2020 Fall Prime Therapeutics Report

Prime Therapeutics

Magellan Rx Report

MEDICAL AND PHARMACY BENEFIT MANAGEMENT

Hemophilia: Treatment Options and Gene Therapy

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 frst 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+

11,000+ patients treated with SMA worldwide4§

FDA=US Food and Drug Administration; SMA=spinal muscular atrophy.

*Includes clinical trial patients.

3,700+

3700+ adults with SMA treated worldwide4§

† Clinical studies of SPINRAZA did not include suffcient 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 frst 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

EARLY-ONSET SMA, TREATED WITH SPINRAZA

ASHLEY // AGE 7

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 frst 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-frst-drug-spinal-muscular-atrophy. Accessed August 26, 2020. 2. Biogen announces frst 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-frst-patient-treated-higher-dose-spinrazar. Accessed August 26, 2020. 3. SPINRAZA [Prescribing Information]. Cambridge, MA: Biogen. 4. Biogen, Data on fle.

Cambridge, MA 02142

1 INDICATIONS AND USAGE

SPINRAZA®

(nusinersen) injection, for intrathecal use

Brief Summary of Full Prescribing Information

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 Dosa e

The recommended dosage is 12 mg (5 mL) per administration.

Initiate SPINRAZA treatment ith loadin doses The frst three loadin doses should be administered at 1 -day intervals The th loadin 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.

Allo the SPINRAZA vial to arm to room temperature (25 F) prior to administration Do not use e ternal 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 e ternal flters is not required

Withdra 12 m (5 mL) of SPINRAZA from the sin le-dose vial into a syrin e 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 uid

• 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 s in here there are si ns of infection or in ammation [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 onduct quantitative spot urine protein testin (preferably usin a frst mornin urine specimen) at baseline and prior to each dose of SPINRAZA For urinary protein concentration reater than 0 2 L, consider repeat testin and further evaluation

6 ADVERSE REACTIONS

The following serious adverse reactions are described in detail in other sections of the labeling:

• Thrombocytopenia and Coagulation Abnormalities [see Warnings and Precautions (5.1)]

• 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 dru s and may not re ect 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 (appro imately days to 16 years of a e at frst dose) ith symptomatic SMA in a sham-controlled trial in infants ith 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 ( 5% vs 22%), s allo in or feedin diffculties (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)

12 mg1

Adverse Reactions

1 Loading doses followed by 12 mg (5 mL) once every 4 months

2 Includes adenovirus infection, bronchiolitis, bronchitis, bronchitis viral, corona virus infection, in uen a, lo er respiratory tract infection, lo er respiratory tract infection viral, lun infection, parain uen ae virus infection, pneumonia, pneumonia bacterial, pneumonia in uen al, pneumonia mora ella, pneumonia parain uen ae 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)

Adverse Reactions SPINRAZA 12 mg1

1 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 specifcity of the assay Additionally, the observed incidence of antibody (includin neutrali in antibody) positivity in an assay may be in uenced by several factors, includin assay methodolo y, sample handlin , timin of sample collection, concomitant medications, and underlyin disease For these reasons, comparison of the incidence of antibodies to nusinersen in the studies described belo ith 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-emer ent ADAs, of hich 5 ere transient,12 ere considered to be persistent Persistent as defned as havin one positive test follo ed by another one more than 100 days after the frst positive test In addition, persistent is also defned as havin one or more positive samples and no sample more than 100 days after the frst positive sample Transient as defned as havin one or more positive results and not confrmed to be persistent There are insuffcient data to evaluate an effect of ADAs on clinical response, adverse events, or the pharmaco inetic profle of nusinersen

6.3 Postmarketing Experience

The follo in adverse reactions have been identifed durin post-approval use of SPINRAZA ecause these reactions are reported voluntarily from a population of uncertain si e, it is not al ays possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Serious infections associated ith lumbar puncture, such as menin itis, have been observed Hydrocephalus, aseptic menin itis, 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 ris associated ith the use of SPINRAZA in pre nant omen When nusinersen as 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 miscarria e in clinically reco ni ed pre nancies is 2 to % and 15 to 20%, respectively The bac round ris of ma or birth defects and miscarriage for the indicated population is unknown.

Data

Animal Data

When nusinersen (0, , 10, or 25 m ) as 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 , 5 , or 1 2 m ) as administered to pre nant female mice by subcutaneous in ection every other day throughout organogenesis and continuing once every six days throughout the lactation period, adverse neurobehavioral effects (alterations in locomotor activity, learnin and memory defcits) ere observed hen offsprin ere tested after eanin 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 benefts of breastfeedin should be considered alon ith the mother 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)].

uvenile Animal To icity 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 hi h doses and acute, transient defcits in lo er spinal re e es at the hi h dose in each study In addition, possible neurobehavioral defcits ere observed on a learnin and memory test at the hi h dose in the 5 - ee mon ey 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 SF volume

8.5 Geriatric Use

linical studies of SPINRAZA did not include suffcient numbers of sub ects a ed 65 and over to determine hether 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. © Biogen 2016-2020

IN THIS ISSUE | Fall 2020

Published By

Magellan Rx Management

15950 N. 76th St. Scottsdale, AZ 85260

Tel: 401-344-1000

Fax: 401-619-5215 magellanrx.com

Editor Lindsay Speicher, J.D. Project Manager, Magellan Method lspeicher@magellanhealth.com 401-344-1105

Advertising, Sales and Distribution

Carole Kallas ckallas@magellanhealth.com 401-344-1132

The content of Magellan 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.

Contributors

Caroline Carney, M.D., M.Sc., FAPM, CPHQ CMO, Magellan Rx Management

Steve Cutts, Pharm.D. SVP, Market General Manager, MRx Specialty

Haita Makanji, Pharm.D. VP, Clinical Strategy and Innovation, Specialty

Misty Grefcz Director, Marketing

Joe Tavares SVP, Sales and Business Development, Specialty

Corrado Panno VP, Business Development, Magellan Method

Stacy Inman, Pharm.D. Senior Clinical Project Manager

Carole Kallas

Project Manager

Brian Kinsella, Esq. Senior Legal Counsel

Lilly Ackley VP, External Communications

Kristen Durocher Director, External Communications

Editorial Advisory Board

Mona M. Chitre, Pharm.D., CGP

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

Dennis Bourdette M.D., FAAN, FANA Chair and Roy and Eulalia Swank Family Research Professor, Department of Neurology, Oregon Health & Science University

Yousaf Ali M.D., FACR Chief, Division of Rheumatology, Mount Sinai West; 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 Ofcer, International Myeloma Foundation

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

Steve Marciniak, R.Ph.

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

Saira A. Jan, M.S., Pharm.D. Director of Pharmacy Strategy and Clinical Integration, Horizon BlueCross BlueShield of New Jersey

A NOTE FROM OUR 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, specifcally 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.

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

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 in u 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

SUBSCRIBE TODAY!

Stay on top of managed care trends and become a Magellan Rx Report subscriber. Email us at MagellanRxReport@magellanhealth.com to subscribe today. Magellan Rx Report provides pharmacy and medical management solutions for managed care executives and clinicians. We hope you enjoy the issue; thank you for reading.

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.

• 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.

Taskforce on Telehealth Policy Issues Final Report

Twenty-three of the nation’s leading healthcare experts released their muchanticipated fnal 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 fndings and recommendations. The taskforce posted the full report online for public review. Among highlights of the report s ey fndings and recommendations:

• 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.

