing clinical study of the relative efficacy of ADVATE use in 2 prophylactic treatment regimens compared to that of on-demand treatment. 53 previously treated patients (PTPs) with severe to moderately severe hemophilia A (FVIII level <2 IU/dL) were analyzed in the per-protocol group. Subjects were initially treated for 6 months of on-demand therapy and then randomized to 12 months of either a standard prophylaxis regimen (20–40 IU/kg every 48 hours) or a PK-driven prophylaxis regimen (20–80 IU/kg every 72 hours) − 98% reduction in median annualized bleeding rate (ABR) from 44 to 1 when 53 patients in the clinical study switched from on-demand to prophylaxis − 0 bleeds in 42% (22/53) of patients during 1 year on prophylaxis

ADVATE Important Information

DETAILED IMPORTANT RISK INFORMATION

ADVATE is a recombinant antihemophilic factor indicated for use in children and adults with hemophilia A (congenital factor VIII deficiency) for: • Control and prevention of bleeding episodes. • Perioperative management. • Routine prophylaxis to prevent or reduce the frequency of bleeding episodes. ADVATE is not indicated for the treatment of von Willebrand disease.

Patients who have life-threatening hypersensitivity reactions, including anaphylaxis, to mouse or hamster protein or other constituents of the product.

Indications

CONTRAINDICATIONS

WARNINGS & PRECAUTIONS Hypersensitivity Reactions Allergic-type hypersensitivity reactions, including anaphylaxis, have been reported with ADVATE. Symptoms include dizziness, paresthesia, rash, flushing, facial swelling, urticaria, dyspnea, pruritus, and vomiting. Discontinue ADVATE if hypersensitivity symptoms occur and administer appropriate emergency treatment.

ADVATE has over 15 years of treatment experience in the real world and provides clinically proven bleed protection* for patients with hemophilia A.1 Proven clinical record 2

Extensively studied—15 years with 15 prospective studies 2,3

The most widely used FVIII product, with 33 billion IUs sold globally2†

AdvateRealLife.com/HCP WARNINGS & PRECAUTIONS (continued) Neutralizing Antibodies Neutralizing antibodies (inhibitors) have been reported following administration of ADVATE predominantly in previously untreated patients (PUPs) and previously minimally treated patients (MTPs). Monitor all patients for the development of factor VIII inhibitors by appropriate clinical observation and laboratory testing. If expected plasma factor VIII activity levels are not attained, or if bleeding is not controlled with an expected dose, perform an assay that measures factor VIII inhibitor concentration.

ADVERSE REACTIONS • Serious adverse reactions seen with ADVATE are hypersensitivity reactions, including anaphylaxis, and the development of high-titer inhibitors necessitating alternative treatments to factor VIII. • The most common adverse reactions observed in clinical trials (>5% of subjects) were pyrexia, headache, cough, nasopharyngitis, arthralgia, vomiting, upper respiratory tract infection, limb injury, nasal congestion, and diarrhea.

Please see the following page for the Brief Summary of the ADVATE full Prescribing Information. For Full Prescribing Information, visit www.advatepro.com. REFERENCES: 1. ADVATE Prescribing Information. 2. Takeda data on file. 3. Grillberger L, Kreil TR, Nasr S, Reiter M. Emerging trends in plasma-free manufacturing of recombinant protein therapeutics expressed in mammalian cells. Biotechnol J. 2009;4(2):186-201. Copyright © 2020 Takeda Pharmaceutical Company Limited. 300 Shire Way, Lexington, MA 02421. 1-800-828-2088. All rights reserved. TAKEDA and the TAKEDA logo are trademarks or registered trademarks of Takeda Pharmaceutical Company Limited. ADVATE is a registered trademark of Baxalta Incorporated, a Takeda company. US-ADV-0100v1.0 05/20

ADVATE [Antihemophilic Factor (Recombinant)] Rx Only Lyophilized Powder for Reconstitution for Intravenous Injection BRIEF SUMMARY: Consult the Full Prescribing Information for complete product information. INDICATIONS AND USAGE

ADVERSE REACTIONS

ADVATE is a recombinant antihemophilic factor indicated for use in children and adults with hemophilia A for: • Control and prevention of bleeding episodes. • Perioperative management. • Routine prophylaxis to prevent or reduce the frequency of bleeding episodes. ADVATE is not indicated for the treatment of von Willebrand disease.

Serious adverse reactions seen with ADVATE are hypersensitivity reactions, including anaphylaxis, and the development of high-titer inhibitors necessitating alternative treatments to factor VIII.

CONTRAINDICATIONS ADVATE is contraindicated in patients who have life-threatening hypersensitivity reactions, including anaphylaxis, to mouse or hamster protein or other constituents of the product (mannitol, trehalose, sodium chloride, histidine, Tris, calcium chloride, polysorbate 80, and/or glutathione). WARNINGS and PRECAUTIONS Hypersensitivity Reactions Allergic-type hypersensitivity reactions, including anaphylaxis, have been reported with ADVATE. Symptoms include dizziness, paresthesia, rash, flushing, facial swelling, urticaria, dyspnea, pruritus, and vomiting. ADVATE contains trace amounts of mouse immunoglobulin G (MuIgG) ≤0.1 ng/IU ADVATE, and hamster proteins ≤1.5 ng/IU ADVATE. Patients treated with this product may develop hypersensitivity to these non-human mammalian proteins. Discontinue ADVATE if hypersensitivity symptoms occur and administer appropriate emergency treatment. Neutralizing Antibodies Neutralizing antibodies (inhibitors) have been reported following administration of ADVATE predominantly in previously untreated patients (PUPs) and previously minimally treated patients (MTPs). Monitor all patients for the development of factor VIII inhibitors by appropriate clinical observation and laboratory testing. If expected plasma factor VIII activity levels are not attained, or if bleeding is not controlled with an expected dose, perform an assay that measures factor VIII inhibitor concentration. Monitoring Laboratory Tests • Monitor plasma factor VIII activity levels by the one-stage clotting assay to confirm the adequate factor VIII levels have been achieved and maintained when clinically indicated. • Monitor for development of factor VIII inhibitors. Perform the Bethesda assay to determine if factor VIII inhibitor is present. If expected factor VIII activity plasma levels are not attained, or if bleeding is not controlled with the expected dose of ADVATE, use Bethesda Units (BU) to titer inhibitors. – If the inhibitor titer is less than 10 BU per mL, the administration of additional antihemophilic factor concentrate may neutralize the inhibitor and may permit an appropriate hemostatic response. – If the inhibitor titer is above 10 BU per mL, adequate hemostasis may not be achieved. The inhibitor titer may rise following ADVATE infusion as a result of an anamnestic response to factor VIII. The treatment or prevention of bleeding in such patients requires the use of alternative therapeutic approaches and agents.

The most common adverse reactions observed in clinical trials (frequency greater than 5% of subjects) were pyrexia, headache, cough, nasopharyngitis, arthralgia, vomiting, upper respiratory tract infection, limb injury, nasal congestion, and diarrhea. Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in clinical practice. ADVATE has been evaluated in eleven clinical trials in previously treated patients (PTPs) and one trial in previously untreated patients (PUPs) with severe to moderately severe hemophilia A (factor VIII ≤2% of normal). A total of 418 subjects have been treated with ADVATE as of January 2012. Total exposure to ADVATE was 63,188 infusions. The median duration of participation per subject was 397 (min-max: 2−1620) days and the median number of exposure days to ADVATE per subject was 97 (min-max: 1−709). The summary of adverse reactions with a frequency >5% are shown in Table 1 below. No subject was withdrawn from a clinical trial due to an adverse reaction. Table 1 Summary of Adverse Reactions (ARs)a with a Frequency Greater than 5% in 418b Subjects MedDRAc System Organ Class

MedDRA Preferred Term

Number of Number of Adverse Reactions Subjects

Percent of Subjects

General Disorders and Administration Site Conditions

Pyrexia

110

Nervous System Disorders

Headache

114

Respiratory, Thoracic and Mediastinal Cough Disorders

Infections and Infestations

Nasopharyngitis

Musculoskeletal and Connective Tissue Disorders

Arthralgia

Gastrointestinal Disorders

Vomiting

Infections and Infestations

Upper Respiratory Tract Infection

Injury, Poisoning and Procedural Complications

Limb Injury

Respiratory, Thoracic and Mediastinal Nasal Congestion Disorders

Gastrointestinal Disorders

Diarrhea

Injury, Poisoning and Procedural Complications

Procedural Pain

Respiratory, Thoracic Oropharyngeal and Mediastinal Pain Disorders

Infections and Infestations

Ear Infection

a Adverse reactions are defined as all adverse events that occurred (a) within 24 hours after being infused with investigational product, or (b) all adverse events assessed related or possibly related to investigational product, or (c) adverse events for which the investigator’s or sponsor’s opinion of causality was missing or indeterminate.b The ADVATE clinical program included 418 treated subjects from 11 completed studies in PTPs and 1 completed trial in PUPs. cMedDRA version 8.1 was used.

Immunogenicity The development of factor VIII inhibitors with the use of ADVATE was evaluated in clinical trials with pediatric PTPs (<6 years of age with ≥50 factor VIII exposures) and PTPs (≥10 years of age with ≥150 factor VIII exposures). Of 276 subjects who were treated with ADVATE for at least 10 exposure days or on study for a minimum of 120 days, 1 adult developed a low-titer inhibitor (2 BU in the Bethesda assay) after 26 exposure days. Eight weeks later, the inhibitor was no longer detectable, and in vivo recovery was normal at 1 and 3 hours after infusion of another marketed recombinant factor VIII concentrate. This event results in a factor VIII inhibitor frequency in PTPs of 0.4% (95% CI of 0.01 and 2% for the risk of any factor VIII inhibitor development). No factor VIII inhibitors were detected in the 53 treated pediatric PTPs. In clinical trials that enrolled previously untreated subjects (defined as having had up to 3 exposures to a factor VIII product at the time of enrollment), 16 (29.1%) of 55 subjects who received ADVATE developed inhibitors to factor VIII. Seven subjects developed high titer (>5 BU) and nine subjects developed low-titer inhibitors. Inhibitors were detected at a median of 13 exposure days (min-max: 6−26 exposure days) to the product. Immunogenicity also was evaluated by measuring the development of antibodies to heterologous proteins. When assessed for anti-Chinese hamster ovary (CHO) cell protein antibodies, of 229 treated subjects, 3 showed an upward trend in antibody titer over time and 10 showed repeated but transient elevations of antibodies. When assessed for muIgG protein antibodies, of the 229 treated subjects, 10 showed an upward trend in anti-muIgG antibody titer over time and 2 showed repeated but transient elevations of antibodies. Four subjects who demonstrated antibody elevations to CHO cell or muIgG proteins, reported isolated events of urticaria, pruritus, rash, and slightly elevated eosinophil counts. All of these subjects had numerous repeat exposures to the product without recurrence of the events and a causal relationship between the antibody findings and these clinical events has not been established. When assessed for the presence of anti-human von Willebrand Factor (VWF) antibodies, of the 228 treated subjects, none displayed laboratory evidence indicative of a positive serologic response. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to ADVATE with the incidence of antibodies to other products may be misleading.

USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary There are no data with ADVATE use in pregnant women to inform a drug-associated risk. Animal reproduction studies have not been conducted with ADVATE. It is not known whether ADVATE can cause fetal harm when administered to a pregnant woman or whether it can affect reproductive capacity. In the U.S. general population, the estimated background risk of major birth defect and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Lactation Risk Summary There is no information regarding the presence of ADVATE in human milk, the effect on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ADVATE and any potential adverse effects on the breastfed child from ADVATE or from the underlying maternal condition. Pediatric Use Pharmacokinetic studies in children have demonstrated higher clearance, a shorter half-life and lower recovery of factor VIII compared to adults. This may be explained by differences in body composition and should be taken into account when dosing or following factor VIII levels in the pediatric population. Because clearance (based on per kg body weight) has been demonstrated to be higher in the pediatric population, dose adjustment or more frequent dosing based on per kg body weight may be needed in this population. In the ADVATE routine prophylaxis clinical trial, 3 children aged 7 to <12 and 4 adolescents aged 12 to <16 were included in the per-protocol analysis. The reductions in annualized bleeding rate per subject per year during any prophylaxis regimen as compared to during on-demand therapy were similar among children, adolescents, and adults. Geriatric Use Clinical trials of ADVATE did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently compared to younger subjects. Individualize dose selection for geriatric patients.

Post-Marketing Experience The following adverse reactions have been identified during post-approval use of ADVATE. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Table 2 represents the most frequently reported post-marketing adverse reactions as MedDRA Preferred Terms. Table 2 Post-Marketing Experience Organ System [MedDRA Primary SOC]

Preferred Term

Immune system disorders

Anaphylactic reactiona Hypersensitivitya

Blood and lymphatic system disorders

Factor VIII inhibition

General disorders and administration site conditions

Injection site reaction Chills Fatigue/Malaise Chest discomfort/pain Decreased therapeutic effect

These reactions have been manifested by dizziness, paresthesias, rash, flushing, face swelling, urticaria, and/or pruritus.

