Autoimmune Diseases: Emerging Therapies and Management Strategies

Rare Liver Disease Managing Obesity: Multiple Gene Therapy: Magellan Rx Report Spring 2020 Spring Report Rx Magellan Update: Nonalcoholic Weight-Management Sclerosis: Therapy Changing Market Steatohepatitis Programs and Gaps Recommendations and Landscape and Pipeline in Strategies Treatment Advances Magellan Rx Report MEDICAL AND PHARMACY BENEFIT MANAGEMENT Spring 2020

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IN THIS ISSUE | Spring 2020

Managed Care Newsstand Gene Therapy: 4 30 Changing Market Landscape and Pipeline

Autoimmune Diseases: Rare Liver Disease Update: 6 Emerging Therapies and Management 36 Nonalcoholic Steatohepatitis Strategies

Multiple Sclerosis: Managing Obesity: 18 Therapy Recommendations and 45 Employer Weight-Management Programs Treatment Advances and Gaps in Strategies

Introducing MRx Navigate: Pipeline 26 Whole Patient Care Meets Digital Innovation 50

Published By Contributors Yousaf Ali M.D., FACR Magellan Rx Management Caroline Carney, M.D., M.Sc., FAPM, CPHQ Chief, Division of Rheumatology, Mount Sinai West; CMO, Magellan Rx Management Associate Professor of Medicine, Icahn School of Medicine at 15950 N. 76th St. Mount Sinai Scottsdale, AZ 85260 Steve Cutts, Pharm.D. SVP, Market General Manager, MRx Specialty Steven L. D’Amato, B.S.Pharm. Tel: 401-344-1000 Executive Director, New England Cancer Specialists Fax: 401-619-5215 Haita Makanji, Pharm.D. VP, Clinical Strategy and Innovation, Specialty Joseph Mikhael M.D., M.Ed., FRCPC, FACP magellanrx.com Chief Medical Officer, International Myeloma Foundation Misty Greficz Director, Marketing Natalie Tate, Pharm.D., MBA, BCPS Editor Vice President, Pharmacy Management, Joe Tavares BlueCross BlueShield of Tennessee Lindsay Speicher, J.D. SVP, Sales and Business Development, Specialty Project Manager, Magellan Method Steve Marciniak, R.Ph. [email protected] Corrado Panno Director II, Medical Benefit Drug Management, 401-344-1105 VP, Business Development, Magellan Method BlueCross BlueShield of Michigan Stacy Inman, Pharm.D. Saira A. Jan, M.S., Pharm.D. Advertising, Sales and Distribution Senior Clinical Project Manager Director of Pharmacy Strategy and Clinical Integration, Carole Kallas Horizon BlueCross BlueShield of New Jersey [email protected] Carole Kallas 401-344-1132 Project Manager Brian Kinsella, Esq. The content of Magellan RxTM Report — including text, graphics, Senior Legal Counsel images, and information obtained from third parties, licensors, and other material (“content”) — is for informational purposes Lilly Ackley only. The content is not intended to be a substitute for VP, External Communications professional medical advice, diagnosis, or treatment. Magellan RxTM Report does not verify any claims or other information Kristen Durocher appearing in any of the advertisements contained in the Director, External Communications publication and cannot take responsibility for any losses or other damages incurred by readers in reliance on such content. Editorial Advisory Board Developed by D Custom. Mona M. Chitre, Pharm.D., CGP Chief Pharmacy Officer & VP Clinical Analytics, Strategy & Innovation, Excellus BlueCross BlueShield