• 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 e pand e orts to ensure access to broadband and technology infrastructure to promote equity and not exacerbate care disparities as healthcare digitally transforms.

• 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

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 enefciary 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

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

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 specifed types of drugs under Medicare Parts B and D.

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.

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.

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 e a day delay in the e ective date of the fnal rule, instead of the standard 60-day delay.

• 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.

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 e e ective until Jan 1, 2022, rather than the Jan. 1, 2021, statutory e ective date

Muscular Dystrophy and Spinal Muscular Atrophy: Treatment

Update

New gene therapies could give patients life-enhancing and -lengthening treatment options — a frst in this space

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

Magellan Rx Management

Scott McLelland,

Pharm.D. VP, Commercial and Specialty Programs

Florida Blue

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 y the specifc muscle groups a ected and further classifed y genotypes and phenotypes Signs and symptoms appear at di erent ages and vary in severity 2 Although muscular dystrophy can e hereditary, some patients may e the frst in their family to have the disease 2

The most common types of muscular dystrophy are:

•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 a ects in , to , new orns 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 f ers

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.

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 a ects appro imately 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 SMN protein, which is insufcient for spinal motor neurons’ survival.6 he di erent 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 difculties, and respiratory distress he life e pectancy for a type 1 SMA patient is typically less than two years.

• SMA type 2 presents etween 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 etween months of age and adulthood Individuals with type can stand and wal unassisted, ut progression of wea ness may cause increased difculty 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® de azacort 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 OND S eteplirsen in and V OND S golodirsen in 10, 11 In August, Viltepso (viltolarsen) received FDA approval. These therapies are approved for patients with specifc mutations of the dystrophin gene 10, 11

e a acort ®)

De azacort MF A A®) 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 de azacort mg g day, de azacort mg g day, or prednisone mg g day versus a place o All treatment groups saw signifcant muscle strength improvement after wee s compared with the place o group he most nota le di erence was that patients ta ing prednisone gained signifcantly more weight in comparison with oth de azacort groups and the place o 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 14

teplirsen OND S is an antisense oligonucleotide indicated for the treatment of DMD in patients with a confrmed mutation in the DMD gene amena le to e on s ipping 10 A trial assessing the efcacy of eteplirsen included male children with DMD ranging in age from to nrolled patients had confrmed DMD gene deletions correcta le y s ipping e on and were a le 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 place o for wee s reatment was

MUSCULAR DYSTROPHY AND SPINAL MUSCULAR ATROPHY |

Continued

open la el after wee , when place o patients switched to or mg g of eteplirsen fcacy was ased on the percentage of dystrophin positive f ers and the M results Biopsies performed at wee in the mg g eteplirsen group found that dystrophin positive f ers increased to of normal, while the place o group had no increase p Biopsies performed at wee found that dystrophin positive f ers 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 place o p

Golo ir en

Golodirsen V OND S is an antisense oligonucleotide indicated for the treatment of DMD in patients with a confrmed mutation in the DMD gene amena le to e on s ipping 11 A two part trial evaluated the efcacy of golodirsen Part one consisted of 12 patients randomized to receive either golodirsen n or a place o 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 fndings were consistent with those previously observed in pediatric patients with DMD he efcacy outcome assessed was the change in the mean percent normal dystrophin protein level from baseline At wee , dystrophin protein e pression signifcantly increased by about 16-fold from baseline, and the mean percent

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

iltolar en iltep o 16

Approved in August, viltolarsen is an antisense oligonucleotide indicated for the treatment of DMD in patients with a confrmed mutation in the DMD gene amena le to e on s ipping Findings from a 16-participant phase two clinical trial (of ages 4 to 9) showed signifcant drug induced dystrophin production in oth 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 confrm clinical eneft, showing that treatment with viltolarsen improves a patient’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 SPINRAZA® (nusinersen), an SMN2-directed antisense oligonucleotide.19

In May 2019, the FDA approved ZOLGENSMA® (onasemnogene a eparvovec ioi as the frst gene replacement therapy for SMA treatment Most recently, in August, the FDA approved vrysdi (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 efcacy 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 fnal analysis revealed that the percentage of patients with a motor milestone response in the nusinersen group was signifcantly 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 panded HFMS score at months of treatment 19, 22 This trial was also terminated early after positive fndings during the interim analysis.19, 22 The interim analysis revealed a least-squares mean increase in the HFMS score from aseline to month in the nusinersen group by 4 points and a decrease by -1.9 points in the control group, which correlates to a di erence of points etween groups confdence interval, to p 19, 22 he fnal analysis results were similar, with of the children in

the nusinersen group achieving an increase from baseline to month in the HFMS 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 G ®)

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 efcacy 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 a ility 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 a eparvovec ioi vg g 20 Interim results of this trial demonstrate that of patients did not re uire permanent ventilation by 14 months of age, and 47.6% of patients were a le 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 vr i

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 vrysdi , an SMN NA 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 fve 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 e ects associated with risdiplam were fever, diarrhea, rash, mouth ulcers, joint pain, and urinary tract infections.24 Side e ects 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

MUSCULAR

casimersen S P Sarepta Therapeutics antisense oligonucleotidepending (Q2 2021)

ataluren (Translarna) PTC Therapeutics

givinostat I F Italfarmaco SpA

edasalonexent (Edasa) Catabasis

inhibitor of premature protein translation termination phase three

histone deacetylase (HDAC) inhibitor

phase three

NF-kB inhibitor phase three

PF Pfzer gene therapy

phase three

pamrevluma FG FibroGen anti-CTGF antibody phase three

branaplam (LMI070) Novartis

S Scholar Rock latent myostatin precursor activation inhibitor types and phase two Drug

SMN2 RNA splice modulatortype 1

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 efcacy 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

phase one-two

criteria. As more treatment options for SMA and DMD come to the market, formulary management and preferred agents may ecome a focus Additionally in the SMA space specifcally, due to di erent mechanisms of action without clinical evidence of eneft, com ination therapies may e 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.

Table 1. DMD

Table 2. SMA

References

1. “Muscular Dystrophy.” Mayo Clinic, Mayo Foundation for Medical ducation and esearch, Jan , https www mayoclinic org diseases conditions muscular dystrophy symptoms causes syc

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

“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 duchenne and ec er muscular dystrophy defnition

4. “Spinal Muscular Atrophy.” Muscular Dystrophy Association, https www mda org disease spinal muscular atrophy

“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 disease education spinal muscular atrophy html

7. “Duchenne Muscular Dystrophy.” Muscular Dystrophy Association, https www mda org disease duchenne muscular dystrophy

Birn rant, David J 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

9. Birn rant, David J 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. ondys pac age insert Cam ridge, MA Sarepta herapeutics Inc July

11. Vyondys pac age insert Cam ridge, MA Sarepta herapeutics Inc; December 2019.

12. EMFLAZA® pac age insert South Plainfeld, NJ P C herapeutics Inc June

Griggs, o ert C et al fcacy and Safety of De azacort vs Prednisone and Placebo for Duchenne Muscular Dystrophy.” Neurology, vol , no , , pp , doi N

14. Mendell, Jerry et al teplirsen for the reatment of Duchenne Muscular Dystrophy.” Annals of Neurology, vol , no , pp , doi ana

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

16. Clemens, Paula et al Safety, olera ility, and fcacy of Viltolarsen in Boys with Duchenne Muscular Dystrophy Amenda le to on Skipping: A Phase 2 Randomized Clinical Trial.” JAMA Neurology, vol. , no , , pp , doi amaneurol

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 nmd

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 nmd

19. Spinraza® pac age insert Cam ridge, MA Biogen June

20. Zolgensma® pac age insert Bannoc urn, I Ave is July

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 ne moa

22. Mercuri, Eugenio, et al. “Nusinersen versus Sham Control in LaterOnset Spinal Muscular Atrophy.” New England Journal of Medicine, vol , no , , pp , doi N JMoa

Mendell, Jerry , et al Single Dose Gene eplacement herapy for Spinal Muscular Atrophy.” New England Journal of Medicine, vol , no , , pp , doi N JMoa

24. “FDA Approves Oral Treatment for Spinal Muscular Atrophy.” U.S. Food and Drug Administration, Aug , https www fda gov news events press announcements fda approves oral treatment spinal muscular-atrophy.