Copyright © 2020 Takeda Pharmaceutical Company Limited. 300 Shire Way, Lexington, MA 02421. 1-800-828-2088. All rights reserved. TAKEDA and the TAKEDA logo are trademarks or registered trademarks of Takeda Pharmaceutical Company Limited. ADVATE is a registered trademark of Baxalta Incorporated, a Takeda company. Patented: see https://www.takeda.com/en-us/patents/ U.S. License No. 2020 Issued: 12/2018 US-ADV-0105v1.0 05/20

Hemophilia: reatment Options and ene herapy ith several potential innovative gene therapies in the pipeline ensuring patient access while balancing responsible pricing will be a challenge for payers manufacturers and providers to conquer together Hemophilia is an X-lin ed genetic bleeding disorder that affects approximately in individuals people globally primarily men Previous estimates suggested that there were approximately living with hemophilia; however a recently published meta-analysis suggests that there may be as many as men worldwide living with the disorder including approximately in the S Hemophilia A and B are the disease s two predominant subtypes Associated with deficiencies in coagulation factors VIII (FVIII) and IX (FIX) respectively they are caused by mutations in clotting factor genes Resulting disruption in the clotting cascade may lead to spontaneous bleeding or unexplained excessive bleeding from minor injuries or after surgical or dental procedures Hemophilia A also called FVIII deficiency or classic hemophilia is the most common subtype accounting for approximately to of cases Anja Shaughnessey, Pharm.D., PRS, R.Ph. Senior Pharmacy Contract Consultant Tufts Health Plan

Disease severity often correlates with baseline clotting factor level Patients with to of normal levels have mild disease and may experience severe bleeding with major trauma or surgery; however spontaneous bleeding is rare Patients with to of normal levels have moderate disease and may experience occasional spontaneous bleeding or prolonged bleeding with minor trauma or surgery he most severe group of patients has less than of normal levels and may experience spontaneous bleeding into joints or muscles that occurs without an injury or trauma Spontaneous bleeding episodes typically affect weight-bearing joints including the nees and an les and may ultimately lead to painful debilitating hemophilic arthropathy and resulting immobility - Individuals with the most severe form of hemophilia also have increased ris for life-threatening bleeds including intracranial hemorrhage o reduce the ris of morbidity and mortality hemophilia is traditionally managed with exogenous clotting factor concentrates (CFCs) to replace the patient s missing clotting factor both in the acute treatment setting and prophylactically -

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Overall, an average hemophilia patient incurs inpatient costs nine times higher than the average insured patient. Some patients treated with CFC may develop inhibitors immunoglobulin antibodies that neutralize infused clotting factors In these patients the anticipated recovery and half-life of the CFC are severely diminished leading to significantly higher clotting-factor doses Inhibitors occur more commonly in hemophilia A with a cumulative incidence of up to in patients with severe disease 7 he ris of developing inhibitors also increases with heightened exposure to exogenous clotting factor In patients with severe hemophilia A the median age at inhibitor development is years; in mild to moderate disease the median age is years and development typically coincides with an event such as surgery

Economic Burden of Hemophilia Currently there is no cure for this chronic condition that requires indefinite treatment he cost of hemophilia therapy which can be significant varies from patient to patient based on several factors including severity of disease presence of inhibitors and frequency of bleeding events Compared to those without the disease hemophilia patients use a significant amount of healthcare resources as they require more o ce visits hospitalizations medical procedures and laboratory tests - Across all levels of severity the total annual cost of care for the average hemophilia patient is nearly In patients with severe hemophilia A who develop inhibitors the average annual cost exceeds million due to more aggressive treatment 9 he cost of clotting factor accounts for more than of the total healthcare expenditures for hemophilia patients - Overall an average hemophilia patient incurs inpatient costs nine times higher than the average insured patient Additionally there are significant indirect costs associated with hemophilia including lost productivity absenteeism disability and reduced quality of life 9

to a wide variety of hemostatic agents with diverse mechanisms; the goal is to prevent and treat bleeding episodes allowing an active lifestyle and a quality of life comparable to nonhemophilic individuals he benefits of prophylaxis with CFCs or nonfactorreplacement agents are superior to those associated with episodic therapy he FH recommends regular long-term prophylaxis as the standard of care in order to prevent hemarthrosis and other spontaneous and brea through bleeding; maintain musculos eletal health; and promote quality of life for patients with severe phenotype hemophilia A or B hen prophylaxis is not feasible episodic therapy is essential treatment for acute hemorrhages; however it will not prevent long-term joint damage he recommended treatment for patients with severe phenotype hemophilia A or B is replacement of clotting factor (either standard or extended half-life) with FVIII concentrate in hemophilia A and FIX concentrate in hemophilia B here are currently several factor-replacement products on the mar et As such the selection of a factor-replacement product is based on the safety and purity of the product the ris of developing inhibitors the half-life of the product and cost Extended half-life (EHL) products factor-concentrate products with a longer half-life allow for less-frequent administration reducing the ris of catheter-associated complications However an analysis presented at the Academy of Managed Care Pharmacy s annual meeting showed that the average cost of products more than doubled for a small number of patients with hemophilia A who switched from standard to EHL products

Treatment Landscape According to updated treatment guidelines from the orld Federation of Hemophilia ( FH) hemophilia patients need access

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HEMOPHILIA | Continued

bleeding for patients with severe hemophilia A without inhibitors; however long-term data on patient outcomes is needed

With the high annual cost of lifelong hemophilia treatment, the idea of a onetime, curative therapy may be appealing for patients, providers, and health plans. Aside from clotting-factor placement treatment options for hemophilia have been limited In ovember emicizumab- xwh (HEMLIBRAÂŽ Roche) became the first new nonfactor product for hemophilia to be approved by the S Food and Drug Administration (FDA) in years Emicizumab is a bispecific factor IXa- and factor X-directed monoclonal antibody administered as a subcutaneous injection for routine prophylaxis to prevent or reduce the occurrence of bleeding episodes in adult and pediatric patients (newborn and older) with hemophilia A with or without inhibitors Emicizumab is designed to be used in place of exogenous factor concentrate and bypassing agents; however FVIII products may continue to be used during the first wee of therapy with emicizumab - Emicizumab may be dosed wee ly every two wee s or every four wee s based on provider and patient preference Clinical trials demonstrated that treatment with emicizumab may significantly improve the prevention of bleeding events in hemophilia A compared to standard-of-care exogenous factor concentrate Emicizumab offers a novel approach to hemophilia treatment but it has a significant price tag As of the wholesale acquisition cost was approximately for the first year of treatment followed by for each subsequent year; this cost is based on a -pound patient and cost can vary significantly based on the patient s weight A review by the Institute for Clinical and Economic Review (ICER) found treatment with emicizumab to be cost-saving in patients with inhibitors because it may reduce the need for exogenous factor concentrate which can be very costly On Oct ICER released a report assessing emicizumab and a gene therapy According to the report emicizumab provides comparable or even superior clinical benefits than prophylactic FVIII replacement therapy among adults with severe hemophilia A; the report concluded that emicizumab is also cost-saving The 2020 FH recommendations include prophylaxis with emicizumab to prevent hemarthrosis as well as spontaneous and brea through

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Competition to emicizumab may be on the horizon soon in the form of concizumab a subcutaneous monoclonal antibodytargeting tissue-factor pathway inhibitor In March ovo ordis suspended clinical trials of concizumab due to three cases of nonfatal thrombotic events; however the FDA recently lifted the clinical hold after new safety measures and guidelines were agreed upon Other late-phase nonfactor pipeline agents include marstacimab another tissue factor pathway inhibitor and fitusiran a subcutaneously administered synthetic double-stranded siR A oligonucleotide that targets antithrombin III hese products will compete with traditional clotting-factor concentrate products and novel therapies expected to enter the mar et in the coming years

Novel Therapy Pipeline ene therapy is designed to correct the disease s underlying genetic defect he goal of gene therapy is to provide patients with the genetic code that will enable their bodies to manufacture and maintain a constant level of FVIII via a modified virus (which does not cause disease) his could potentially reduce or eliminate bleeds and the requirement for multiple lifelong exogenous factor-replacement therapies CRISPR-Cas is another novel treatment strategy that could potentially allow a patient s body to produce its own blood-clotting factor his type of treatment uses a piece of genetic material and enzyme that acts li e molecular scissors to repair the geneticerror-causing clotting-factor deficiency ith the high annual cost of lifelong hemophilia treatment the idea of a one-time curative therapy may be appealing for patients providers and health plans An analysis determined that hemophilia A gene therapy was cost-effective compared to disease management with prophylactic factor-replacement therapy which has a predicted cost of million 9 Over a decade total per-person gene therapy costs were million and resulted in quality-adjusted life years ( AL s) compared to million per patient and AL s for prophylactic therapy ene therapy was found to be costeffective unless initial costs exceeded million per patient and were less than per one AL gained compared to prophylaxis if initial costs were less than million per patient 9 However current mar et projections indicate that the cost of gene therapy may be between million and million suggesting that they may not meet this cost-effectiveness threshold when they reach the mar et Below is a loo at some of the recent developments in gene therapies for hemophilia

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Valoctocogene Roxaparvovec Valoctocogene roxaparvovec (BioMarin) an investigational adenoassociated virus serotype (AAV )-mediated gene therapy was under FDA review which delayed an anticipated August approval It wor s by delivering a B-domain deleted gene to cells in the liver producing an active variant of FVIII 20 In a phase one-two study that included wee s of data for patients who received the phase three dose of trillion vectors/ g patients experienced a reduction in their mean annualized bleeding rate (ABR) and most patients no longer required prophylactic factor-replacement therapy Also in the first year of treatment with valoctocogene roxaparvovec of patients experienced no bleeds at all compared to just at enrollment However the efficacy did appear to plateau in year two; the year four study data showed a decrease in mean FVIII compared to year three In May BioMarin announced that the phase three E Er study of valoctocogene roxaparvovec had achieved prespecified clinical criteria for regulatory review in the S and Europe As of May of patients enrolled in the study had achieved FVIII levels of at least I /dL at to wee s Of the patients who had reached wee before the April cutoff the estimated median ABR was and the estimated mean ABR was representing an reduction from baseline when patients were receiving standard-of-care prophylaxis A Biologics License

Application (BLA) for valoctocogene roxaparvovec was accepted for priority review by the FDA in February ; the FDA previously awarded both the brea through therapy and orphan drug designations 22 In delaying approval the FDA noted that more and longer-term data is needed for confirmation In the Oct review ICER reported that valoctocogene roxaparvovec could be a more effective and cost-saving treatment; however further evidence will be needed

Etranacogene Dezaparvovec Etranacogene dezaparvovec (uni ure) is an investigational gene therapy consisting of a recombinant AAV viral vector carrying a gene cassette containing the FIX Padua variant under the control of a liver-specific promoter In a phase two-b study three adults with moderate to severe hemophilia B with low levels of preexisting neutralizing antibodies to AAV were given a single intravenous infusion of genome copies/ g 22 Six wee s after dosing the mean FIX activity was (range to ) and increased to at wee s (range to ) Furthermore two patients achieved sustained FIX activity of During the -wee period all three patients achieved cessation of bleeding and had no need for FIX replacement therapy At the -wee mar no patient in the study reported any bleeding events and all patients remained free of prophylaxis after receiving etranacogene dezaparvovec Etranacogene dezaparvovec is currently being studied in the ongoing open-label phase three HOPE-B trial which enrolled patients with moderate to severe hemophilia B with or without preexisting neutralizing antibodies opline data from HOPE-B is expected in ni ure announced in October that it expects to submit a Biologics License Application for mar eting authorization of etranacogene dezaparvovec in he FDA has designated etranacogene dezaparvovec a brea through therapy; approval is predicted for

Fidanacogene Elaparvovec Fidanacogene elaparvovec (Spar herapeutics/Pfizer) is an investigational bioengineered AAV vector utilizing a high-activity F transgene for the treatment of hemophilia B Similar to etranacogene dezaparvovec fidanacogene elaparvovec utilizes the Padua variant of FIX Phase one-two data demonstrated a reduction in ABR four wee s after treatment Of the patients enrolled only one experienced a bleeding event four or more wee s post-infusion hree patients who received an enhanced version of fidanacogene elaparvovec achieved FIX activity of to at wee or more of follow-up Spar /Pfizer reported Phase three studies of fidanacogene elaparvovec are ongoing

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HEMOPHILIA | Continued

he anticipated completion date for primary data from the ongoing phase three trial is ovember If results are positive approval could occur in

Giroctocogene fitelparvovec iroctocogene fitelparvovec (Pfizer/Sangamo BioSciences) comprises a recombinant AAV serotype (AAV ) vector encoding the complementary deoxyribonucleic acid for B-domain deleted human FVIII Phase one-two trial data presented in une demonstrated that all five patients with severe hemophilia A who received the e vg/ g dose showed sustained FVIII activity levels with a median of via chromogenic assay reflecting measurements up to wee s o patients experienced bleeding events or required FVIII infusions 29

TAK-754/TAK-748

wo gene therapies for hemophilia A and B A and A ( a eda) are in early development A is in phase one studies while A is in preclinical studies Both potential gene therapies utilize recombinant versions of adeno-associated virus serotype (AAV ) In December a eda released research at the American Society of Hematology meeting that both highlighted the challenge of natural immunity to AAV in hemophilia patients and strategies to overcome that challenge; researchers developed an immune adsorption column (IAC) that was designed to remove anti-AAV antibodies from patients plasma hese therapies are still very early in development; however a eda has committed to simultaneously investigating approaches to overcome AAV-gene-therapy-associated challenges while advancing its gene therapy program