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

ISSN:2159-5372 10444M A NOTE FROM OUR CMO

Dear Managed Care Colleagues,

Welcome to our spring 2020 Other timely topics include the shifting landscape of gene issue of the Magellan Rx Report! therapy (page 30) and a new medical management program, MRx 2020 is off to an exciting and Navigate (page 26). fast-paced start. Already this year, 11 novel drugs have been No issue of the Magellan Rx Report would be complete without approved by the U.S. Food and our Managed Care Newsstand highlighting current hot topics Drug Administration (FDA), with (page 4). To learn more about Magellan Rx Management and our many more to come. Magellan Rx Management is committed support of the payer initiatives of the future, please feel free to to keeping our clients and partners informed by reporting up- contact us at [email protected]. As always, to-date managed care trends and offering valuable insight into we value any feedback you may have. I hope you enjoy the Report! anticipated drugs in our MRx Pipeline. Sincerely, This issue’s cover story (page 6) focuses on the current state of treatment, FDA approvals, and the pipeline for autoimmune diseases and associated implications for managed care. A second feature (page 18) discusses current treatment guidelines and therapy recommendations, advances in treatment, and pipeline therapies for multiple sclerosis. Caroline Carney, M.D., M.Sc., FAPM, CPHQ In the first installment of a new MRx Report series, this issue Chief Medical Officer also explores the importance of obesity management and Magellan Rx Management gaps in employer-sponsored weight management programs (page 45). The series will dive into the structure of an effective weight-management program and conclude with the results of an implemented, real-world, employer-sponsored weight- management program.

SUBSCRIBE TODAY! Stay on top of managed care trends and become a Magellan Rx™ Report subscriber. Email us at [email protected] 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.

Visit us online at www.magellanrx.com | 3 MANAGED passed 19-9 with all Democrats voting CARE in favor of the bill and nine Republicans NEWSSTAND on the Republican-led committee voting In February, against it. FDA Proposes Rule to Allow the Centers Importation of Prescription CMS Releases Advance Drugs for Medicare & Notice and Proposed Rule for Medicare Advantage The U.S. Food and Drug Administration Medicaid Services and Part D Programs (FDA) issued a proposed rule in Decem- issued its proposed ber seeking comments on a proposal to In February, the Centers for Medicare amend Section 804 of the Food, Drug, rule and Advance & Medicaid Services (CMS) issued its and Cosmetic Act that would allow the proposed rule and Advance Notice Part importation of prescription drugs from Notice Part II for II for changes to the Medicare Advantage Canada. President Trump has expressed (MA) and Part D programs. The proposed support for the notion as a way to reduce changes to the changes are expected to increase drug costs. States including Florida, Colo- payments in the MA program by 0.93% rado, Maine, and Vermont have expressed Medicare Advantage and in the Part D program by 2.85%. The interest in the proposal. PhRMA, the and Part D programs. proposed rule intends to do the following: trade association representing the drug- manufacturing industry, has expressed • Codify the SUPPORT Act, a recent law concern, calling the proposal a political dealing with opioids that requires move rather than a pragmatic policy solu- Part D plans to implement drug- tion. There are no estimates as to the pos- pricing index. The Congressional Budget management programs by 2022. sible savings under the rule, since it is un- Office (CBO) estimated that the bill • Amend network adequacy requirements. clear how many states might participate. would save more than $450 billion over • Prevent contracting with look-alike The FDA framed it as a proof-in-concept 10 years. The bill, HR3, passed 230- Dual-Eligible Special Needs Plans. proposal that could be expanded if suc- 192 with two Republicans in support • Allow individuals with end-stage cessful. The rule-making process is expect- and no Democrats in opposition. The renal disease to enroll in MA plans ed to take some time. White House stated it would veto the beginning in 2021, removing the bill if it reached the president’s desk. prohibition that has been in place The Senate majority leader stated that before the passage of the 21st House of Representatives the bill would not be brought up in the Century Cures Act. Passes Legislation to Require Senate. Senate leaders continue to push • Allow for a second “preferred” Government Negotiations of for their own drug-pricing legislation. specialty tier with lower cost-sharing High-Cost Drugs The Senate Finance Committee passed obligations. drug-pricing legislation in July that would • Call for real-time drug-pricing cost The U.S. House of Representatives limit Medicare drug-price increases to comparisons beginning in 2022. passed legislation in December that the inflation rate; CBO estimated 10- would require the federal government year savings at $100 billion. However, to negotiate payment rates for up to the bill has yet to reach the Senate floor. CREATES Act Included in Final 250 of the highest-priced drugs in the Many Republican senators oppose the End-of-Year Spending Bill U.S. that face little or no competition. bill, calling it government interference in Passed by Congress Negotiations would be based on an the marketplace. Senate majority leader international pricing index that averaged Mitch McConnell stated in February that President Trump reached an agreement the prices of drugs from six developed the bill faced “internal divisions” among with Congress in December on an end-of- countries (France, Canada, Germany, Republicans and would not likely move year spending bill for 2020. The federal UK, Japan, and Australia), with prices to a floor vote until those divisions government had been operating on a capped at 120% of the international could be overcome. The committee bill temporary spending bill since Oct. 1, the