*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 ef cacy 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 Indications

ADVATE is a recombinant antihemophilic factor indicated for use in children and adults with hemophilia A (congenital factor VIII de ciency) 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.

DETAILED IMPORTANT RISK INFORMATION

CONTRAINDICATIONS

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

WARNINGS & PRECAUTIONS

Hypersensitivity Reactions

Allergic-type hypersensitivity reactions, including anaphylaxis, have been reported with ADVATE. Symptoms include dizziness, paresthesia, rash, ushing, 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

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.

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

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 le. 3. Grillberger L, Kreil TR, Nasr S, Reiter M. Emerging trends in plasma-free manufacturing of recombinant protein therapeutics expressed

ADVATE [Antihemophilic Factor (Recombinant)]

Lyophilized Powder for Reconstitution for Intravenous Inje ct ion

BRIEF SUMMARY: Consult the Full Pr escribing Information for complete product information.

INDICATIONS AND USAGE

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.

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.

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 (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 Adverse Reactions Number of Subjects Percent of Subjects

General Disorders and Administration Site Conditions Pyrexia 1106616

Nervous System Disorders Headache 1145613

Respiratory, Thoracic and Mediastinal Disorders Cough 865413

Infections and Infestations Nasopharyngitis724912

Musculoskeletal and Connective Tissue Disorders Arthralgia 49328

Gastrointestinal Disorders Vomiting 41317

Infections and Infestations Upper Respiratory Tract Infection 35297

Injury, Poisoning and Procedural Complications Limb Injury 56256

Respiratory, Thoracic and Mediastinal Disorders Nasal Congestion32256

Gastrointestinal Disorders Diarrhea 29246

Injury, Poisoning and Procedural Complications Procedural Pain26225

Respiratory, Thoracic and Mediastinal Disorders Oropharyngeal Pain 25225

Infections and Infestations Ear Infection30215

aAdverse 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.

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

Hypersensitivity a

Blood and lymphatic system disordersFactor VIII inhibition

Injection site reaction

Chills

General disorders and administration site conditions

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 benefts 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.

Fatigue/Malaise

Chest discomfort/pain

Decreased therapeutic effect

aThese 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 Gene herapy

ith several potential innovative gene therapies in the pipeline, ensuring patient access while alancing responsi le pricing will e a challenge for payers, manufacturers, and providers to con uer together

Anja Shaughnessey, Pharm.D., PRS, R.Ph. Senior Pharmacy Contract Consultant

Tufts Health Plan

Hemophilia is an lin ed genetic leeding disorder that a ects appro imately in , individuals, primarily men Previous estimates suggested that there were appro imately , people glo ally living with hemophilia however, a recently pu lished meta analysis suggests that there may e as many as , , men worldwide living with the disorder, including appro imately , in the U S ,

Hemophilia A and B are the disease s two predominant su types Associated with defciencies in coagulation factors VIII FVIII and I FI , respectively, they are caused y mutations in clotting factor genes esulting disruption in the clotting cascade may lead to spontaneous leeding or une plained, e cessive leeding from minor in uries or after surgical or dental procedures Hemophilia A, also called FVIII defciency or classic hemophilia, is the most common su type, accounting for appro imately to of cases ,

Disease severity often correlates with aseline clotting factor level Patients with to of normal levels have mild disease and may e perience severe leeding with ma or trauma or surgery however, spontaneous leeding is rare Patients with to of normal levels have moderate disease and may e perience occasional spontaneous leeding or prolonged leeding with minor trauma or surgery he most severe group of patients has less than of normal levels and may e perience spontaneous leeding into oints or muscles that occurs without an in ury or trauma Spontaneous leeding episodes typically a ect weight earing oints, including the nees and an les, and may ultimately lead to painful, de ilitating hemophilic arthropathy and resulting immo ility , Individuals with the most severe form of hemophilia also have increased ris for life threatening leeds, including intracranial hemorrhage o reduce the ris of mor idity and mortality, hemophilia is traditionally managed with e ogenous clotting factor concentrates CFCs to replace the patient s missing clotting factor, oth in the acute treatment setting and prophylactically

Overall, an average hemophilia patient incurs inpatient costs nine times higher than the average insured patient.

Some patients treated with CFC may develop inhi itors immunoglo ulin G anti odies that neutralize infused clotting factors In these patients, the anticipated recovery and half life of the CFC are severely diminished, leading to signifcantly higher clotting factor doses Inhi itors occur more commonly in hemophilia A, with a cumulative incidence of up to in patients with severe disease 7 he ris of developing inhi itors also increases with heightened e posure to e ogenous clotting factor In patients with severe hemophilia A, the median age at inhi itor 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 re uires indefnite treatment he cost of hemophilia therapy, which can e signifcant, varies from patient to patient ased on several factors, including severity of disease, presence of inhi itors, and fre uency of leeding events Compared to those without the disease, hemophilia patients use a signifcant amount of healthcare resources, as they re uire more ofce visits, hospitalizations, medical procedures, and la oratory 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 inhi itors, the average annual cost e ceeds million due to more aggressive treatment 9 he cost of clotting factor accounts for more than of the total healthcare e penditures for hemophilia patients Overall, an average hemophilia patient incurs inpatient costs nine times higher than the average insured patient Additionally, there are signifcant indirect costs associated with hemophilia, including lost productivity, a senteeism, disa ility, and reduced uality of life 9

Treatment Landscape

According to updated treatment guidelines from the orld Federation of Hemophilia FH , hemophilia patients need access

to a wide variety of hemostatic agents with diverse mechanisms the goal is to prevent and treat leeding episodes, allowing an active lifestyle and a uality of life compara le to nonhemophilic individuals he enefts of prophyla is with CFCs or nonfactor replacement agents are superior to those associated with episodic therapy he FH recommends regular, long term prophyla is as the standard of care in order to prevent hemarthrosis and other spontaneous and rea through leeding maintain musculos eletal health and promote uality of life for patients with severe phenotype hemophilia A or B hen prophyla is is not feasi le, episodic therapy is essential treatment for acute hemorrhages however, it will not prevent long term oint damage

he recommended treatment for patients with severe phenotype hemophilia A or B is replacement of clotting factor either standard or e tended half life with FVIII concentrate in hemophilia A and FI 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 ased on the safety and purity of the product, the ris of developing inhi itors, the half life of the product, and cost tended half life H products factor concentrate products with a longer half life allow for less fre uent 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 dou led for a small num er of patients with hemophilia A who switched from standard to H products

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.

leeding for patients with severe hemophilia A without inhi itors however, long term data on patient outcomes is needed