24 | Magellan Rx Report | Fall 2020

Managed Care Implications hile gene therapy has the potential to transform hemophilia treatment the potential upfront costs associated with the one-time infusions may be staggering In February BioMarin s CEO suggested that valoctocogene roxaparvovec may cost between million and million per patient citing the potential cost -savings compared to factor-replacement therapy in the long term Experts suggest that a hemophilia B gene therapy such as etranacogene dezaparvovec could be priced between million and million per patient While the annual per-patient cost of exogenous replacement therapy is significant the cost is more manageable for payers when spread out over time Current strategies for replacement therapy management utilized by payers revolve around the personalization and optimization of therapy Approximately of S hemophilia patients receive care through a federally recognized Hemophilia reatment Center (H C) Because hemophilia is so rare some providers do not have the experience needed to provide optimal care for hemophilia patients H Cs have a multidisciplinary team specializing in hemophilia to improve patient outcomes and quality of life by providing a comprehensive list of services such as ongoing monitoring of coagulation education physical therapy genetic counseling social wor services and nutrition among others his approach has been shown to reduce emergency department visits and avoid hospitalization In addition to H Cs many specialty pharmacies offer a variety of clinical management and adherence programs to improve patient outcomes and reduce costs Almost of Medicaid-

managed care plans require patients with hemophilia to fill their factor-replacement therapy from a specialty pharmacy Studies have shown that case management programs through specialty pharmacies may yield significant cost savings In addition development and implementation of digital technologies may also present a positive opportunity for improving hemophilia management hile many gene therapies in development focus on rare diseases without a cure the availability of effective treatment options such as factor-replacement therapy presents a unique challenge to payers It is a straightforward decision to provide a patient with a rare disease and no other treatment options access to a lifesaving gene therapy However deciding between lifelong factorreplacement therapy and a one-time potentially curative gene therapy will prove to be more challenging Payers and providers will need to carefully identify the optimal candidates for gene therapy to ensure cost-effectiveness o truly understand costeffectiveness payers will need to understand the true cost of care for the various subgroups of hemophilia patients including those with inhibitors those using factor-replacement therapy and those using other existing therapies such as emicizumab a ing into account FDA approval broadness clinical trial data and the cost of care for certain subgroups in their plan membership payers may consider limiting access to certain groups who may not be appropriate candidates for gene therapy hese groups might include patients who are under age have inhibitors have mild or moderate disease and may have antibodies to the gene therapy delivery vector Another challenge is that the availability of hemophilia treatments may lead to payers being more aggressive in their management approach and in leveraging discounts from manufacturers If the cost of gene therapy is too prohibitive for payers it may be excluded from plan formularies which could have a cascading effect in the mar et Because other treatments are available the need for gene therapy may be less urgent resulting in patients switching to a health plan that provides more favorable access leading to unequal distribution of costs As the way we treat hemophilia patients changes the treatment cost and method of payment will also change hile payers have found ways to optimize factor-replacement therapy to reduce costs a one-time treatment with an upfront cost of million or more will require a drastically different approach ICER and other groups have already ta en on the tas of determining the potential value and cost-effectiveness of gene therapy; however it is di cult to fully assess the value of gene therapy in hemophilia until we have more long-term data describing the durability of the effect

Payers may consider similar strategies to those discussed for other gene therapies such as amortized payment structures where payments align with agreed-upon clinical milestones and value-based agreements with manufacturers Because response durability is of concern value-based agreements may be designed to offer payer rebates if patients do not maintain e cacy to an agreed-upon timepoint where therapy would be considered cost-effective Other endpoints that may be considered include hospitalizations and bleeding events Payers may also consider using healthcare reinsurance; under a healthcare reinsurance system proposed by ovartis ma er of the novel high-cost CAR- therapy escartaÂŽ (axicabtagene ciloleucel) the high aggregate costs of cell and gene therapies would be redistributed among a pool of multiple payers This type of cost-sharing model may lessen the burden on individual payers and improve access to high-cost therapies Lastly as we see more gene therapies and other novel treatments enter the hemophilia mar et there may be opportunities to leverage competing products for rebates by selecting a preferred product It will be critical for payers manufacturers and providers to wor together to ensure that patients have access to these innovative therapies and that responsible pricing and risk-sharing is maintained across all sta eholders

References Srivastava Alo et al FH uidelines for the Management of Hemophilia rd Edition Haemophilia Aug doi: hae

Inserro Allison Prevalence of Hemophilia orldwide Is riple hat of Previous Estimates ew Study Says American Journal of Managed Care Sept https://www ajmc com/view/prevalence-ofhemophilia-worldwide-is-triple-that-of-previous-estimates-newstudy-sayshat Is Hemophilia Centers for Disease Control and Prevention uly https://www cdc gov/ncbddd/hemophilia/facts html Hemophilia Mayo Clinic Mayo Foundation for Medical Education and Research Aug https://www mayoclinic org/diseasesconditions/hemophilia/symptoms-causes/sycChen Sheh-Li Economic Costs of Hemophilia and the Impact of Prophylactic reatment on Patient Management American Journal of Managed Care Apr https://www ajmc com/ view/incorporating-emerging-innovation-hemophilia-ab-tailoringprophylaxis-management-strategies-managed-care-environmenteconomic-costs

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HEMOPHILIA | Continued

Escobar M A Health Economics in Haemophilia: a Review from the Clinician s Perspective Haemophilia vol pp doi: /j x Inhibitors and Hemophilia Centers for Disease Control and Prevention Centers for Disease Control and Prevention uly https://www cdc gov/ncbddd/hemophilia/inhibitors html horat eja et al Hemophilia Burden of Disease: A Systematic Review of the Cost- tility Literature for Hemophilia Journal for Managed Care & Specialty Pharmacy vol no uly pp doi: /jmcp Machin icoletta et al ene herapy in Hemophilia A: A CostEffectiveness Analysis Blood Advances vol no pp doi: /bloodadvances he High Price of Hemophilia ASH Clinical News Feb https://www ashclinicalnews org/spotlight/feature-articles/highprice-hemophilia/ HEMLIBRAÂŽ pac age insert South San Francisco CA: enentech Inc; FDA Approves enentech s Hemlibra (Emicizumab- xwh) for Hemophilia A ithout Factor VIII Inhibitors Genentech enentech Oct www gene com/media/pressreleases/ / - - /fda-approves-genentechs-hemlibraemicizu Emicizumab for Hemophilia A with Inhibitors: Effectiveness and Value Institute for Clinical and Economic Review ew England CEPAC Apr https://icer-review org/wp-content/uploads/ / / ICER Hemophilia Final Evidence Report pdf Valoctocogene Roxaparvovec and Emicizumab for Hemophilia A without Inhibitors: Effectiveness and Value Institute for Clinical and Economic Review ew England CEPAC Oct https:// icerreview org/wpcontent/uploads/ / /ICER Hemophilia-A Evidence-Report pdf Adams Ben ovo ordis s Concizumab rials Can Resume After Safety rial Halt FierceBiotech Aug https://www fiercebiotech com/biotech/novo-nordis -s-concizumab-trials-canresume-after-safety-trial-halt BM ene herapy for Hemophilia A BioMarin https://www biomarin com/wp-content/uploads/ / / BM ene herapyInfographics pdf Malcolm Emily ene herapy Hemophilia News Today https://www hemophilianewstoday com/gene-therapy/ Healthcare lobalData ni ure s Etranacogene Dezaparvovec in Haemophilia B Has Experts Positive on Phase III Prospects Clinical Trials Arena an https://www clinicaltrialsarena com/ comment/uniqure-etranacogene-dezaparvovec/ Valoctocogene Roxaparvovec and Emicizumab for Hemophilia A: Effectiveness and Value Institute for Clinical and Economic Review ew England CEPAC an https://icer-review org/ wp-content/uploads/ / /ICER Hemophilia-A Draft-ScopingDocument pdf aylor Phil BioMarin ps the Ante for Pivotal Haemophilia ene herapy rial PMLive PM roup orldwide Limited May http://www pmlive com/pharma news/biomarin ups the ante for pivotal haemophilia gene therapy trial

26 | Magellan Rx Report | Fall 2020

BioMarin Announces hat Phase Cohort of Valoctocogene Roxaparvovec ene herapy Study in Severe Hemophilia A Met Pre-Specified Criteria for Regulatory Submissions in the S and Europe BioMarin May https://investors biomarin com/ - - -BioMarin-Announces-that-Phase- Cohort-of-Valoctocogene-Roxaparvovec- ene- herapy-Study-inSevere-Hemophilia-A-Met-Pre-Specified-Criteria-for-RegulatorySubmissions-in-the- -S-and-Europe BioMarin s Biologics License Application for Valoctocogene Roxaparvovec Accepted for Priority Review by FDA with Review Action Date of August PR Newswire Feb https://www prnewswire com/news-releases/biomarins-biologicslicense-application-for-valoctocogene-roxaparvovec-accepted-forpriority-review-by-fda-with-review-action-date-of-august- html Von Drygals i Annette et al Etranacogene Dezaparvovec (AM Phase b): ormal/near ormal FIX Activity and Bleed Cessation in Hemophilia B Blood Advances vol no pp doi: /bloodadvances Hemophilia - ene herapy uniQure https://www uniqure com/ gene-therapy/hemophilia php uni ure Announces One- ear Follow- p Data from the Phase IIb Study of Etranacogene Dezaparvovec and Long- erm Follow- p Data for AM in Patients with Hemophilia B Euroland uni ure Dec https://www tools eurolandir com/tools/Pressreleases/ etPressRelease/ ID= lang=en- B companycode=nlqure v= Mel o Alice FH SP Reduces Bleeding Rates by in Hemophilia B Patients Phase / rial Shows Hemophilia News Today une https://hemophilianewstoday com/ / / /sp -promotes-sustained-factor-ix-increasehemophilia-phase- - -trial/ Our Scientific Platform and Programs Spark Therapeutics https:// spar tx com/scientific-platform-programs/ Armstrong Madeleine niqure urns the Screw on Spar and Pfizer Evaluate Feb https://www evaluate com/vantage/articles/ news/trial-results/uniqure-turns-screw-spar -and-pfizer Pfizer and Sangamo Announce pdated Phase / Results Showing Sustained Factor VIII Activity Levels and o Bleeding Events or Factor sage in E vg/ g Cohort Following iroctocogene Fitelparvovec (SB) ene herapy Pfizer une https://www pfizer com/news/press-release/press-release-detail/pfizer-and-sangamoannounce-updated-phase- -results Pena Ana a eda Presents Early Data About Improving E ciency of Hemophilia A and B ene herapy Hemophilia News Today Dec https://hemophilianewstoday com/ / / /ta edapresents-early-data-about-improving-e ciency-of-hemophilia-aand-b-gene-therapy/ Dalton Dan R Hemophilia in the Managed Care Setting American Journal of Managed Care Apr https://www ajmc com/view/ ace mar hemophilia dalton Funding for Costly ext- en herapies: Is Reinsurance the Answer Pharmaceutical Technology an https://www pharmaceutical-technology com/comment/funding-next-gen-drugs/

Oncology Update: Emerging NSCLC and Breast Cancer Therapies This active space continues to evolve and show promise, with 700 drugs in the gene therapy and biosimilar pipeline. The annual cost of cancer care in the U.S. is estimated at around $150 billion.1 According to the 2019 Magellan Rx Medical Pharmacy Trend Report, oncology was the highest-cost category across all lines of business, making up at least one-third of total medical drug spend in 2019.2 There is a lot of activity in the oncology space and more on the horizon, with 700 drugs in the gene therapy and biosimilar pipelines in clinical trials. This year alone, the U.S. Food and Drug Administration (FDA) has approved several novel treatments for non-small cell lung cancer (NSCLC) and breast cancer.

NSCLC Carly Rodriguez, Pharm.D. Pharmacy Director, Clinical Innovation Moda Health

It is estimated that 228,820 adults in the U.S. will be diagnosed with lung cancer in 2020, which would account for about 13% of all new cancer diagnoses.3 While the number of new diagnoses of lung cancer has dropped (3% annually in men and 1.5% annually in women), lung cancer remains the second most common cancer and the leading cause of cancer-related deaths.3 The lifetime cost of lung cancer is estimated at around $282,000 per patient.1 As the most common type of lung cancer, NSCLC accounts for 84% of all lung cancer diagnoses.3 The subtypes of NSCLC include squamous cell carcinoma, large cell carcinoma, and adenocarcinoma, along with less common types such as pleomorphic, carcinoid tumor, salivary gland carcinoma, and unclassified carcinoma 4 Smoking is the major risk factor of NSCLC, but additional risk factors include exposure to asbestos, arsenic, and other toxins in the workplace; exposure to radiation; air pollution; and family history SCLC does not always cause early symptoms in those affected and symptoms may be caused by other conditions; however, some symptoms may include chest discomfort or pain, a consistent cough, trouble breathing, wheezing, blood in sputum, hoarseness, appetite loss, unintentional weight loss, fatigue di culty swallowing and swelling in the face and/or veins in the nec SCLC can be detected diagnosed, and staged through a number of tests and procedures, which may include a combination of the following: a physical exam and health history, laboratory tests, chest X-ray, CT scan, sputum cytology, and thoracentesis.4

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ONCOLOGY UPDATE | Continued

The survival rate among patients with NSCLC is dependent on the stage of disease. The overall survival rate is 61% for patients with localized NSCLC, meaning the cancer has not spread outside of the lung; 35% for regional NSCLC, meaning the cancer has spread outside of the lung to nearby areas; and 6% for metastatic lung cancer, meaning the cancer has spread to distant parts of the body.3

NSCLC Treatment Treatment for NSCLC is largely dependent on the individual case and stage of the disease. Early-stage NSCLC is mostly treated with surgery, with the addition of radiation therapy where appropriate. Stage II and further-progressed NSCLC is often treated with some combination of surgery and adjuvant chemotherapy. Much progress has been made in the advanced, or metastatic, NSCLC treatment landscape; progress can be linked to the discovery of gene mutations and the development of targeted therapies. Comprehensive biomarker testing is recommended for advancedstage SCLC patients to ensure that the most effective therapy is used;4 these biomarker tests can determine the presence of a particular gene mutation or protein. Targeted therapies for NSCLC include angiogenesis, epidermal growth factor receptor (EGFR), ALK, BRAF, MEK, RET, and NTRK inhibitors, as well as drugs that target cells with ROS1 gene changes.5 Immunotherapies used in the treatment of advanced-stage SCLC include PD- /PD-L inhibitors (e.g., pembrolizumab, nivolumab, or atezolizumab) and CTLA-4 inhibitors (e.g., ipilimumab).6

New NSCLC Therapy Approvals There has been much movement in the NSCLC treatment landscape in 2020, with several FDA approvals occurring this past spring.