4 | Magellan Rx Report | Spring 2020 start of the federal fiscal year. Included CMS Allows for States to • Ban spread pricing, or the shifting of in the package of tax and spending bills Shift to Block Grant the variability of risk from plans to was legislation titled the Creating and Funding for Medicaid pharmacy benefit managers (PBMs), Restoring Equal Access to Equivalent in both commercial and government Samples (CREATES) Act of 2019. This bill, In late January, the CMS announced op- markets, and instead require that all first introduced in 2016, prevents brand- tional demonstration authority for states contracts have passthrough pricing, name drug manufacturers from refusing to to shift their Medicaid program to a block meaning risk is borne by the plan sell samples to generic manufacturers in grant financing model, which the CMS re- sponsor and not the PBM. order to block the introduction of generic ferred to as the Healthy Adult Opportuni- • Require that all rebates and discounts alternatives and allows generic companies ty (HAO) program. While the CMS cannot be passed through to plan sponsors. to sue drug manufacturers for access to impose block grants on states, it invites • Require regular reporting to plan these samples. The legislation will help states to opt into a block grant or per cap- sponsors of all costs, fees, discounts, speed the introduction of generic drugs ita cap funding model as a demonstration and rebates associated with PBM to the marketplace and carries estimated project, also known as a waiver under Sec- contracts. savings of $3.8 billion to Medicare and tion 1115 of the Social Security Act. The The House Ways and Means Committee Medicaid programs over 10 years. demonstration would provide states with marked up surprise medical billing unprecedented flexibility to tailor their legislation in February that differs state Medicaid programs. Under the guid- significantly from the other committees’ FCC Approves 988 as ance, states could pursue an aggregate bills. Given that the significant policy Future Suicide Prevention cap or a per capita cap financing model for discrepancies reflect the differences in Hotline Number populations not eligible under their state insurers’ and hospital and provider groups’ plan. Under both financing approaches, views on how to address surprise medical In December, the Federal Communications states could design benefit packages (in- billing, it is not clear if the legislation will Commission (FCC) unanimously approved cluding drug formularies), cost-sharing pass this year. the creation of a three-digit suicide- requirements, and delivery care models prevention hotline — 988 — similar to within broad parameters. As part of the the current 911 emergency call system. program, and to ensure accountability, the SCOTUS to Hear PBM/ERISA Congress passed legislation in 2018 di- CMS would impose various monitoring, Case: Rutledge v. PCMA recting the FCC to examine the feasibility evaluation, and reporting requirements of establishing a nationwide hotline simon states. At this point, it is not clear if any On Jan. 10, 2020, the U.S. Supreme Court ilar to 911. The FCC approval begins the state will pursue block grant demonstra- announced that it will hear Rutledge process to establish the hotline, which will tion with the federal government. v. Pharmaceutical Care Management take an estimated 18 months. It will cost Association (PCMA). In 2015, Arkansas approximately $500 million in the first Language to Ban Spread enacted a MAC Transparency law that year of operation, with costs dropping to imposed new regulations on PBMs and under $200 million in year two. Approxi- Pricing in PBM Contracts their relationships with pharmacies. The mately 2.2 million people called the cur- Included in Surprise Medical PCMA filed suit challenging the Arkansas rent 10-digit suicide prevention lifeline in Billing Legislation statute preempted by the Employee 2018. Approximately 47,000 people died Retirement Income Security Act of 1974 of suicide in 2017, an increase of over In December, committee leaders in the (ERISA) and Medicare Part D plans. The 33% since 1999. Suicide rates have in- Senate HELP Committee and House Energy Supreme Court will hear the case in April; creased from 10.5 per 100,000 to 14 per and Commerce Committee announced an a decision is expected by the end of 100,000 over the past two decades. agreement on surprise medical billing June. ERISA has long enabled employers legislation that would limit costs to to provide consistent, nationwide consumers who seek care at an in-network healthcare benefits due to its preemption facility but are charged out-of-network of state laws. costs by providers who are not in-network within that facility. The legislation includes provisions that would:

Visit us online at www.magellanrx.com | 5

Autoimmune Diseases: Emerging Therapies and Management Strategies With millions of patients in need of effective treatments, there are several strategies around formulary management that managed care organizations can consider for managing the growing use and cost of biologics.

A primary function of the body’s immune system is to protect against foreign microorganisms, such as viruses or bacteria, to prevent infection and disease.1, 2 Under normal conditions, the immune system identifies these foreign invaders and produces antibodies or sensitized lymphocytes to target and destroy unhealthy cells.1 However, in individuals with an autoimmune disease, the immune system becomes unable to differentiate between normal cells and unhealthy cells and therefore targets and attacks healthy organs and tissues; the exact causes of this phenomenon are not fully understood.2

According to the American Autoimmune Related Diseases Association (AARDA), more than 100 autoimmune diseases have been identified to date.1 Furthermore, a 2016 report from PhRMA on medicines in development for autoimmune diseases highlights the fact that autoimmune disease affects more than Saira A. Jan, M.S., Pharm.D. 23.5 million Americans, with more than 75% of those individuals being women.2 Progress in under- Director, Enterprise standing potential developmental factors of autoimmune disease continues; current research suggests Pharmacy a genetic component and a higher incidence in women. Although the cause is unclear, environmental Horizon BlueCross BlueShield of New Jersey factors such as foods, chemicals, and physical trauma can also trigger the immune system to target and attack normal, healthy cells.1, 2

Here, we focus on rheumatoid arthritis, psoriasis, and inflammatory bowel disease — including both Crohn’s disease and ulcerative colitis — which are among the most common autoimmune diseases in the U.S., collectively affecting approximately 10 million individuals.3 These chronic conditions, all char- acterized by immune-mediated inflammation of unknown cause, are without cure. Affected individuals experience significant morbidity, reduced survival, and lower health-related quality of life compared to their healthy peers.3

Current State of Treatment

Generally, the primary goal of treatment in autoimmune disease is to control the patient’s symptoms by controlling the autoimmune reaction that caused the disorder.4 In many cases, proper drug

6 | Magellan Rx Report | Spring 2020 Table 1. FDA-Approved Targeted Immune Modulators*7-26

Rheumatoid Crohn’s Ulcerative Targeted Immune Modulator Psoriasis Arthritis Disease Colitis