Competition to emicizuma may e on the horizon soon in the form of concizuma , a su cutaneous monoclonal anti ody targeting tissue factor pathway inhi itor In March , Novo Nordis suspended clinical trials of concizuma due to three cases of nonfatal throm otic 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 marstacima , another tissue factor pathway inhi itor, and ftusiran, a su cutaneously administered synthetic, dou le stranded si NA oligonucleotide that targets antithrom in III hese products will compete with traditional clotting factor concentrate products and novel therapies e pected to enter the mar et in the coming years

Aside from clotting factor placement, treatment options for hemophilia have een limited In Novem er , emicizuma wh H M IB A®, oche ecame the frst new nonfactor product for hemophilia to e approved y the U S Food and Drug Administration FDA in years , micizuma is a ispecifc factor I a and factor directed monoclonal anti ody administered as a su cutaneous in ection for routine prophyla is to prevent or reduce the occurrence of leeding episodes in adult and pediatric patients new orn and older with hemophilia A with or without inhi itors micizuma is designed to e used in place of e ogenous factor concentrate and ypassing agents however, FVIII products may continue to e used during the frst wee of therapy with emicizuma micizuma may e dosed wee ly, every two wee s, or every four wee s, ased on provider and patient preference Clinical trials demonstrated that treatment with emicizuma may signifcantly improve the prevention of leeding events in hemophilia A compared to standard of care e ogenous factor concentrate

micizuma o ers a novel approach to hemophilia treatment, ut it has a signifcant price tag As of , the wholesale ac uisition cost was appro imately , for the frst year of treatment, followed y , for each su se uent year this cost is ased on a pound patient, and cost can vary signifcantly ased on the patient s weight A review y the Institute for Clinical and conomic eview IC found treatment with emicizuma to e cost saving in patients with inhi itors ecause it may reduce the need for e ogenous factor concentrate, which can e very costly On Oct , IC released a report assessing emicizuma and a gene therapy According to the report, emicizuma provides compara le or even superior clinical enefts than prophylactic FVIII replacement therapy among adults with severe hemophilia A the report concluded that emicizuma is also cost saving The 2020 FH recommendations include prophyla is with emicizuma to prevent hemarthrosis, as well as spontaneous and rea through

Novel Therapy Pipeline

Gene 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 ena le their odies to manufacture and maintain a constant level of FVIII via a modifed virus which does not cause disease his could potentially reduce or eliminate leeds and the re uirement for multiple lifelong e ogenous factor replacement therapies ,

C ISP Cas is another novel treatment strategy that could potentially allow a patient s ody to produce its own lood clotting factor his type of treatment uses a piece of genetic material and enzyme that acts li e molecular scissors to repair the genetic error causing clotting factor defciency

ith the high annual cost of lifelong hemophilia treatment, the idea of a one time, curative therapy may e appealing for patients, providers, and health plans An analysis determined that hemophilia A gene therapy was cost e ective 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 uality ad usted life years A s compared to million per patient and A s for prophylactic therapy Gene therapy was found to e cost e ective unless initial costs e ceeded million per patient and were less than , per one A gained compared to prophyla is if initial costs were less than million per patient 9 However, current mar et pro ections indicate that the cost of gene therapy may e etween million and million, suggesting that they may not meet this cost e ectiveness threshold when they reach the mar et Below is a loo at some of the recent developments in gene therapies for hemophilia

DISEASES

Valoctocogene Roxaparvovec

Valoctocogene ro aparvovec BioMarin , an investigational adeno associated virus serotype AAV mediated gene therapy, was under FDA review, which delayed an anticipated August approval , It wor s y 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 e perienced a reduction in their mean annualized leed ing rate AB , and most patients no longer re uired prophylactic factor replacement therapy Also, in the frst year of treatment with valoctocogene ro aparvovec, of patients e perienced no leeds at all, compared to ust at enrollment However, the ef fcacy 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 G N r study of valoctocogene ro aparvovec had achieved prespecifed clinical criteria for regulatory review in the U S and urope As of May , , of patients enrolled in the study had achieved FVIII levels of at least IU d at to wee s Of the pa tients who had reached wee efore the April , , cuto , the estimated median AB was , and the estimated mean AB was , representing an reduction from aseline when patients were receiving standard of care prophyla is A Biologics icense

Application B A for valoctocogene ro aparvovec was accepted for priority review y the FDA in Fe ruary the FDA previ ously awarded oth the rea through therapy and orphan drug designations 22 In delaying approval, the FDA noted that more and longer term data is needed for confrmation In the Oct review, IC reported that valoctocogene ro aparvovec could e a more e ective and cost saving treatment however, further evidence will e needed

Etranacogene Dezaparvovec

tranacogene dezaparvovec uni ure is an investigational gene therapy consisting of a recom inant AAV viral vector carrying a gene cassette containing the FI Padua variant under the control of a liver specifc promoter In a phase two study, three adults with moderate to severe hemophilia B with low levels of pree isting neutralizing anti odies to AAV were given a single intra venous infusion of genome copies g 22 Si wee s after dosing, the mean FI activity was range, to and increased to at wee s range, to Fur thermore, two patients achieved sustained FI activity of During the wee period, all three patients achieved cessation of leeding and had no need for FI replacement therapy , At the wee mar , no patient in the study reported any leeding events, and all patients remained free of prophyla is after receiv ing etranacogene dezaparvovec

tranacogene dezaparvovec is currently eing studied in the ongo ing open la el, phase three HOP B trial, which enrolled patients with moderate to severe hemophilia B with or without pree isting neutralizing anti odies opline data from HOP B is e pected in Uni ure announced in Octo er that it e pects to su mit a Biologics icense Application for mar eting authorization of etranacogene dezaparvovec in he FDA has designated etranacogene dezaparvovec a rea through therapy approval is predicted for

Fidanacogene Elaparvovec

Fidanacogene elaparvovec Spar herapeutics Pfzer is an inves tigational ioengineered AAV vector utilizing a high activity F transgene for the treatment of hemophilia B , Similar to etra nacogene dezaparvovec, fdanacogene elaparvovec utilizes the Padua variant of FI , Phase one two data demonstrated a reduction in AB four wee s after treatment Of the patients enrolled, only one e perienced a leeding event four or more wee s post infusion hree patients who received an enhanced version of fdanacogene elaparvovec achieved FI activity of to at wee or more of follow up, Spar Pfzer reported , Phase three studies of fdanacogene elaparvovec are ongoing

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

Giroctocogene ftelparvovec

Giroctocogene ftelparvovec Pfzer Sangamo BioSciences comprises a recom inant AAV serotype AAV vector encoding the complementary deo yri onucleic acid for B domain deleted human FVIII Phase one two trial data presented in June demonstrated that all fve patients with severe hemophilia A who received the e vg g dose showed sustained FVIII activity levels, with a median of via chromogenic assay re ecting measurements up to wee s No patients e perienced leeding events or re uired FVIII infusions 29

TAK-754/TAK-74830

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 recom inant versions of adeno associated virus serotype AAV In Decem er , a eda released research at the American Society of Hematology meeting that oth 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 anti odies 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

Managed Care Implications

hile gene therapy has the potential to transform hemophilia treatment, the potential upfront costs associated with the one time infusions may e staggering In Fe ruary , BioMarin s C O suggested that valoctocogene ro aparvovec may cost etween million and million per patient, citing the potential cost savings compared to factor replacement therapy in the long term perts suggest that a hemophilia B gene therapy such as etranacogene dezaparvovec could e priced etween million and million per patient While the annual per patient cost of e ogenous replacement therapy is signifcant, the cost is more managea le for payers when spread out over time