Pralsetinib (GAVRETO™)7 In September, the FDA granted accelerated approval for pralsetinib (GAVRETO™, Roche) for the treatment of adults with metastatic rearranged during transfection (RET) fusion-positive NSCLC as detected by an FDA-approved test. Pralsetinib, a once-daily oral precision therapy, selectively targets RET alterations, including fusions and mutations. This accelerated approval was based on data from the phase one-two ARROW study, and continued approval may be contingent upon verification and description of clinical benefit in a confirmatory trial In the study pralsetinib demonstrated an overall response rate (ORR) of 57% and complete response (CR) rate of 5.7% in NSCLC patients previously treated with platinum-based chemotherapy. In the treatment-naïve patients, ORR was 70% with

28 | Magellan Rx Report | Fall 2020

Much progress has been made in the advanced, or metastatic, NSCLC treatment landscape; progress can be linked to the discovery of gene mutations and the development of targeted therapies. an 11% CR rate. Common adverse reactions in this study included fatigue, constipation, musculoskeletal pain, and increased blood pressure. Pralsetinib will compete directly with selpercatinib as described below.

Capmatinib (TABRECTA™)8 In May, the FDA granted accelerated approval for capmatinib ( ABREC A™ ovartis) for the treatment of SCLC with specific mutations (those that lead to mesenchymal-epithelial transition or MET exon 14 skipping). FoundationOne CDx (F1CDx) assay was also approved as a companion diagnostic for capmatinib. Participants in the trial received capmatinib 400 mg orally twice daily until the disease progressed or participants experienced unacceptable toxicity. The ORR for participants who had never undergone NSCLC treatment was 68%, with 4% having complete response and 64% having partial response; the ORR for patients who were previously treated was 41%, all having a partial response. Of participants who had never undergone NSCLC treatment, 47% had a response lasting 12 months or longer, compared to 31% of those who had been previously treated. Common adverse reactions associated with capmatinib are peripheral edema, nausea, fatigue, vomiting, dyspnea and decreased appetite Other more serious side effects include interstitial lung disease or pneumonitis. According to the NCCN guidelines, either capmatinib (category 2A, preferred) or crizotinib (category A) may be used as first-line therapy in advanced NSCLC patients with MET exon 14 skipping.9

Selpercatinib (Retevmo™)10 The FDA approved selpercatinib (Retevmo™, Loxo Oncology) in May under the accelerated approval pathway. Selpercatinib is a RET inhibitor indicated to treat NSCLC in patients whose tumors have a

RE gene alteration which must be identified via laboratory testing prior to treatment. A clinical trial was conducted with 105 adults with RET fusion-positive NSCLC who were previously treated with platinum chemotherapy; the ORR was 64%. The response lasted at least six months for 81% of patients who had a response to the treatment. In 39 patients with RET fusion-positive NSCLC who had never undergone treatment, the ORR was 84%, and the response lasted at least six months for 58% of these patients. Common side effects included increased aspartate aminotransferase and alanine aminotransferase in the liver, increased blood sugar, decreased white blood cell count, decreased albumin in the blood, decreased calcium in the blood, dry mouth, diarrhea, increased creatinine, increased alkaline phosphatase, hypertension, fatigue, swelling in the body or limbs, low blood platelet count, increased cholesterol, rash, constipation, and decreased sodium in the blood. More serious adverse reactions included hepatotoxicity, elevated blood pressure, QT prolongation, bleeding, and allergic reactions. Selpercatinib will compete directly with pralsetinib as described above.

Atezolizumab (TECENTRIQ )

® 11

Atezolizumab (TECENTRIQ®) was previously approved by the FDA for use as second-line therapy of advanced NSCLC and was also previously approved in the first-line setting regardless of PD-L status, in combination with bevacizumab, paclitaxel, and carboplatin in patients with no EGFR and ALK genomic tumor aberrations. In May, atezolizumab received FDA approval for use as a monotherapy in the first-line setting for adults with metastatic SCLC whose tumors have high PD-L1 expression with no EGFR or ALK genomic tumor aberrations. The FDA also approved a companion diagnostic device, VENTANA PD-L1 (SP142) Assay (Ventana Medical Systems Inc.), for selecting patients with NSCLC for monotherapy treatment with atezolizumab. An open-label trial was conducted for patients with stage-four NSCLC whose tumors expressed PD-L1 and who had not received prior chemotherapy. Participants were randomized to receive a dose of atezolizumab 1200 mg every three weeks until the disease progressed or participants experienced unacceptable toxicity Results showed statistically significant improvement in median overall survival (OS) for patients with high PD-L1 tumor expression receiving atezolizumab (20.2 months) compared to those treated with platinum chemotherapy (13.1 months). The most common side effects were fatigue or asthenia

Brigatinib (ALUNBRIG®)12 In May, the FDA approved brigatinib (ALUNBRIG®, ARIAD Pharmaceuticals) as a first-line treatment for adults with anaplastic lymphoma kinase (ALK)-positive metastatic NSCLC. Brigatinib had received FDA approval in 2017 for use in the same population of patients who had progressed on or were intolerant to crizotinib

(Xalkori®). The FDA also approved the Vysis ALK Break Apart FISH Probe Kit (Abbott Molecular Inc.) as a companion diagnostic for brigatinib; an FDA-approved test must be used to detect ALK-positive metastatic NSCLC prior to using brigatinib. A trial measuring for progression-free survival (PFS) was conducted in adults with advanced ALK-positive NSCLC who had not previously received an ALK-targeted therapy. Participating patients were to have an ALK rearrangement based on local standard-of-care testing, and 275 patients were randomized to receive brigatinib 180 mg orally once daily, with a seven-day lead-in at 90 mg once daily, or crizotinib 250 mg orally once daily. The Vysis test was used retrospectively to test a subset of clinical samples, and of the enrolled patients, 239 had positive results using the diagnostic test. Patients treated with brigatinib had an estimated median PFS of 24 months, compared with 11 months for those treated with crizotinib. The most common side effects were diarrhea fatigue nausea rash cough myalgia headache, hypertension, vomiting, and dyspnea.

Nivolumab (OPDIVO®) Plus Ipilimumab (YERVOY®)13 and Chemotherapy In May, the FDA granted approval for the combination of nivolumab (OPDIVO®, Bristol Myers Squibb) plus ipilimumab (YERVOY®, Bristol Myers Squibb) and two cycles of platinum-doublet chemotherapy as first-line treatment for patients with metastatic or recurrent NSCLC with no EGFR or ALK genomic tumor aberrations. In a randomized, open-label trial, 361 patients received the combination of nivolumab plus ipilimumab and two cycles of platinum-doublet chemotherapy, and 358 received platinumdoublet chemotherapy for four cycles. Results showed a statistically significant benefit in median overall OS for those treated with the combination therapy (14.1 months) versus those on chemotherapy ( months) he most common side effects in of patients receiving the combination therapy were fatigue, musculoskeletal pain, nausea, diarrhea, rash, decreased appetite, constipation, and pruritis. Earlier in May, the FDA approved the combination of nivolumab and ipilumab as first-line treatment for patients with metastatic SCLC whose tumors express PD-L with no E FR or ALK genomic tumor aberrations.14 The FDA also approved the PD-L1 IHC 28-8 pharmDx (Agilent Technologies Inc.) as a companion diagnosis device for selecting patients for this combination treatment A trial demonstrated significant improvement in OS for patients with PD-L1 tumor expression receiving the combination therapy compared to those treated with platinum-doublet chemotherapy (17.1 months vs. 14.9 months, respectively).14 Most common side effects were fatigue, rash, decreased appetite, musculoskeletal pain, diarrhea/colitis dyspnea cough pruritis nausea and hepatitis

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ONCOLOGY UPDATE | Continued

NSCLC Pipeline Drug

amivantamab

Manufacturer

anssen/ enmab

Route of Administration

Mechanism of Action

Anticipated NSCLC Settings

Status

anti-EGFR antibody; anti-c-MET antibody

metastatic NSCLC with EGFR exon 20 insertion mutations

phase three

cemiplimab-rwlc (LIBTAYO®)

Regeneron/ Sanofi

PD-1 inhibitor

PD-L1-positive advanced NSCLC

phase three

tiragolumab (RG6058)

Roche/ Genentech

anti-TIGIT antibody

PD-L1-positive metastatic NSCLC

phase three

Source: IPD Analytics

Nivolumab had previously been approved as a single agent for patients with metastatic NSCLC and progression on or after platinumbased chemotherapy. Ipilimumab is not indicated as a single agent in the treatment of NSCLC.

Ramucirumab (CYRAMZA®) Plus Erlotinib15 In May, the FDA approved ramucirumab (CYRAMZA®, Eli Lilly) in combination with erlotinib as a first-line treatment of metastatic NSCLC with EGFR exon 19 deletions or exon 21 (L858R) mutations. In a randomized study, 449 patients received either ramucirumab mg/ g or a placebo every two wee s as an intravenous infusion in combination with erlotinib 150 mg orally once daily, until the disease progressed or the participant experienced unacceptable toxicity. The patients receiving combination ramucirumab therapy had a median PFS of 19.4 months compared to 12.4 months in those receiving a placebo plus erlotinib Side effects reported by those treated with the combination therapy were infections, hypertension, stomatitis, proteinuria, alopecia, epistaxis, and peripheral edema. The NCCN guidelines give the combination of ramucirumab plus erlotinib a 2A recommendation in this setting while osimertinib (TAGRISSO®) is the category one, preferred drug according to the NCCN guidelines. Ramucirumab was previously approved in combination with docetaxel for the treatment of patients with metastatic NSCLC with disease progression on or after platinum-based chemotherapy.

Pemetrexed (Pemfexy™)16 In February, the FDA granted approval via the 505b pathway to a novel formulation of pemetrexed for injection (Pemfexy™, Eagle

30 | Magellan Rx Report | Fall 2020

Pharmaceuticals) for the treatment of patients with advanced or metastatic NSCLC. The ready-to-dilute formulation pemetrexed is meant for treatment of locally advanced or metastatic NSCLC in combination with cisplatin chemotherapy as either a combination therapy, maintenance therapy after four cycles of progression-free chemotherapy, or after chemotherapy as a single agent. Pemetrexed powder for injection requiring reconstitution is already available as ALIMTA® (Eli Lilly). The launch date for Pemfexy™ is uncertain, and the loss of exclusivity for Eli Lilly’s ALIMTA® will likely not occur before mid-2022.

Breast Cancer Around 1 in 8 women in the U.S. will be diagnosed with invasive breast cancer in her lifetime, with an estimated 276,840 new cases expected to be diagnosed in 2020.17 Breast cancer is the largest share of cancer spend, making up 14.4%; the disease cost $19.7 billion in 2018.18 About 5% to 10% of breast cancer cases occur in patients with an inherited gene mutation, most commonly the BRCA1 and BRCA2 genes. However, 85% of breast cancer cases are found in women with no family history of breast cancer, with the most significant ris factors being sex and age 17 About 64% of breast cancer patients have local-stage breast cancer at the time of diagnosis; 27% have regional-stage breast cancer; and 6% have metastatic disease.19 The death rate associated with breast cancer has decreased steadily between 2013 and 2017 by about 1.3% per year; this decline has been attributed to earlier detection and treatment improvements.19

Breast Cancer Treatment

New Breast Cancer Therapy Approvals

Treatment modalities for breast cancer can vary depending on the stage and subtype. Some systemic therapies include chemotherapy, hormonal therapy, and targeted therapy. Targeted therapies are available for treatment of HER2+ subtype, accounting for 15% of all breast cancer cases in women in the S; the first approved drug of this type was trastuzumab, a monoclonal antibody that targets the HER2 protein.18 Newer drugs have been developed to be used in combination with trastuzumab or when trastuzumab is no longer effective argeted therapies for mar ers other than HER have become available for advanced-stage breast cancer; these include CD / inhibitors PARP inhibitors and PI inhibitors 18

Sacituzumab govitecan-hziy (TRODELVY™)20

Immunotherapy, such as checkpoint inhibitors, is an emerging treatment for breast cancer. Atezolizumab (TECENTRIQ®, Genentech) is a checkpoint inhibitor that can be used along with chemotherapy for certain patients with triple-negative breast cancer.18 Continued research on the use of immunotherapy in metastatic breast cancer treatment is ongoing.

Sacituzumab govitecan-hziy (TRODELVY™, Immunomedics), an antibody-drug conjugate immune-targeted therapy, received accelerated approval from the FDA in April for the treatment of adults with metastatic triple-negative breast cancer (mTNBC) who received at least two prior therapies for metastatic disease. In an uncontrolled trial, 108 patients with mTNBC who had received at least two prior treatments for metastatic disease received sacituzumab govetican-hziy mg/ g via IV on days one and eight every 21 days. Throughout the trial, tumor imaging was conducted every eight weeks, and patients were treated until disease progressed or they experienced intolerance. The ORR was 33.3%, and the median response duration was 7.7 months. The most common side effects were nausea neutropenia diarrhea fatigue anemia vomiting, alopecia, constipation, rash, decreased appetite, and abdominal pain. As approval was accelerated, continued approval may be contingent upon verification and description of clinical benefit in confirmatory trials

Tucatinib (TUKYSA®)21

Continued research on the use of immunotherapy in metastatic breast cancer treatment is ongoing.

In April, the FDA approved tucatinib (TUKYSA®), an oral kinase inhibitor, in combination with chemotherapy (trastuzumab) for advanced forms of HER2+ breast cancer that cannot be surgically removed or have spread to other parts of the body, including the brain, as a second- or third-line treatment. Approval was based on a clinical trial of 612 patients with HER2+ positive advanced unresectable or metastatic breast cancer who

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ONCOLOGY UPDATE | Continued

had prior treatment with trastuzumab, pertuzumab, and adotrastuzumab emtansine; 48% of participants had brain metastases at the start of the trial. Median PFS in patients who received tucatinib, trastuzumab, and capecitabine was 7.8 months compared to 5.6 months in patients who received a placebo plus trastuzumab and capecitabine. Median OS for patients receiving tucatinib plus trastuzumab and capecitabine was 21.9 months versus 17.4 months in those receiving a placebo plus trastuzumab and capecitabine. For patients with brain metastases at the start of the trial who received tucatinib, median PFS was 7.6 months compared to 5.4 months for patients receiving a placebo. Common adverse reactions reported were diarrhea, palmar-plantar erythrodysesthesia, vomiting, stomatitis, decreased appetite, abdominal pain, headache anemia and rash More serious side effects caused by tucatinib included severe diarrhea associated with dehydration, acute kidney injury, and death.

Neratinib (NerlynxÂŽ)22 In February, the FDA approved neratinib (NerlynxÂŽ, Puma Biotechnology Inc.), an oral kinase inhibitor, in combination with capecitabine for the treatment of adults with advanced or metastatic HER2+ breast cancer who have received two or more anti-HER2based regimens. Neratinib was previously approved in 2017 for use as extended adjuvant treatment of early stage HER2+ breast cancer. In a clinical trial, 621 patients with metastatic HER2+ breast cancer who had received two or more anti-HER2-based regimens were randomized to one of two treatment arms. For each 21-day cycle, one arm received neratinib 240 mg orally once daily on Days through with capecitabine mg/m given orally twice daily on Days 1 through 14; the other arm received lapatinib 1250 mg orally once daily on Days 1 through 21 with capecitabine 1000 mg/m given orally twice daily on Days through for each day cycle. Treatment continued until the disease progressed or the participant experienced unacceptable toxicity. Patients who were treated with the neratinib-capecitabine combination

therapy had a median PFS of 5.6 months compared to 5.5 months for those receiving lapatinib. The PFS rate at 12 months was 29% for those receiving neratinib versus 15% for those receiving lapatinib.

Managed Care Implications Precision medicine, which enables personalized drug therapy based on the patient s tumor molecular profiling has advanced the treatment of many types of cancer. Certain diseases such as SCLC now have a variety of different targetable mutations that may be exploited. For certain molecular aberrations, more than one drug in the class is now approved and on the market. Unfortunately, there is a paucity of head-to-head trials between these agents with overlapping indications. Selecting which drug to use when there is more than one option may require an overall assessment of the value of each product. Managed care professionals, working in conjunction with oncology specialists, should evaluate these classes based on e cacy toxicity and cost of the individual products in order to arrive at a value-driven management approach.

Breast Cancer Pipeline Drug

Manufacturer

Route of Administration

Mechanism of Action

Anticipated Breast Cancer Setting

Status

pembrolizumab (KEYTRUDAÂŽ)

Merck & Co.

PD-1 inhibitor

triple-negative breast cancer

pending ( / /

margetuximab (MGAH22)

MacroGenics

anti-HER2 antibody

metastatic HER2+

pending (Q4 2020)

Source: IPD Analytics

32 | Magellan Rx Report | Fall 2020

)

References 1.

McGrail, Samantha. “Cost of Cancer Care Reaches Nearly $150B Nationally.” HealthPayerIntelligence an https://www healthpayerintelligence com/news/cost-of-cancer-care-reachesnearly-150b-nationally.

“Magellan Rx Management Medical Pharmacy Trend Report™ 2019 Tenth Edition.” Magellan Rx Management https://www issuu com/magellanrx/docs/mptr fr=sMmE M MDI w

“Lung Cancer - Non-Small Cell - Statistics.” Cancer.Net, 28 May 2020, https://www cancer net/cancer-types/lung-cancer-non-small-cell/ statistics.

“Biomarker Testing.” LUNGevity Foundation an lungevity org/for-patients-caregivers/lung-cancerlung-cancer/biomar er-testing

“Targeted Drug Therapy for Non-Small Cell Lung Cancer.” American Cancer Society Sept https://www cancer org/cancer/lungcancer/treating-non-small-cell/targeted-therapies html

“Immunotherapy for Non-Small Cell Lung Cancer.” American Cancer Society May https://www cancer org/cancer/lung-cancer/ treating-non-small-cell/immunotherapy html

“Roche Announces FDA Approval of Gavreto (Prasletinib) for the Treatment of Adults with Metastatic RET Fusion-Positive Non-Small Cell Lung Cancer.” Roche Sept https://www roche com/ media/releases/med-cor- - htm

https://www /diagnosing-

“FDA Approves First Targeted Therapy to Treat Aggressive Form of Lung Cancer.” U.S Food and Drug Administration May https:// www fda gov/news-events/press-announcements/fda-approves-firsttargeted-therapy-treat-aggressive-form-lung-cancer. Ettinger, D.S. et al. “National Comprehensive Cancer Network (NCCN) clinical practice guidelines in oncology. Non-small cell lung cancer.” National Comprehensive Cancer Network Sept https://www nccn org/professionals/physician gls/pdf/nscl pdf

10. “FDA Approves First Therapy for Patients with Lung and Thyroid Cancers with a Certain Genetic Mutation or Fusion.” U.S. Food and Drug Administration May https://www fda gov/news-events/ press-announcements/fda-approves-first-therapy-patients-lung-andthyroid-cancers-certain-genetic-mutation-or-fusion. 11.

FDA approves atezolizumab for first-line treatment of metastatic NSCLC with high PD-L1 expression.” U.S. Food and Drug Administration May https://www fda gov/drugs/resourcesinformation-approved-drugs/fda-approves-atezolizumab-first-linetreatment-metastatic-nsclc-high-pd-l1-expression.

12. “FDA approves brigatinib for ALK-positive metastatic NSCLC.” U.S. Food and Drug Administration May https://www fda gov/ drugs/drug-approvals-and-databases/fda-approves-brigatinib-al positive-metastatic-nsclc.

13. “FDA approves nivolumab plus ipilimumab and chemotherapy for first-line treatment of metastatic SCLC U.S. Food and Drug Administration May https://www fda gov/drugs/drugapprovals-and-databases/fda-approves-nivolumab-plus-ipilimumaband-chemotherapy-first-line-treatment-metastatic-nsclc 14.

FDA approves nivolumab plis ipilimumab for first-line m SCLC (PD-L tumor expression ) U.S. Food and Drug Administration, May https://www fda gov/drugs/drug-approvals-anddatabases/fda-approves-nivolumab-plus-ipilimumab-first-linemnsclc-pd-l1-tumor-expression-1.

15.

FDA approves ramucirumab plus erlotinib for first-line metastatic NSCLC.” U.S. Food and Drug Administration une https:// www fda gov/drugs/drug-approvals-and-databases/fda-approvesramucirumab-plus-erlotinib-first-line-metastatic-nsclc

16.

illmurray Conor Pemfexy Approval for Advanced/Metastatic onsquamous SCLC Could Offer Price Alternative Cure Today, 17 Feb https://www curetoday com/view/pemfexy-approvalfor-advancedmetastatic-nonsquamous-nsclc-could-offer-pricealternative.

17. “U.S. Breast Cancer Statistics.” Breastcancer.org, 25 June 2020, https://www breastcancer org/symptoms/understand bc/statistics 18. Jaggar, Karuna. “SABCS 2019: Spending, Cost, and ‘Value’ of Breast Cancer Treatments.” Breast Cancer Action Dec https:// www bcaction org/ / / /spending-cost-and-value-of-breastcancer-treatments/ 19. “Breast Cancer Facts & Figures 2019-2020.” American Cancer Society, https://www cancer org/content/dam/cancer-org/research/ cancer-facts-and-statistics/breast-cancer-facts-and-figures/breastcancer-facts-and-figurespdf 20. Melillo, Gianna. “FDA Approves Trodelvy for Metastatic TripleNegative Breast Cancer.” American Journal of Managed Care, 22 Apr https://www ajmc com/view/fda-approves-trodelvy-formetastatic-triplenegative-breast-cancer. 21. “FDA Approves First New Drug Under International Collaboration, A Treatment Option for Patients With HER2-Positive Metastatic Breast Cancer.” U.S. Food and Drug Administration Apr https:// www fda gov/news-events/press-announcements/fda-approvesfirst-new-drug-under-international-collaboration-treatment-optionpatients-her2. 22. “FDA Approves Neratinib for Metastatic HER2-Positive Breast Cancer.” U.S. Food and Drug Administration Feb https://www fda gov/drugs/resources-information-approved-drugs/fda-approvesneratinib-metastatic-her2-positive-breast-cancer.

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NOW APPROVED

Now available for TRICARE® patients

Proven to provide efficacy in infants, children, and adults with spinal muscular atrophy (SMA) IN TWO ONGOING PIVOTAL TRIALS, PARTICIPANTS WHO RECEIVED EVRYSDI EXPERIENCED BENEFITS IN MOTOR FUNCTION1*†

IN INFANTILE-ONSET SMA

IN LATER-ONSET SMA

• After 12 months of treatment with Evrysdi, 90% (19/21) of all infants were alive without permanent ventilation, and 81% (17/21) were alive without permanent ventilation at 23 months1‡ • At 12 months, 41% (7/17) of infants who received the recommended dosage of Evrysdi were able to sit without support for at least 5 seconds, as measured by Item 22 on the BSID-III gross motor scale§

Significant improvement in motor function with Evrysdi (n=115) from baseline at 12 months versus placebo (n=59) in children and adults, as measured by MFM-32 (1.55-point difference between the means; 95% CI: 0.30, 2.81; P=0.0156)1 • Evrysdi demonstrated a 1.36-point mean change from baseline (95% CI: 0.61, 2.11) versus a –0.19-point mean change from baseline for placebo (95% CI: –1.22, 0.84)1

(n=21; age range, 3-7 months for Part 1)

(n=180; age range, 2-25 years)

Learn more at www.Evrysdi-HCP.com/NowApproved BSID-III=Bayley Scales of Infant and Toddler Development-Third Edition; MFM-32=Motor Function Measure-32 items. *FIREFISH is a 2-part, multicenter, open-label trial to investigate the efficacy, safety, and tolerability of Evrysdi in infants between 2 and 7 months at the time of enrollment, diagnosed with Type 1 SMA. No data are available for patients under 2 months. Part 1 was a dose-finding portion in 21 infants; efficacy was established on the basis of achievement of a key motor milestone, as measured by the BSID-III gross motor scale, and on the basis of survival without permanent ventilation. Efficacy and safety were assessed at the 12-month time point, after which all infants were switched to the recommended dosage (0.2 mg/kg/day) and will continue to be monitored for an additional 12 months. †SUNFISH is a 2-part, multicenter trial to investigate the efficacy, safety, and tolerability of Evrysdi in children and adults between 2 and 25 years, diagnosed with Type 2 or Type 3 SMA. Part 2 was the randomized, double-blind, placebo-controlled portion in 180 nonambulatory patients with Type 2 (71%) or Type 3 (29%) SMA. Patients were randomized 2:1 to receive either Evrysdi at the recommended dosage or placebo. The primary efficacy endpoint was mean change from baseline in motor function as measured by MFM-32. ‡ Permanent ventilation was defined as requiring a tracheostomy or more than 21 consecutive days of either noninvasive ventilation (≥16 hours per day) or intubation, in the absence of an acute reversible event. § Results from the recommended-dosage cohort (n=17/21), which included patients whose dosage was adjusted to 0.2 mg/kg/day before 12 months of treatment.

Indication Evrysdi is indicated for the treatment of spinal muscular atrophy (SMA) in patients 2 months of age and older.

Important Safety Information Interactions with Substrates of MATE Transporters • Based on in vitro data, Evrysdi may increase plasma concentrations of drugs eliminated via MATE1 or MATE2-K, such as metformin • Avoid coadministration of Evrysdi with MATE (multidrug and toxin extrusion) substrates. If coadministration cannot be avoided, monitor for drug-related toxicities and consider dosage reduction of the coadministered drug if needed Pregnancy • In animal studies, administration of Evrysdi during pregnancy or throughout pregnancy and lactation resulted in adverse effects on development • Based on animal data, advise pregnant women of the potential risk to the fetus. Pregnancy testing is recommended for females of reproductive potential prior to initiating Evrysdi. Advise female patients of reproductive potential to use effective contraception during treatment with Evrysdi and for at least 1 month after the last dose Breastfeeding • There is no data on the presence of Evrysdi in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Evrysdi and any potential adverse effects on the breastfed infant

Potential Effects on Male Fertility • Male fertility may be compromised by treatment with Evrysdi. Counsel male patients on the potential effects on fertility. Male patients may consider sperm preservation prior to treatment Hepatic Impairment • The safety and efficacy of Evrysdi in patients with hepatic impairment have not been studied • Because Evrysdi is predominantly metabolized in the liver, hepatic impairment may potentially increase the exposures to Evrysdi. Avoid use of Evrysdi in patients with impaired hepatic function Most Common Adverse Reactions • The most common adverse reactions in later-onset SMA (incidence in at least 10% of patients treated with Evrysdi and more frequent than control) were fever, diarrhea, and rash • The most common adverse reactions in infantile-onset SMA were similar to those observed in later-onset SMA patients. Additionally, adverse reactions with an incidence of at least 10% were upper respiratory tract infection, pneumonia, constipation, and vomiting You may report side effects to the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Genentech at 1-888-835-2555. Please see Brief Summary of Prescribing Information on adjacent pages.