Current strategies for replacement therapy management utilized y payers revolve around the personalization and optimization of therapy Appro imately of U 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 e perience needed to provide optimal care for hemophilia patients H Cs have a multidisciplinary team specializing in hemophilia to improve patient outcomes and uality of life y 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 een shown to reduce emergency department visits and avoid hospitalization In addition to H Cs, many specialty pharmacies o er a variety of clinical management and adherence programs to improve patient outcomes and reduce costs Almost of Medicaid

managed care plans re uire patients with hemophilia to fll their factor replacement therapy from a specialty pharmacy Studies have shown that case management programs through specialty pharmacies may yield signifcant 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 availa ility of e ective treatment options, such as factor replacement therapy, presents a uni ue challenge to payers It is a straightforward decision to provide a patient with a rare disease and no other treatment options access to a life saving gene therapy However, deciding etween lifelong factor replacement therapy and a one time, potentially curative gene therapy will prove to e more challenging Payers and providers will need to carefully identify the optimal candidates for gene therapy to ensure cost e ectiveness o truly understand cost e ectiveness, payers will need to understand the true cost of care for the various su groups of hemophilia patients, including those with inhi itors, those using factor replacement therapy, and those using other e isting therapies such as emicizuma a ing into account FDA approval roadness, clinical trial data, and the cost of care for certain su groups in their plan mem ership, payers may consider limiting access to certain groups who may not e appropriate candidates for gene therapy hese groups might include patients who are under age , have inhi itors, have mild or moderate disease, and may have anti odies to the gene therapy delivery vector

Another challenge is that the availa ility of hemophilia treatments may lead to payers eing more aggressive in their management approach and in leveraging discounts from manufacturers If the cost of gene therapy is too prohi itive for payers, it may e e cluded from plan formularies, which could have a cascading e ect in the mar et Because other treatments are availa le, the need for gene therapy may e less urgent, resulting in patients switching to a health plan that provides more favora le access, leading to une ual distri ution 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 re uire a drastically di erent approach IC and other groups have already ta en on the tas of determining the potential value and cost e ectiveness of gene therapy however, it is difcult to fully assess the value of gene therapy in hemophilia until we have more long term data descri ing the dura ility of the e ect

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 ased agreements with manufacturers Because response dura ility is of concern, value ased agreements may e designed to o er payer re ates if patients do not maintain efcacy to an agreed upon timepoint where therapy would e considered cost e ective Other endpoints that may e considered include hospitalizations and leeding events

Payers may also consider using healthcare reinsurance under a healthcare reinsurance system proposed y Novartis ma er of the novel, high cost CA therapy escarta® a ica tagene ciloleucel the high aggregate costs of cell and gene therapies would e redistri uted among a pool of multiple payers This type of cost sharing model may lessen the urden on individual payers and improve access to high cost therapies astly, as we see more gene therapies and other novel treatments enter the hemophilia mar et, there may e opportunities to leverage competing products for re ates y selecting a preferred product It will e 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 Guidelines for the Management of Hemophilia, rd dition Haemophilia, Aug , doi hae

Inserro, Allison Prevalence of Hemophilia orldwide Is riple hat of Previous stimates, New Study Says American Journal of Managed Care, Sept , https www a mc com view prevalence of hemophilia worldwide is triple that of previous estimates new study says

hat Is Hemophilia Centers for Disease Control and Prevention, July , https www cdc gov nc ddd hemophilia facts html Hemophilia Mayo Clinic, Mayo Foundation for Medical ducation and esearch, Aug , https www mayoclinic org diseases conditions hemophilia symptoms causes syc

Chen, Sheh i conomic Costs of Hemophilia and the Impact of Prophylactic reatment on Patient Management American Journal of Managed Care, Apr , https www a mc com view incorporating emerging innovation hemophilia a tailoring prophyla is management strategies managed care environment economic costs

sco ar, M A Health conomics in Haemophilia a eview from the Clinician s Perspective Haemophilia, vol , , pp , doi

Inhi itors and Hemophilia Centers for Disease Control and Prevention, Centers for Disease Control and Prevention, July , https www cdc gov nc ddd hemophilia inhi itors html

horat, e a et al Hemophilia Burden of Disease A Systematic eview of the Cost Utility iterature for Hemophilia Journal for Managed Care & Specialty Pharmacy, vol , no , July , pp , doi mcp

Machin, Nicoletta et al Gene herapy in Hemophilia A A Cost ectiveness Analysis Blood Advances, vol , no , , pp , doi loodadvances

he High Price of Hemophilia ASH Clinical News, Fe , https www ashclinicalnews org spotlight feature articles high price hemophilia

H M IB A® pac age insert South San Francisco, CA Genentech, Inc

FDA Approves Genentech s Hemli ra micizuma wh for Hemophilia A ithout Factor VIII Inhi itors Genentech, Genentech, Oct , www gene com media press releases fda approves genentechs hemli ra emicizu

micizuma for Hemophilia A with Inhi itors ectiveness and Value Institute for Clinical and Economic Review, New ngland C PAC, Apr , https icer review org wp content uploads IC Hemophilia Final vidence eport pdf

Valoctocogene o aparvovec and micizuma for Hemophilia A without Inhi itors ectiveness and Value Institute for Clinical and Economic Review, New ngland C PAC, Oct , https icerreview org wpcontent uploads IC Hemophilia A vidence eport pdf

Adams, Ben Novo Nordis s Concizuma rials Can esume After Safety rial Halt FierceBiotech, Aug , https www ferce iotech com iotech novo nordis s concizuma trials can resume after safety trial halt

BMN Gene herapy for Hemophilia A BioMarin, https www iomarin com wp content uploads BMN Gene herapyInfographics pdf

Malcolm, mily Gene herapy Hemophilia News Today, https www hemophilianewstoday com gene therapy

Healthcare, Glo alData Uni ure s tranacogene Dezaparvovec in Haemophilia B Has perts Positive on Phase III Prospects Clinical Trials Arena, Jan , https www clinicaltrialsarena com comment uni ure etranacogene dezaparvovec

Valoctocogene o aparvovec and micizuma for Hemophilia A ectiveness and Value Institute for Clinical and Economic Review, New ngland C PAC, Jan , https icer review org wp content uploads IC Hemophilia A Draft Scoping Document pdf

aylor, Phil BioMarin Ups the Ante for Pivotal Haemophilia Gene herapy rial PMLive, PMGroup orldwide imited, May , http www pmlive com pharma news iomarin ups the ante for pivotal haemophilia gene therapy trial

BioMarin Announces hat Phase Cohort of Valoctocogene o aparvovec, Gene herapy Study in Severe Hemophilia A Met Pre Specifed Criteria for egulatory Su missions in the U S and urope BioMarin, May , https investors iomarin com BioMarin Announces that Phase Cohort of Valoctocogene o aparvovec Gene herapy Study in Severe Hemophilia A Met Pre Specifed Criteria for egulatory Su missions in the U S and urope

BioMarin s Biologics icense Application for Valoctocogene o aparvovec Accepted for Priority eview y FDA with eview Action Date of August , PR Newswire, Fe , https www prnewswire com news releases iomarins iologics license application for valoctocogene ro aparvovec accepted for priority review y fda with review action date of august html