TRICARE is a registered trademark of the Department of Defense (DoD), DHA. All rights reserved. Reference: 1. Risdiplam (EVRYSDI™) Prescribing Information. South San Francisco, CA; Genentech, Inc; 2020. © 2020 Genentech USA, Inc. All rights reserved. Printed in USA. M-US-00006122(v1.0) 08/20

BRIEF SUMMARY OF PRESCRIBING INFORMATION EVRYSDI™ (risdiplam) for oral solution Initial U.S. Approval: 2020 This is a brief summary of information about EVRYSDI. Before prescribing, please see full Prescribing Information.

SMA patients treated with EVRYSDI in Study 1 were similar to those observed in later-onset SMA patients in Study 2. Additionally, the following adverse reactions were reported in ≥ 10% of patients: upper respiratory tract infection (including nasopharyngitis, rhinitis, respiratory tract infection), pneumonia, constipation, and vomiting.

1 INDICATIONS AND USAGE EVRYSDI is indicated for the treatment of spinal muscular atrophy (SMA) in patients 2 months of age and older.

7 7.1

4 CONTRAINDICATIONS None. 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice. In clinical trials including patients with infantile-onset SMA and later-onset SMA, a total of 337 patients (52% female, 72% Caucasian) were exposed to EVRYSDI for up to a maximum of 32 months, with 209 patients receiving treatment for more than 12 months. Forty-seven (14%) patients were 18 years and older, 74 (22%) were 12 years to less than 18 years, 154 (46%) were 2 years to less than 12 years, and 62 (18%) 2 months to less than 2 years. Clinical Trial in Later-Onset SMA The safety of EVRYSDI for later-onset SMA is based on data from a randomized, double-blinded, placebo-controlled study (Study 2 Part 2) in patients with SMA Type 2 or 3 (n = 180) [see Clinical Studies (14.2)]. The patient population in Study 2 Part 2 ranged in age from 2 to 25 years at the time of treatment start. The most common adverse reactions (reported in at least 10% of patients treated with EVRYSDI and at an incidence greater than on placebo) in Study 2 Part 2 were fever, diarrhea, and rash. Table 2 lists the adverse reactions that occurred in at least 5% of patients treated with EVRYSDI and at an incidence ≥ 5% greater than on placebo in Study 2 Part 2. Table 2 Adverse Reactions Reported in ≥ 5% of Patients Treated with EVRYSDI and with an Incidence ≥ 5% Greater Than on Placebo in Study 2 Part 2 Adverse Reaction

EVRYSDI (N = 120) % 22 17 17 7

Placebo (N = 60) % 17 8 2 0

Fever1 Diarrhea Rash2 Mouth and aphthous ulcers Arthralgia 5 0 Urinary tract infection3 5 0 1 Includes pyrexia and hyperpyrexia. 2 Includes rash, erythema, rash maculo-papular, rash erythematous, rash papular, dermatitis allergic, and folliculitis. 3 Includes urinary tract infection and cystitis. Clinical Trial in Infantile-Onset SMA The safety of EVRYSDI therapy for infantile-onset SMA is based on data from an open-label study in 62 patients (Study 1) [see Clinical Studies (14.1)]. In Study 1 Part 1 (n = 21) and Part 2 (n = 41), 62 patients received EVRYSDI for up to 30 months (31 patients for more than 12 months). The patient population ranged in age from 2 to 7 months at the time of treatment start (weight range 4.1 to 10.6 kg). The most frequent adverse reactions reported in infantile-onset

DRUG INTERACTIONS Effect of EVRYSDI on Substrates of Multidrug and Toxin Extrusion (MATE) Protein Transporters Based on in vitro data, EVRYSDI may increase plasma concentrations of drugs eliminated via MATE1 or MATE2-K [see Clinical Pharmacology (12.3)], such as metformin. Avoid coadministration of EVRYSDI with MATE substrates. If coadministration cannot be avoided, monitor for drug-related toxicities and consider dosage reduction of the coadministered drug (based on the labeling of that drug) if needed. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no adequate data on the developmental risk associated with the use of EVRYSDI in pregnant women. In animal studies, administration of risdiplam during pregnancy or throughout pregnancy and lactation resulted in adverse effects on development (embryofetal mortality, malformations, decreased fetal body weights, and reproductive impairment in offspring) at or above clinically relevant drug exposures [see Data]. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated background risk of major birth defect and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Based on animal data, advise pregnant women of the potential risk to the fetus. Data Animal Data Oral administration of risdiplam (0, 1, 3, or 7.5 mg/kg) to pregnant rats throughout organogenesis resulted in decreased fetal body weights and increased incidences of fetal structural variations at the highest dose tested, which was not associated with maternal toxicity. The no-effect level for adverse effects on embryofetal development (3 mg/kg/day) was associated with maternal plasma exposure (AUC) approximately 2 times that in humans at the maximum recommended human dose (MRHD) of 5 mg. Oral administration of risdiplam (0, 1, 4, or 12 mg/kg) to pregnant rabbits throughout organogenesis resulted in embryofetal mortality, fetal malformations (hydrocephaly), and structural variations at the highest dose tested, which was associated with maternal toxicity. The no-effect dose for adverse effects on embryofetal development (4 mg/kg/day) was associated with maternal plasma exposure (AUC) approximately 4 times that in humans at the MRHD. When risdiplam (0, 0.75, 1.5, or 3 mg/kg/day) was orally administered to rats throughout pregnancy and lactation, gestation was prolonged in the dams, and delayed sexual maturation (vaginal opening) and impaired reproductive function (decreased numbers of corpora lutea, implantation sites, and live embryos) were observed in female offspring at the highest dose. The noeffect dose for adverse effects on pre- and postnatal development in rats (1.5 mg/kg/day) was associated with maternal plasma exposure (AUC) similar to that in humans at the MRHD. 8.2 Lactation Risk Summary There are no data on the presence of risdiplam in human milk, the effects on the breastfed infant, or the effects on milk production. Risdiplam was excreted in the milk of lactating rats orally administered risdiplam.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for EVRYSDI and any potential adverse effects on the breastfed infant from EVRYSDI or from the underlying maternal condition. 8.3 Females and Males of Reproductive Potential Studies of risdiplam in juvenile and adult rats and in monkeys demonstrated adverse effects on the reproductive organs, including germ cells, in males at clinically-relevant plasma exposures [see Use in Specific Populations (8.4) and Nonclinical Toxicology (13.1)]. Pregnancy Testing Pregnancy testing is recommended for females of reproductive potential prior to initiating EVRYSDI [see Use in Specific Populations (8.1)]. Contraception EVRYSDI may cause embryofetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Female Patients Advise female patients of reproductive potential to use effective contraception during treatment with EVRYSDI and for at least 1 month after her last dose. Infertility Male Patients Male fertility may be compromised by treatment with EVRYSDI [see Nonclinical Toxicology (13.1)]. Counsel male patients of reproductive potential receiving EVRYSDI about the potential effects on fertility. Male patients may consider sperm preservation prior to treatment. 8.4 Pediatric Use The safety and effectiveness of EVRYSDI in pediatric patients ≥ 2 months of age have been established [see Clinical Studies (14)]. Safety has not been established in pediatric patients < 2 months of age. Juvenile Animal Toxicity Data Oral administration of risdiplam (0, 0.75, 1.5, 2.5 mg/day) to young rats from postnatal day (PND) 4 through PND 31 resulted in decreased growth (body weight, tibia length) and delayed sexual maturation in males at the mid and high dose. The skeletal and body weight deficits persisted after cessation of dosing. Ophthalmic changes consisting of vacuoles in the anterior vitreous were seen at the high dose. Decreases in absolute B lymphocyte counts were observed at all doses after cessation of dosing. Decreases in testis and epididymis weights, which correlated with degeneration of the seminiferous epithelium in the testis, occurred at the mid and high doses; the histopathology findings were reversible, but organ weight persisted after cessation of dosing. Impaired female reproductive performance (decreased mating index, fertility index, and conception rate) was observed at the high dose. A no-effect dose for adverse developmental effects on preweaning rats was not identified. The lowest dose tested (0.75 mg/kg/day) was associated with plasma exposures (AUC) lower than that in humans at the maximum recommended human dose (MRHD) of 5 mg/day. Oral administration of risdiplam (0, 1, 3, or 7.5 mg/day) to young rats from PND 22 through PND 112 produced a marked increase in micronuclei in the bone marrow, male reproductive organ

histopathology (degeneration/necrosis of the seminiferous tubule epithelium, oligo/aspermia in the epididymis, spermatic granulomas), and adverse effects on sperm parameters (decreased sperm concentration and motility, increased sperm morphology abnormalities) at the highest dose tested. Increases in T lymphocytes (total, helper, and cytotoxic) were observed at the mid and high doses. The reproductive and immune effects persisted after cessation of dosing. The no-effect dose (1 mg/kg/day) for adverse effects on postweaning juvenile rats was associated with plasma exposures (AUC) lower than that in humans at the MRHD. 8.5 Geriatric Use Clinical studies of EVRYSDI did not include patients aged 65 years and over to determine whether they respond differently from younger patients. 8.6 Hepatic Impairment The safety and efficacy of EVRYSDI in patients with hepatic impairment have not been studied. Because risdiplam is predominantly metabolized in the liver, hepatic impairment may potentially increase the exposures to risdiplam [see Clinical Pharmacology (12.3)]. Avoid use of EVRYSDI in patients with impaired hepatic function. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use). Pregnancy and Fetal Risk Inform pregnant women and women of reproductive potential that, based on animal studies, EVRYSDI may cause fetal harm [see Use in Specific Populations (8.1)]. Discuss with women of childbearing age whether they are pregnant, might be pregnant, or are trying to become pregnant. Advise women of childbearing potential to use effective contraception during treatment with EVRYSDI and for at least 1 month after stopping EVRYSDI. Advise a female patient to immediately inform the prescriber if she is pregnant or planning to become pregnant [see Use in Specific Populations (8.3)]. Potential Effects on Male Fertility Advise male patients that their fertility may be compromised while on treatment with EVRYSDI [see Use in Specific Populations (8.3)]. Instructions for Preparation of Oral Solution Advise patients to ensure that EVRYSDI is in liquid form when received from the pharmacy. Instruct patients/caregivers to take EVRYSDI after a meal or after breastfeeding at approximately the same time each day. However, instruct caregivers to not mix EVRYSDI with formula or milk. Instruct patients/caregivers to take EVRYSDI immediately after it is drawn up into the reusable oral syringe [see Dosage and Administration (2.1)].

EVRYSDI™ (risdiplam) Distributed by: Genentech, Inc. A Member of the Roche Group 1 DNA Way South San Francisco, CA 94080-4990

COVID-19 Vaccine Pipeline pdate Throughout the past few months, there have been several treatment and vaccine advances in the COVID-19 space, as medical professionals around the world learn more about the virus. The global healthcare ecosphere is facing unparalleled challenges and rapid advances due to the COVID- pandemic In late the world saw the first case of COVID- in uhan China Since then cases have surpassed approximately 48 million worldwide and deaths have surpassed 1.2 million. At the time of publication there were more than million confirmed cases and approximately deaths in the S

Maryam Tabatabai, Pharm.D. Senior Director, Drug Information Magellan Health Services

COVID- is caused by the novel severe acute respiratory syndrome (SARS) coronavirus- (SARS-CoV- ) which belongs to the family of coronaviruses. Coronaviruses can cause the common cold as well as serious respiratory illnesses such as SARS and Middle East respiratory syndrome (MERS) SARS-CoV- is thought to be primarily transmitted via respiratory droplets through person-to-person contact, particularly when in close proximity. Ongoing research seeks to better understand the ways that the virus can spread hile most cases occur four to five days after exposure the incubation period ranges from two to 14 days. A wide range of COVID-19 symptoms — including fever, cough, fatigue, shortness of breath, new loss of smell or taste, runny nose, and muscle pain — have been reported, and symptom severity varies from none to mild to severe. Advanced age and underlying chronic health conditions — including diabetes, obesity, and cardiovascular and pulmonary conditions — are risk factors for severe complications. Our nowledge of the virus and therapeutic advances are ever-evolving In May Magellan Rx Management published a bonus edition of the MRx Pipeline highlighting treatment and vaccine advances in the COVID-19 space.1 This report expands on that with available information about vaccines that is as up-todate as possible. Currently, there are no FDA-approved drugs or vaccines for COVID-19. As of ov there are vaccine candidates undergoing clinical evaluation ( able ) and preclinical candidates. For a list of the 155 preclinical candidates, as well as any additional up-to-date information, visit: https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidatevaccines.2

Visit us online at www.magellanrx.com | 37

I E PIPE I E UP A E | Continued

Important Developments and Dates to Watch Researchers and government agencies are wor ing tirelessly toward a safe and effective vaccine In October the ational Academies of Sciences Engineering and Medicine released their final COVID-19 vaccine equitable allocation framework, recommending four tiers of vaccine allocation priorities. he S Food and Drug Administration (FDA) panel held a meeting Oct at which the Center for Biologics Evaluation and Research s (CBER) Vaccines and Related Biological Products Advisory Committee (VRBPAC) discussed the development, authorization and/or licensure of vaccines to prevent COVID-19.4 he FDA briefing document outlining anticipated topics was released ahead of the October VRBPAC meeting 5 he FDAs CBER issued final COVID- vaccine guidance for emergency use authorization (E A) he agency plans to convene an open session of VRBPAC prior to any E A for a COVID- vaccine 6 he Advisory Committee on Immunization Practices (ACIP) plans to host an emergency meeting and vote on recommendations for use if and when the FDA announces a decision on a vaccine.

Figure 1. Standard Development Timeline

10-15 YEARS

EXPLORATORY

PRECLINICAL

CLINICAL DEVELOPMENT

REGULATORY REVIEW & APPROVAL

MANUFACTURING

QUALITY CONTROL

VACCINE

Table 1. COVID-19 Vaccine Pipeline: Candidates in Clinical Evaluation1 Developer/Manufacturer

Platform

Type of Candidate

Number of Doses

Timing of Doses

Route of Administration

Clinical Stage*

Sinovac

inactivated

0, 14 days

phase three

uhan Institute of Biological Products/ Sinopharm

inactivated

0, 21 days

phase three

Beijing Institute of Biological Products/ Sinopharm

inactivated

0, 21 days

phase three

38 Magellan Rx Report Fall

Developer/Manufacturer

Platform

Type of Candidate

Number of Doses

Timing of Doses

Route of Administration

Clinical Stage*

University of Oxford/AstraZeneca

non-replicating viral vector

ChAdOx -S

–

phase three

CanSino Biological Inc /Beijing Institute of Biotechnology

non-replicating viral vector

adenovirus Type 5 vector

–

phase three

amaleya Research Institute of Epidemiology and Microbiology

non-replicating viral vector

adeno-based (rAd26S rAd -S)

0, 21 days

phase three

non-replicating viral vector

0, 56 days

phase three

Novavax

protein subunit

full-length recombinant SARSCoV-2 glycoprotein nanoparticle vaccine adjuvanted Matrix-M™

0, 21 days

phase three

Moderna/ IAID

R A

L P-encapsulated mR A

0, 28 days

phase three

Bio

R A

0, 28 days

phase three

0, 28 or 0, 28, 56 days

phase two

anssen Pharmaceutical Companies

ech/Fosun Pharma/Pfizer

COVS

L P-mR As

Anhui Zhifei Longcom Biopharmaceutical/Institute of Microbiology Chinese Academy of Sciences

protein subunit

adjuvanted recombinant protein (RBD-dimer)

CureVac

R A

mR A

0, 28 days

phase two

Institute of Medical Biology Chinese Academy of Medical Sciences

inactivated

0, 28 days

phase one-two

Research Institute for Biological Safety Problems Republic of aza hstan

inactivated

0, 21 days

phase one-two

Inovio Pharmaceuticals/International Vaccine Institute

DNA

D A plasmid vaccine electroporation

0, 28 days

phase one-two

Osaka University/AnGes/Takara Bio

DNA

D A plasmid vaccine adjuvant

0, 14 days

phase one-two

Cadila Healthcare Limited

DNA

DNA plasmid vaccine

0, 28, 56 days

phase one-two

Genexine

DNA

D A vaccine ( X-

0, 28 days

phase one-two

Bharat Biotech

inactivated

whole-virion inactivated

0, 14 days

phase one-two

protein subunit

RBD-based

0, 21 days

phase one-two

protein subunit

S protein (baculovirus production)

0, 21 days

phase one-two

R A

mR A

–

phase one-two

VLP

RBD-HBsAg VLPs

0, 28 days

phase one-two

entuc y Bioprocessing Inc

Sanofi Pasteur/ laxoSmith line

Arcturus herapeutics/Du e-

SpyBiotech/Serum Institute of India

)

Visit us online at www.magellanrx.com | 39

I E PIPE I E UP A E | Continued

Developer/Manufacturer

Platform

Type of Candidate

Number of Doses

Timing of Doses

Route of Administration

Clinical Stage*

Beijing Minhai Biotechnology Co Ltd

inactivated

–

phase one-two

Israel Institute for Biological Research/ eizmann Institute of Science

replicating viral vector

VSV-S

–

phase onetwo

ImmunityBio Inc / ant west Inc

non-replicating viral vector

second-generation human adenovirus Type vector (hAd ) spi e (S) nucleocapsid ( )

0, 21 days

phase one

Rei hera/LE

non-replicating viral vector

replication-defective simian adenovirus ( RAd) encoding S

–

phase one

CanSino Biological Inc /Institute of Biotechnology Academy of Military Medical Sciences People s Liberation Army Academy of Military Science

non-replicating viral vector

Ad5-nCoV

0, 28 days

IM/mucosal

phase one

Vaxart

non-replicating viral vector

Ad5 adjuvanted oral vaccine platform

0, 28 days

oral

phase one

Ludwig-Maximilians- niversit t M nchen

non-replicating viral vector

MVA-SARS- -S

0, 28 days

phase one

Clover Biopharmaceuticals Inc./ laxoSmith line/Dynavax Technologies Corporation

protein subunit

native-like trimeric subunit spike protein vaccine

0, 21 days

phase one

Vaxine Pty Ltd /Medytox

protein subunit

recombinant spike protein with Advax™ adjuvant

–

phase one

protein subunit

molecular clamp stabilized spike protein with MF adjuvant

0, 28 days

phase one

Medigen Vaccine Biologics Corporation/NIAID/Dynavax Technologies Corporation

protein subunit

S- P protein 1018

0, 28 days

phase one

Instituto Finlay de Vacunas, Cuba

protein subunit

RBD

0, 28 days

phase one

Instituto Finlay de Vacunas, Cuba

protein subunit

rRBD produced in CHO-cell chemically conjugate to tetanus toxoid

0, 28 days

phase one

FBRI SRC VB VEC OR Rospotrebnadzor oltsovo

protein subunit

peptide

0, 21 days

phase one

est China Hospital Sichuan University

protein subunit

RBD (baculovirus production expressed in Sf cells)

0, 28 days

phase one

protein subunit

SARS-CoV- HLA-DR peptides

–

phase one

replicating viral vector

replication-competent VSV delivering SARSCoV-2 spike

–

phase one

OCARE/ nivercells

niversity of ueensland/CSL/Seqirus

niversity Hospital

Merc Sharp

bingen

Dohme/IAVI

40 Magellan Rx Report Fall

adjuvant

Developer/Manufacturer

Platform

Type of Candidate

Number of Doses

Timing of Doses

Route of Administration

Clinical Stage*

COVAXX/United Biomedical Inc. Asia

protein subunit

S -RBD-protein

0, 28 days

phase one

Institut Pasteur/ hemis/ niversity of Pittsburgh CVR/Merc Sharp Dohme

replicating viral vector

measles-vector-based

1 or 2

0, 28 days

phase one

Beijing antai Biological Pharmacy/ Xiamen University

replicating viral vector

intranasal flu-based RBD

–

phase one

Imperial College London

R A

L P-nCoVsaR A

–

phase one

People s Liberation Army (PLA) Academy of Military Sciences/ alvax Biotech

R A

mR A

0, 14 or 0, 28 days

phase one

Medicago Inc

VLP

plant-derived VLP adjuvanted with laxoSmith line or Dynavax Technologies Corporation adjs.

0, 21 days

phase one

Symvivo

DNA

VSV-S

–

oral

phase one

Adapted from the World Health Organization (WHO) draft landscape document *Study phases may vary ID = intradermal; IM = intramuscular

ALL INFORMATION AND DATA PRESENTED ARE CURRENT AS OF NOV. 5, 2020.

References 1.

MRx Pipeline Bonus COVID- Edition Magellan Rx Management May covid fr=sZjgxZ E jI MjM

DRAF landscape of COVID- candidate vaccines World Health Organization landscape-of-covid-19-candidate-vaccines

https://issuu com/magellanrx/docs/mrx pipeline plus Sept

https://www who int/publications/m/item/draft-

Framewor for equitable allocation of COVID- vaccine National Academies of Sciences, Engineering, and Medicine, 2020, https://www.nap.edu/ catalog/25917/framework-for-equitable-allocation-of-covid-19-vaccine. 4.

Vaccines and related biological products advisory committee Oct meeting announcement U.S. Food and Drug Administration Sept 2020, https://www.fda.gov/advisory-committees/advisory-committee-calendar/vaccines-and-related-biological-products-advisory-committeeoctober-22-2020-meeting-announcement.

FDA briefing document: Vaccines and Related Biological Products Advisory Committee meeting U.S. Food and Drug Administration, 22 Oct. 2020, https://www fda gov/media/ /download

FDA in brief: FDA issues guidance on emergency use authorization for COVID- vaccines U.S. Food and Drug Administration, 6 Oct. 2020, https:// www fda gov/news-events/fda-brief/fda-brief-fda-issues-guidance-emergency-use-authorization-covid- -vaccines utm medium=email utm source=govdelivery

Advisory Committee on Immunizaton Practices notice of meeting and request for comment Federal Register Sept federalregister.gov/documents/2020/09/21/2020-20705/advisory-committee-on-immunization-practices-acip.

https://www

Visit us online at www.magellanrx.com | 41

Method Capability Spotlight: Virtual Mar et Research and Payer Insights One of the most popular solutions Magellan Method offers its clients is custom mar et research programs Method builds on its strong payer and pharma relationships to develop tailored payer insight discussions focusing on relevant timely topics Method bridges the gap giving pharma manufacturers access to diverse payer insights Due to long-standing relationships with payer clients the feedbac and insights gathered in these customized discussions are unbiased honest and actionable Additionally because Method gains insights about what matters most to payer clients the team is able to ta e the process a step further in designing tailored clinical programs and collaborations addressing specific payer challenges and concerns his customized platform can even be augmented with data insights from Method s rich medical and pharmacy claims database here appropriate these small focused payer discussions can lead to follow-up collaborations with payer clients and manufacturers in the form of clinical programs and educational initiatives

into groups of four to six managed care and payer executives Method is able to cover multiple relevant topics while gathering the valuable insights of all participants his new virtual discussion format has allowed the Method team to quic ly turn ey payer perspectives into valuable mar et research reports for pharmaceutical manufacturers his new virtual structure has improved Method mar et research offerings to allow for faster delivery and more e cient discussions Mar et research discussions held by Method in covered a range of hot topics including biosimilars digital therapeutics multiple sclerosis and autoimmune diseases

he Method team always wor s with pharma manufacturers to ensure that payer insight discussions are customized and specific to their needs In order to facilitate a panel discussion that is as productive as possible pre-panel surveys are sent out to participants in order to gauge their interest and nowledge of the subject matter at hand and to understand perspectives in a way that allows for a better guided discussion In the current unprecedented times when in-person meetings and conferences are not viable or safe Method has ta en this opportunity to develop a streamlined process for effective and productive virtual mar et research discussions Brea ing down larger groups

42 | Magellan Rx Report | Fall 2020

For more information on Method capabilities and offerings visit magellanrx.com/method

Magellan Method

AT MAGELLAN METHOD, we are uniquely qualiďŹ ed to solve

complex healthcare challenges. As a subsidiary of Magellan Health, a Fortune 500 company, we have access to a wide range of resources and expertise from across our PBM, Medicare, and behavioral health divisions. We leverage up-to-date healthcare data to implement solutions that transform how care is delivered. Our team of analytic experts partners with you to develop a customized solution that delivers results.

How can we put our Method to work for you? Payer & Provider Insights Implementation Within Health Plan Network

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VIEW OUR RESEARCH at magellanrx.com/read to see our insights in action!

Biosimilar pdate: Current Landscape and Impact After five years on the mar et biosimilars continue to show cost-savings opportunities for potential payers In the five years since the first one launched biosimilars have changed the landscape Currently the S Food and Drug Administration (FDA) has approved biosimilar products of which have launched spanning three therapeutic areas

Impact Across Categories As biosimilars became available in two of the top-spend medical benefit categories their impact on the mar et was much anticipated According to Magellan data in the autoimmune category Remicade® (infliximab) biosimilars Renflexis® and Inflectra® started gaining mar et share (Figure ) hile immunotherapy and gene therapy will continue to contribute to the high spend in the oncology category opportunities for savings are anticipated with biosimilar launches for Avastin® Herceptin® and Rituxan® he predicted negative trend in spend illustrates the impact of several biosimilars in the oncology-support category for long- and short-acting CSFs and ESAs gaining mar et share specifically eulasta® biosimilars such as Fulphila® and denyca® (Figure ) Biosimilars have impacted medical pharmacy strategy since entering the mar et in According to a Magellan-conducted survey of payer clients in summer of plans were reimbursing based on a maximum allowable cost (equivalent reimbursement

44 | Magellan Rx Report | Fall 2020

Figure 1. Health Plan Infliximab Market Share

100%

86% 80%

80% 56%

60%

44%

40%

20%

20% 0%

0% Q3 2017

14%

0% Q4 2017 Biosimilar

Q1 2018

Q2 2018

Q3 2018

Reference

Source: 2019 Magellan Rx Management internal data

for reference and biosimilar) and payers were planning to utilize the same formulary strategies including step therapy for oncology biosimilar products

Magellan Oncology Biosimilar Solution Data has shown that adopting a comprehensive utilization management solution helps payers shift to lower-cost biosimilars Initial results from a Magellan oncology biosimilar solution illustrate

after Dec were excluded from the analysis Payer clients either chose to implement step therapy for all patients who had not previously received the reference products or chose to manage oncology biosimilars at parity with reference products