Von Drygals i, Annette et al tranacogene Dezaparvovec AM Phase Normal near Normal FI Activity and Bleed Cessation in Hemophilia B Blood Advances, vol , no , , pp , doi loodadvances

Hemophilia Gene herapy uniQure, https www uni ure com gene therapy hemophilia php uni ure Announces One ear Follow Up Data from the Phase II Study of tranacogene Dezaparvovec and ong erm Follow Up Data for AM in Patients with Hemophilia B Euroland, uni ure, Dec , https www tools eurolandir com tools Pressreleases GetPress elease ID &lang en GB&companycode nl ure&v

Mel o, Alice FH SP educes Bleeding ates y in Hemophilia B Patients, Phase rial Shows Hemophilia News Today, June , https hemophilianewstoday com sp promotes sustained factor i increase hemophilia phase trial

Our Scientifc Platform and Programs Spark Therapeutics, https spar t com scientifc platform programs

Armstrong, Madeleine Uni ure urns the Screw on Spar and Pfzer Evaluate, Fe , https www evaluate com vantage articles news trial results uni ure turns screw spar and pfzer

Pfzer and Sangamo Announce Updated Phase esults Showing Sustained Factor VIII Activity evels and No Bleeding vents or Factor Usage in vg g Cohort Following Giroctocogene Fitelparvovec SB Gene herapy Pfzer, June , https www pfzer com news press release press release detail pfzer and sangamo announce updated phase results

Pena, Ana a eda Presents arly Data A out Improving fciency of Hemophilia A and B Gene herapy Hemophilia News Today, Dec , https hemophilianewstoday com ta eda presents early data a out improving efciency of hemophilia a and gene therapy

Dalton, Dan Hemophilia in the Managed Care Setting American Journal of Managed Care, Apr , https www a mc com view ace mar hemophilia dalton

Funding for Costly Ne t Gen herapies Is einsurance the Answer Pharmaceutical Technology, Jan , https www pharmaceutical technology com comment funding ne t 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.

Carly Rodriguez, Pharm.D. Pharmacy Director, Clinical Innovation

Moda Health

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

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 unclassifed 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 NSC C does not always cause early symptoms in those a ected, and symptoms may e 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, difculty swallowing, and swelling in the face and or veins in the nec NSC C can e 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

ONCOLOGY UPDATE |

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 NSC C patients to ensure that the most e ective 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 NSC C include PD PD inhi itors (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 verifcation and description of clinical eneft in a confrmatory trial In the study, pralsetini 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

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 AB C A , Novartis for the treatment of NSC C with specifc 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 e ects include interstitial lung disease or pneumonitis. According to the NCCN guidelines, either capmatinib (category 2A, preferred) or crizotini category A may e used as frst 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

gene alteration, which must e identifed via la oratory 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 e ects 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 frst line setting, regardless of PD 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 frst line setting for adults with metastatic NSC C 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 unaccepta le to icity esults showed statistically signifcant 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 e ects were fatigue or asthenia

Brigatinib (ALUNBRIG®)12

In May, the FDA approved brigatinib (ALUNBRIG®, ARIAD Pharmaceuticals as a frst 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 e ects 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 frst 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 signifcant eneft in median overall OS for those treated with the combination therapy (14.1 months) versus those on chemotherapy months he most common side e ects 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 ipiluma as frst line treatment for patients with metastatic NSC C whose tumors e press PD , with no GF 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 com ination treatment A trial demonstrated signifcant improvement in OS for patients with PD-L1 tumor expression receiving the com ination therapy compared to those treated with platinum-doublet chemotherapy (17.1 months vs. 14.9 months, respectively).14 Most common side e ects were fatigue, rash, decreased appetite, musculoskeletal pain, diarrhea colitis, dyspnea, cough, pruritis, nausea, and hepatitis

ONCOLOGY UPDATE |

NSCLC Pipeline

Drug Manufacturer

amivantamab Janssen Genma IV

cemiplimab-rwlc (LIBTAYO®) egeneron Sanof IV

tiragolumab (RG6058) oche Genentech IV

Source: IPD Analytics

anti-EGFR antibody; anti-c-MET antibody

PD-1 inhibitor

anti-TIGIT antibody

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 com ination with erlotini as a frst 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 place o 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 place o plus erlotini Side e ects reported y 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

Status

metastatic NSCLC with EGFR exon 20 insertion mutations phase three

PD-L1-positive advanced NSCLC phase three

PD-L1-positive metastatic NSCLC phase three

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 signifcant ris factors eing se 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

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 reast cancer cases in women in the U S the frst 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 e ective argeted therapies for mar ers other than H have become available for advanced-stage breast cancer; these include CD inhi itors, PA P inhi itors, and PI inhi itors 18

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.

New Breast Cancer Therapy Approvals

Sacituzumab govitecan-hziy (TRODELVY™)20

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 sacituzuma 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 e ects 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 verifcation and description of clinical eneft in confrmatory 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

ONCOLOGY UPDATE |

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 e ects caused y tucatinib included severe diarrhea associated with dehydration, acute kidney injury, and death.

Neratinib (Nerlynx®)22

In February, the FDA approved neratinib (Nerlynx®, 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 capecita ine 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 ased on the patient s tumor molecular profling, has advanced the treatment of many types of cancer. Certain diseases such as NSC C now have a variety of di erent targeta le 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 ased on efcacy, to icity, and cost of the individual products in order to arrive at a value-driven management approach.

Source:

References

1. McGrail, Samantha. “Cost of Cancer Care Reaches Nearly $150B Nationally.” HealthPayerIntelligence, Jan , https www healthpayerintelligence com news cost of cancer care reaches nearly-150b-nationally.

2. “Magellan Rx Management Medical Pharmacy Trend Report™ 2019 Tenth Edition.” Magellan Rx Management, , https www issuu com magellanr docs mptr fr sMm M MDI Nw

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

4. “Biomarker Testing.” LUNGevity Foundation, Jan , https www lungevity org for patients caregivers lung cancer diagnosing lung cancer iomar er testing

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

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

7. “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

8. “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 frst targeted-therapy-treat-aggressive-form-lung-cancer.

9. 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 frst therapy patients lung and thyroid-cancers-certain-genetic-mutation-or-fusion.

11. FDA approves atezolizuma for frst line treatment of metastatic NSCLC with high PD-L1 expression.” U.S. Food and Drug Administration, May , https www fda gov drugs resources information approved drugs fda approves atezolizuma frst line treatment-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 data ases fda approves rigatini al positive-metastatic-nsclc.

13. “FDA approves nivolumab plus ipilimumab and chemotherapy for frst line treatment of metastatic NSC C U.S. Food and Drug Administration, May , https www fda gov drugs drug approvals and data ases fda approves nivoluma plus ipilimuma and chemotherapy frst line treatment metastatic nsclc

14. FDA approves nivoluma plis ipilimuma for frst line mNSC C PD tumor e pression U.S. Food and Drug Administration, May , https www fda gov drugs drug approvals and data ases fda approves nivoluma plus ipilimuma frst line mnsclc-pd-l1-tumor-expression-1.

15. FDA approves ramuciruma plus erlotini for frst line metastatic NSCLC.” U.S. Food and Drug Administration, June , https www fda gov drugs drug approvals and data ases fda approves ramuciruma plus erlotini frst line metastatic nsclc

16. illmurray, Conor Pemfe y Approval for Advanced Metastatic Nons uamous NSC C Could O er Price Alternative Cure Today, 17 Fe , https www curetoday com view pemfe y approval for advancedmetastatic nons uamous nsclc could o er price alternative.