Figure 2. Oncology Support Forecast Commercial

$10.18

Medicare

Medicaid

Pipeline

change

$9.90 $8.99

$9.20

$9.24

$9.33

-8%

In results presented at the Academy of Managed Care Pharmacy s annual meeting Magellan showed that payers equipped with proactive utilization management strategies for oncology biosimilars were able to capitalize on early utilization shifts to the less-expensive biosimilar products Specifically step therapy requirements increased the use of biosimilars and were implemented successfully with minimal disruption In payers who opted for step therapy requirements authorizations for biosimilars made up of approvals compared to of approvals among payers without step therapy requirements (Figure ) he data also indicates that some providers are proactively switching patients to oncology biosimilars even without step therapy requirements Longer-term follow-up and analysis may provide further insight into the true upta e in biosimilar use and cost-savings being achieved However these initial results show the savings potential payers can see with the launch of biosimilars as well as the value that utilization management and other solutions have in helping payers achieve optimal outcomes

2018

2019

2020

2021

2022

2023

Source: Magellan Rx Management Medical Pharmacy Trend Report 2020

proactive utilization management of oncology biosimilar drugs via step therapy Prior to the launch of these products Magellan created an oncology biosimilar action team to evaluate the impact of utilization management strategies he team researched clinical and business aspects related to oncology biosimilars and identified ey areas of focus to equip payer clients with a proactive management strategy hese ey areas of focus included biosimilar and reference product indication similarity and issues of interchangeability; cost-savings projections based on historical utilization; input from ey opinion leaders; manufacturer access strategies; and provider education and discernment of provider mar et dynamics Magellan developed an educational webinar for providers and wor ed with payers to identify their networ s target audiences he action team proactively drafted utilization management policies and payer clients reviewed them with their pharmacy and therapeutics committees prior to the biosimilar launches

Figure 3. Eﬀect on Biosimilar Use: Proportion of Requests by Product (All Authorizations)

9/1/2019–1/31/2020 90%

84.74% Absolute Diﬀerence 33.78% (p<0.0001)

60%

49.04% 50.96%

30%

15.26% 0% Step Therapy*

Percentage of Biosimilar Use

Oncology reference products and biosimilars included in this study were for bevacizumab (Avastin® Mvasi™) and trastuzumab (Herceptin® anjinti™) Any oncology biosimilar products launched

Parity Therapy

Percentage of Reference Product Use

Source: Magellan Rx Management internal data *Step therapy policy was limited to “new start” patients

Visit us online at www.magellanrx.com | 45

PI PE LI N E D RU G LIST

PIPELINE DRUG LIST

Name

Manufacturer

Clinical Use

Dosage Form

Approval Status

Expected FDA Approval

naloxone single-dose prefilled syringe

US WorldMeds

opioid overdose

505(b)(2) NDA

November 2020

viloxazine

Supernus

ADHD

oral

NDA

11/06/2020

amphetamine (immediate-release, tamper-resistant)

Arbor Pharmaceuticals

ADHD (adults, pediatrics)

oral

NDA

11/13/2020

olanzapine/samidorphan

Alkermes

bipolar disorder; schizophrenia

oral

NDA

11/13/2020

sutimlimab

Sanofi

cold agglutinin disease (CAD)

BLA; breakthrough therapy; orphan drug; priority review

11/13/2020

lisocabtagene maraleucel

Bristol Myers Squibb

diffuse large B-cell lymphoma (relapsed/ refractory)

BLA; breakthrough therapy; orphan drug; priority review

11/16/2020

lonafarnib

Eiger

Hutchinson-Gilford progeria syndrome (HGPS)

oral

NDA; breakthrough therapy; orphan drug; priority review

11/20/2020

mepolizumab (Nucala)

GlaxoSmithKline

hypereosinophilic syndrome (HES) (type 1)

sBLA; fast track; orphan drug; priority review

11/20/2020

pembrolizumab (KEYTRUDAÂŽ)

Merck & Co.

breast cancer (triplenegative, locally recurrent, unresectable or metastatic)

sBLA; breakthrough therapy; priority review

11/27/2020

setmelanotide

Rhythm

pro-opiomelanocortin deficiency obesity; leptin receptor deficiency obesity

sBLA; breakthrough therapy; orphan drug; priority review

11/27/2020

naxitamab

Y-mAbs Therapeutics

neuroblastoma (relapsed/refractory, high-risk)

BLA; breakthrough therapy; orphan drug; priority review

11/30/2020

inclisiran

The Medicines Company

dyslipidemia (for secondary prevention in patients with ASCVD or familial hypercholesterolemia)

NDA; orphan drug

December 2020

tanezumab

Pfizer

osteoarthritis pain

BLA; fast track

December 2020

tasimelteon (HetliozÂŽ)

Vanda

Smith-Magenis syndrome (SMS)

oral

sNDA; orphan drug; priority review

12/01/2020

berotralstat

BioCryst

hereditary angioedema (attack prevention)

oral

NDA; fast track; orphan drug

12/03/2020

46 | Magellan Rx Report | Fall 2020

PI PE LI N E D RU G LIST

PIPELINE DRUG LIST CONT.

Name

Manufacturer

Clinical Use

Dosage Form

Approval Status

Expected FDA Approval

lumasiran

Alnylam

hyperoxaluria

NDA; breakthrough therapy; orphan drug; priority review

12/07/2020

margetuximab

MacroGenics

breast cancer (HER2+)

BLA; fast track

12/18/2020

Amgen/Allergan

RA; indolent nonHodgkin’s lymphoma; chronic lymphocytic leukemia/small lymphocytic lymphoma; antineutrophil cytoplasmic antibodiesassociated vasculitis

BLA

12/18/2020

Roxadustat

AstraZeneca

anemia due to chronic renal failure (dialysisdependent and -independent)

oral

NDA

12/18/2020

relugolix

Myovant Sciences

prostate cancer (advanced)

oral

NDA; priority review

12/20/2020

ansofaxine

Luye Pharma Group

major depressive disorder

oral

NDA

12/25/2020

bevacizumab (biosimilar to Genentech’s Avastin®)

Mylan/Biocon

brain cancer; cervical cancer; colorectal cancer; NSCLC; ovarian cancer; renal cell cancer

BLA

12/25/2020

vibegron

Urovant Sciences

overactive bladder

oral

NDA

12/25/2020

eflornithine/sulindac

Mallinckrodt

familial adenomatous polyposis

oral

NDA; fast track; orphan drug

12/29/2020

arbaclofen

Osmotica Pharmaceuticals

multiple sclerosisassociated spasticity

oral

505(b)(2) NDA

12/29/2020

furosemide wearable pump

scPharmaceuticals

congestive heart failure

505(b)(2) NDA

12/30/2020

tirbanibulin

Almirall

actinic keratoses

topical

NDA

12/30/2020

golimumab (Simponi Aria®)

Janssen

juvenile RA

sBLA

January 2021

pegfilgrastim (biosimilar to Amgen’s Neulasta®)

Merck & Co./Fresenius

neutropenia/leukopenia

BLA

January 2021

vericiguat

Merck & Co.

chronic heart failure

oral

NDA; priority review

01/20/2021

rituximab (biosimilar to Genentech’s Rituxan®)

Visit us online at www.magellanrx.com | 47

PI PE LI N E D RU G LIST

PIPELINE DRUG LIST CONT.

Name

Manufacturer

Clinical Use

Dosage Form

Approval Status

Expected FDA Approval

voclosporin

Aurinia

lupus nephritis (LN)

oral

NDA; fast track; priority review

01/22/2021

pegunigalsidase alfa

Chiesi

Fabry disease

BLA; fast track

01/27/2021

tepotinib

Merck & Co.

NSCLC

oral

NDA; breakthrough therapy; priority review; real-time oncology review

February 2021

baricitinib (OlumiantÂŽ)

Eli Lilly

atopic dermatitis

oral

sNDA

February-April 2021

evinacumab

Regeneron

dyslipidemia/ hypercholesterolemia

BLA; breakthrough therapy; priority review

02/11/2021

trilaciclib

G1 Therapeutics

SCLC

NDA; breakthrough therapy; priority review

02/15/2021

umbralisib

TG Therapeutics

marginal zone lymphoma

oral

NDA; breakthrough therapy; orphan drug; priority review

02/15/2021

casimersen

Sarepta Therapeutics

DMD (exon 45 skipping)

NDA; accelerated approval; orphan drug; priority review

02/25/2021

melflufen

Oncopeptides

multiple myeloma (triple-class refractory)

NDA; orphan drug; priority review

02/26/2021

pralsetinib (GAVRETOâ&#x201E;˘)

Blueprint Medicines

thyroid cancer (RET fusion+)

oral

sNDA; breakthrough therapy; priority review; real-time oncology review

02/26/2021

udenafil

Allergan

congenital single ventricle heart disease (adolescents)

oral

NDA; orphan drug

02/26/2021

taurolidine/heparin/citrate

CorMedix

prevention of catheter-related sepsis (hemodialysis patients)

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

02/28/2021

paclitaxel

Athenex

breast cancer

oral

NDA; priority review

02/28/2021

ropeginterferon alfa-2b

PharmaEssentia

polycythemia vera (PV)

BLA; orphan drug

March-April 2021

cabotegravir/rilpivirine

GlaxoSmithKline

HIV-1 infection

NDA

03/01/2021

plasminogen (human)

Liminal

hypoplasminogenemia (HPG)

BLA; fast track; orphan drug

03/01/2021

48 | Magellan Rx Report | Fall 2020

PI PE LI N E D RU G LIST

PIPELINE DRUG LIST CONT.

Name

d-methylphenidate

Manufacturer

Clinical Use

Dosage Form

Approval Status

Expected FDA Approval

Corium

ADHD

oral

505(b)(2) NDA

03/02/2021

axicabtagene ciloleucel (YESCARTA®)

Gilead

follicular lymphoma (relapsed/refractory); marginal zone lymphoma (2+ prior systemic therapies)

sBLA; breakthrough therapy; orphan drug

03/04/2021

aducanumab

Biogen

Alzheimer’s disease

BLA; fast track; priority review

03/05/2021

daratumumab and hyaluronidasefihj (DARZALEX FASPRO™)

Janssen

amyloid light-chain amyloidosis

sBLA; real-time oncology review

03/10/2021

ponesimod

Janssen

multiple sclerosis (relapsing)

oral

NDA

03/18/2021

arimoclomol

Orphazyme

Niemann-Pick disease

oral

NDA; breakthrough therapy; fast track; orphan drug

03/19/2021

dasiglucagon

Zealand

hypoglycemia (diabetesrelated)

NDA; orphan drug

03/27/2021

idecabtagene vicleucel

Bristol Myers Squibb/ bluebird bio

multiple myeloma

BLA; breakthrough therapy; orphan drug

03/29/2021

pembrolizumab (KEYTRUDA®)

Merck & Co.

breast cancer (high-risk, early-stage)

sBLA; breakthrough therapy

03/29/2021

tivozanib

AVEO

renal cell cancer (relapsed/refractory)

oral

NDA

03/31/2021

Abbreviations: ADHD = attention deficit hyperactivity disorder; ASCVD = atherosclerotic cardiovascular disease; BLA = biologics license application; DMD = Duchenne muscular dystrophy; IM = intramuscular; IV = intravenous; NDA = new drug application; NSCLC = non-small cell lung cancer; RA = rheumatoid arthritis; sBLA = supplemental biologics license application; SC = subcutaneous; SCLC = small cell lung cancer; sNDA = supplemental new drug application

Visit us online at www.magellanrx.com | 49

A Comprehensive Approach to Long-Term Narcolepsy Management Is Important for Patients During Their Journey1-3 Studies show that patients with narcolepsy are more likely to have certain comorbid medical conditions than those without narcolepsy4-6,a Narcolepsy is associated with substantial medical and economic burden, which may include emergency room visits, hospital visits, and/or absenteeism7,8,a

For more information, contact your Jazz Account Manager or visit NarcolepsyLink.com. a Based on a retrospective analysis of 5 years (2006-2010) of US medical claims data from the Truven Health Analytics MarketScanÂŽ Research Databases to evaluate medical comorbidity patterns, healthcare utilization patterns, productivity, and associated costs in adults diagnosed with narcolepsy (identified by ICD-9 narcolepsy diagnosis codes) compared with controls without narcolepsy matched on age, gender, geographical region, and payer.4,7

References: 1. Thorpy M, Morse AM. Reducing the clinical and socioeconomic burden of narcolepsy by earlier diagnosis and effective treatment. Sleep Med Clin. 2017;12(1):61-71. 2. Morse AM. Narcolepsy in children and adults: a guide to improved recognition, diagnosis and management. Med Sci (Basel). 2019;7(12):E106. 3. Wise MS, Arand DL, Auger RR, Brooks SN, Watson NF. Treatment of narcolepsy and other hypersomnias of central origin. Sleep. 2007;30(12):1712-1727. 4. Black J, Reaven NL, Funk SE, et al. Medical comorbidity in narcolepsy: findings from the Burden of Narcolepsy Disease (BOND) study. Sleep Med. 2017;33:13-18. 5. Ohayon MM. Narcolepsy is complicated by high medical and psychiatric comorbidities: a comparison with the general population. Sleep Med. 2013;14(6):488-492. 6. Cohen A, Mandrekar J, St Louis EK, Silber MH, Kotagal S. Comorbidities in a community sample of narcolepsy. Sleep Med. 2018;43:14-18. 7. Black J, Reaven NL, Funk SE, et al. The Burden of Narcolepsy Disease (BOND) study: health-care utilization and cost findings. Sleep Med. 2014;15(5):522-529. 8. Thorpy MJ, Hiller G. The medical and economic burden of narcolepsy: implications for managed care. Am Health Drug Benefits. 2017;10(5):233-241. 9. Poli F, Plazzi G, Di Dalmazi G, et al. Body mass index-independent metabolic alterations in narcolepsy with cataplexy. Sleep. 2009;32(11):1491-1497.

US-SLE-2000470 Rev0820

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