17. “U.S. Breast Cancer Statistics.” Breastcancer.org, 25 June 2020, https www reastcancer org symptoms understand c statistics

18. Jaggar, Karuna. “SABCS 2019: Spending, Cost, and ‘Value’ of Breast Cancer Treatments.” Breast Cancer Action, Dec , https www caction org spending cost and value of reast cancer treatments

19. “Breast Cancer Facts & Figures 2019-2020.” American Cancer Society, , https www cancer org content dam cancer org research cancer facts and statistics reast cancer facts and fgures reast cancer facts and fgures pdf

20. Melillo, Gianna. “FDA Approves Trodelvy for Metastatic TripleNegative Breast Cancer.” American Journal of Managed Care, 22 Apr , https www a mc com view fda approves trodelvy for metastatic-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 approves frst new drug under international colla oration treatment option patients-her2.

22. “FDA Approves Neratinib for Metastatic HER2-Positive Breast Cancer.” U.S. Food and Drug Administration, Fe , https www fda gov drugs resources information approved drugs fda approves neratinib-metastatic-her2-positive-breast-cancer.

NOW APPROVED Now available for TRICARE® patients

IN INFANTILE-ONSET SMA

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

• 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§

IN LATER-ONSET SMA

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

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 diference 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

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 e fcacy, 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; efcacy 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. Efcacy 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 e fcacy, 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 efcacy 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 efects 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 efective 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 efects on the breastfed infant, or the efects 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 efects on the breastfed infant

Potential Efects on Male Fertility

• Male fertility may be compromised by treatment with Evrysdi. Counsel male patients on the potential efects on fertility. Male patients may consider sperm preservation prior to treatment

Hepatic Impairment

• The safety and efcacy 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 efects to the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. You may also report side efects to Genentech at 1-888-835-2555.

Please see Brief Summary of Prescribing Information on adjacent pages.

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.

1 INDICATIONS AND USAGE

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

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

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.

7 DRUG INTERACTIONS

7.1 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.

Urinary tract infection3

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

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

EVRYSDI is a trademark of Genentech, Inc.

M-US-00006837(v1.0)

©2020 Genentech, Inc.

COVID-19 Vaccine Pipeline Update

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.

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

The global healthcare ecosphere is facing unparalleled challenges and rapid advances due to the COVID pandemic In late , the world saw the frst 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 pu lication, there were more than million confrmed cases and appro imately , deaths in the U S

COVID is caused y the novel severe acute respiratory syndrome SA S coronavirus SA S CoV , which belongs to the family of coronaviruses. Coronaviruses can cause the common cold as well as serious respiratory illnesses such as SA S and Middle ast respiratory syndrome M S SA S 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 fve days after e posure, the incu ation 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 Management pu lished a onus edition of the M 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 Nov , , there are vaccine candidates undergoing clinical evaluation a le 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

Important Developments and Dates to Watch

esearchers and government agencies are wor ing tirelessly toward a safe and e ective vaccine In Octo er, the National Academies of Sciences, ngineering, and Medicine released their fnal COVID-19 vaccine equitable allocation framework, recommending four tiers of vaccine allocation priorities. he U S Food and Drug Administration FDA panel held a meeting Oct , , at which the Center for Biologics valuation and esearch s CB Vaccines and elated Biological Products Advisory Committee V BPAC discussed the development, authorization and/or licensure of vaccines to prevent COVID-19.4 he FDA riefng document, outlining anticipated topics, was released ahead of the Octo er V BPAC meeting 5 he FDA s CB issued fnal COVID vaccine guidance for emergency use authorization UA he agency plans to convene an open session of V BPAC prior to any UA 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.

10-15 YEARS

EXPLORATORYPRECLINICAL

DEVELOPMENT

REGULATORY REVIEW & APPROVAL

Figure 1. Standard Development Timeline

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

Developer/ManufacturerPlatform

University of Oxford/AstraZeneca

CanSino Biological Inc Bei ing Institute of Biotechnology

Gamaleya esearch Institute of pidemiology and Micro iology

viral vector adeno-based (rAd26S rAd S

subunit full-length recom inant SA S CoV-2 glycoprotein nanoparticle vaccine ad uvanted Matri M

Anhui Zhifei Longcom Biopharmaceutical/Institute of Micro iology, Chinese Academy of Sciences

Institute for Biological Safety Pro

I 1 A I E PIPE I E UP A E |

Developer/ManufacturerPlatform

Bei ing Minhai Biotechnology Co td inactivated inactivated

Israel Institute for Biological esearch eizmann Institute of Science replicating viral vector VSV S

ImmunityBio Inc Nant west Inc non-replicating viral vector

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

ei hera U OCA Univercells non-replicating viral vector replication-defective simian adenovirus G Ad encoding S

CanSino Biological Inc Institute of Biotechnology, Academy of Military Medical Sciences, People s i eration Army Academy of Military Science

Vaxart

udwig Ma imilians Universit t M nchen

Clover Biopharmaceuticals Inc./ Gla oSmith line Dynava Technologies Corporation

Va ine Pty td Medyto

viral vector Ad5-nCoV

trimeric

subunit recombinant spike protein with Adva adjuvant

University of ueensland CS Se irus protein subunit

Medigen Vaccine Biologics Corporation/NIAID/Dynavax Technologies Corporation

Instituto Finlay de Vacunas, Cubaprotein subunit

Instituto Finlay de Vacunas, Cubaprotein subunit

FB I S C VB V C O , ospotre nadzor oltsovo

est China Hospital, Sichuan University

University Hospital ingen protein subunit

Merc Sharp & Dohme IAVI

viral vector

clamp stabilized spike protein with MF ad uvant

r BD produced in CHO-cell chemically conjugate to tetanus toxoid

phase onetwo

Developer/ManufacturerPlatform

Biomedical Inc.

Institut Pasteur hemis University of Pitts urgh CV Merc Sharp & Dohme

Bei ing antai Biological Pharmacy Xiamen University

Inc

derived V P adjuvanted with Gla oSmith line or Dynavax Technologies Corporation adjs.

Adapted from the World Health Organization (WHO) draft landscape document

phases may vary ID = intradermal; IM = intramuscular

1. M Pipeline Bonus COVID dition Magellan Rx Management, May , https issuu com magellanr docs mr pipeline plus covid fr s g N I M M

2. D AF landscape of COVID candidate vaccines World Health Organization, Sept , https www who int pu lications m item draft landscape-of-covid-19-candidate-vaccines

Framewor for e uita le 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 iological 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.

5. FDA riefng document Vaccines and elated Biological Products Advisory Committee meeting U.S. Food and Drug Administration, 22 Oct. 2020, https www fda gov media download

6. FDA in rief 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 rief fda rief fda issues guidance emergency use authorization covid vaccines utm medium email&utm source govdelivery

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

Method Capa ility Spotlight

Virtual Mar et esearch and Payer Insights

One of the most popular solutions Magellan Method o ers its clients is custom mar et research programs Method uilds on its strong payer and pharma relationships to develop tailored payer insight discussions focusing on relevant, timely topics Method ridges the gap, giving pharma manufacturers access to diverse payer insights Due to long standing relationships with payer clients, the feed ac and insights gathered in these customized discussions are un iased, honest, and actiona le Additionally, ecause Method gains insights a out what matters most to payer clients, the team is a le to ta e the process a step further in designing tailored clinical programs and colla orations addressing specifc payer challenges and concerns his customized platform can even e augmented with data insights from Method s rich medical and pharmacy claims data ase here appropriate, these small, focused payer discussions can lead to follow up colla orations with payer clients and manufacturers in the form of clinical programs and educational initiatives

he Method team always wor s with pharma manufacturers to ensure that payer insight discussions are customized and specifc to their needs In order to facilitate a panel discussion that is as productive as possi le, pre panel surveys are sent out to participants in order to gauge their interest and nowledge of the su ect matter at hand and to understand perspectives in a way that allows for a etter guided discussion

In the current unprecedented times, when in person meetings and conferences are not via le or safe, Method has ta en this opportunity to develop a streamlined process for e ective and productive virtual mar et research discussions Brea ing down larger groups

into groups of four to si managed care and payer e ecutives, Method is a le to cover multiple relevant topics while gathering the valua le insights of all participants his new virtual discussion format has allowed the Method team to uic ly turn ey payer perspectives into valua le mar et research reports for pharmaceutical manufacturers

his new virtual structure has improved Method mar et research o erings to allow for faster delivery and more efcient discussions Mar et research discussions held y Method in covered a range of hot topics, including iosimilars, digital therapeutics, multiple sclerosis, and autoimmune diseases

For more information on Method capa ilities and o erings, visit magellanrx.com/method

Magellan Method

AT MAGELLAN METHOD, we are uniquely qualified 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? Contact us at MagellanMethod@magellanhealth.com to

Biosimilar Update

Current andscape and Impact

After fve years on the mar et, iosimilars continue to show cost savings opportunities for potential payers

In the fve years since the frst one launched, iosimilars have changed the landscape Currently, the U S Food and Drug Administration FDA has approved iosimilar products, of which have launched, spanning three therapeutic areas

Impact Across Categories

As iosimilars ecame availa le in two of the top spend medical eneft categories, their impact on the mar et was much anticipated According to Magellan data, in the autoimmune category, emicade® in i ima iosimilars en e is® and In ectra® started gaining mar et share Figure

hile immunotherapy and gene therapy will continue to contriute to the high spend in the oncology category, opportunities for savings are anticipated with iosimilar launches for Avastin®, Herceptin®, and itu an® he predicted negative trend in spend illustrates the impact of several iosimilars in the oncology support category for long and short acting CSFs and SAs gaining mar et share specifcally Neulasta® iosimilars such as Fulphila® and Udenyca® 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 reim ursing ased on a ma imum allowa le cost e uivalent reim ursement

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

Magellan Oncology Biosimilar Solution

Data has shown that adopting a comprehensive utilization management solution helps payers shift to lower cost iosimilars Initial results from a Magellan oncology iosimilar solution illustrate

Figure 1. Health Plan Infiximab Market Share

Source: 2019 Magellan Rx Management internal data

Prior to the launch of these products, Magellan created an oncol ogy iosimilar action team to evaluate the impact of utilization management strategies he team researched clinical and usiness aspects related to oncology iosimilars and identifed ey areas of focus to e uip payer clients with a proactive management strategy hese ey areas of focus included iosimilar and reference product indication similarity and issues of interchangea ility cost savings pro ections ased on historical utilization input from ey opinion leaders manufacturer access strategies and provider education and discernment of provider mar et dynamics Magellan devel oped an educational we inar for providers and wor ed with payers to identify their networ s target audiences he action team pro actively drafted utilization management policies, and payer clients reviewed them with their pharmacy and therapeutics committees prior to the iosimilar launches

Oncology reference products and iosimilars included in this study were for evacizuma Avastin®, Mvasi and trastuzuma Herceptin®, an inti Any oncology iosimilar products launched

after Dec , , were e cluded 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 iosimilars at parity with reference products

In results presented at the Academy of Managed Care Pharmacy s annual meeting, Magellan showed that payers e uipped with proactive utilization management strategies for oncology iosimi lars were a le to capitalize on early utilization shifts to the less e pensive iosimilar products Specifcally, step therapy re uire ments increased the use of iosimilars and were implemented successfully with minimal disruption In payers who opted for step therapy re uirements, authorizations for iosimilars made up of approvals, compared to of approvals among payers with out step therapy re uirements Figure he data also indicates that some providers are proactively switching patients to oncology iosimilars even without step therapy re uirements

onger term follow up and analysis may provide further insight into the true upta e in iosimilar use and cost savings eing achieved However, these initial results show the savings potential payers can see with the launch of iosimilars as well as the value that utilization management and other solutions have in helping payers achieve optimal outcomes

Figure 2. Oncology Support Forecast

Source: Magellan Rx Management Medical Pharmacy Trend Report 2020

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

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

PIPELINE DRUG LIST

nalo one single dose preflled syringe

(immediate-release, tamper-resistant)

lisocabtagene maraleucel Bristol Myers Squibb

lonafarnib Eiger

mepolizumab (Nucala) GlaxoSmithKline

pembrolizumab (KEYTRUDA®)Merck & Co.

setmelanotide Rhythm

naxitamab Y-mAbs Therapeutics

inclisiran The Medicines Company

di use large B cell lymphoma (relapsed/ refractory)

Hutchinson-Gilford progeria syndrome (HGPS)

syndrome (HES) (type 1)

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

pro-opiomelanocortin defciency o esity leptin receptor defciency o esity

neuroblastoma (relapsed/refractory, high-risk)

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

sBLA; breakthrough therapy; priority review 11/27/2020

sBLA; breakthrough therapy; orphan drug; priority review 11/27/2020

NDA; orphan drug December 2020

tanezumab Pfzer osteoarthritis painIV BLA; fast track December 2020

tasimelteon (Hetlioz®) Vanda Smith-Magenis syndrome (SMS)

berotralstat BioCryst hereditary angioedema (attack prevention)

margetuximab

rituximab (biosimilar to Genentech’s Rituxan®) Amgen/Allergan

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

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

bevacizumab (biosimilar to Genentech’s Avastin®) Mylan/Biocon

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

e ornithine sulindac Mallinckrodt

adenomatous polyposis

(Simponi Aria®)Janssen

pegflgrastim iosimilar to Amgen’s Neulasta®)

vericiguat

taurolidine/heparin/citrateCorMedix

of catheter-related sepsis (hemodialysis patients)

plasminogen (human) Liminal

(HPG)

axicabtagene ciloleucel (YESCARTA®) Gilead follicular lymphoma (relapsed/refractory); marginal zone lymphoma (2+ prior systemic therapies)

daratumumab and hyaluronidasefh DA A FASP O Janssen amyloid light-chain amyloidosis

sclerosis (relapsing)

(diabetesrelated)

idecabtagene vicleucel Bristol Myers Squibb/ bluebird bio multiple myelomaIV

pembrolizumab (KEYTRUDA®)Merck & Co.

tivozanib AVEO

reviations

intramuscular; IV = intravenous; NDA = new drug application; NSCLC = non-small cell

cancer (high-risk, early-stage)

cell cancer (relapsed/refractory)

= rheumatoid

= supplemental

license

= subcutaneous; SCLC = small cell lung cancer; sNDA = supplemental new drug application

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.

aBased on a retrospective analysis of 5 years (2006-2010) of US medical claims data from the Truven Health Analytics MarketScan® Research Databases to evaluate medical comorbidity patterns, healthcare utilization patterns, productivity, and associated costs in adults diagnosed with narcolepsy (identifed 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: fndings 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 fndings. 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 Benefts. 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.