TNFα Inhibitors

Adalimumab (Humira®, AbbVie) X X X X

Certolizumab pegol (Cimzia®, UCB) X X X –

Etanercept (Enbrel®, Amgen) X X – –

Golimumab (Simponi®, Simponi Aria®, Janssen) – X – X

Infliximab (Remicade®, Janssen) X X X X

CD20-Directed Cytolytic B-Cell Antibody

Rituximab (Rituxan®, Genentech/Biogen) – X – –

IL Inhibitors

Brodalumab (Siliq™, Bausch Health [formerly Valeant]) IL-17R inhibitor X – – –

Ixekizumab (Taltz®, Eli Lilly) IL-17A inhibitor X – – –

Guselkumab (Tremfya®, Janssen) IL-23 inhibitor X – – –

Risankizumab (Skyrizi™, AbbVie) IL-23 inhibitor X – – –

Sarilumab (Kevzara®, Sanofi/Regeneron) IL-6 inhibitor – X – –

Secukinumab (Cosentyx®, Novartis) IL-17A inhibitor X – – –

Tildrakizumab-asmn (Ilumya™, Merck) IL-23 inhibitor X – – –

Tocilizumab (Actemra®, Genentech) IL-6 inhibitor – X – –

Ustekinumab (Stelara®, Janssen) IL-12/23 inhibitor X – X X

Integrin Receptor Antagonist

Vedolizumab (Entyvio®, Takeda) – – X X

JAK Inhibitors

Baricitinib (Olumiant®, Eli Lilly) – X – –

Tofacitinib (Xeljanz®, Pfizer) – X – X

Upadacitinib (RinvoqTM, AbbVie) – X – –

T-Cell Costimulation Modulator

Abatacept (Orencia®, Bristol-Myers Squibb) – X – –

*Products may have additional indications not listed here. Abbreviations: IL=interleukin, JAK=Janus kinase, R=receptor, TNF=tumor necrosis factor

therapy may lead to symptom remission. Some commonly it is a gut-selective, anti-inflammatory treatment for inflammatory used medications include anti-inflammatory agents such as bowel diseases; evidence suggests targeted, organ-specific ther- corticosteroids, as well as nonsteroidal immunosuppressant agents apies may help patients avoid the adverse safety profiles associ- such as sirolimus, methotrexate, and cyclophosphamide.4 More re- ated with systemic therapeutics.5 Using a variety of mechanisms, cently, disease-modifying drugs such as etanercept, adalimumab, these targeted immune modulators (TIMs) inhibit signaling path- and infliximab have been used to stop inflammation and slow the ways, auto-reactive processes, or excessive protein production to damage in certain autoimmune diseases, including rheumatoid impact the inflammatory cascade in diseases such as rheumatoid arthritis.4 In even more recent advances, we see organ-specific arthritis.6 Many TIMs currently available in the U.S. have multiple therapies such as vedolizumab (Entyvio®), which is unique in that indications (Table 1).7-26

Visit us online at www.magellanrx.com | 7 AUTOIMMUNE DISEASES | Continued

Biosimilars in Autoimmune Treatment

In addition to the currently available branded TIM products, additional clinical trials may also hinder uptake and impact the the FDA has approved several biosimilars since 2016, with the perceptions of biosimilars for patients and prescribers alike. ultimate goal of improving access to care and potentially low- Patients may be comfortable with the process of receiving a ge- ering drug costs (Table 2).27 Although there are no interchange- neric small-molecule drug but may be confused or concerned able products approved, biosimilars may be approved for the by a biosimilar that has a different brand name than the prod- same indications as the reference product.27 There are current- uct with which they are familiar.41-43 Similarly, prescribers may ly 13 FDA-approved biosimilar TIMs; however, due to ongoing have more brand recognition of the originator product and may patent litigation, there are only three biosimilar TIMs on the more readily prescribe the originator product rather than look market.27-40 up brand names of new biosimilars with which they may not be familiar.41 The widespread uptake of biosimilars in the U.S. market presents many more challenges than patent litigation. Duplicating the manufacturing processes required for such complex bio- Recent FDA Approvals logical products is difficult, and the clinical trial requirement for approval of a biosimilar is significantly more complex than While the development of biosimilars continues to be an im- for a small-molecule generic.41-43 The fact that biosimilars may portant focus, several newly approved TIMs may offer advance- not be used interchangeably for the reference product without ments in the treatment of autoimmune disease.

Table 2. FDA-Approved Biosimilar Targeted Immune Modulators27

Biosimilar Name Approval Date Reference Product Market Status

Inflectra® (infliximab-dyyb) April 2016 Remicade® (infliximab) Available28

Erelzi® (etanercept-szzs) August 2016 Enbrel® (etanercept) Not yet available29

Amjevita™ (adalimumab-atto) September 2016 Humira® (adalimumab) Anticipated January 202330

Renflexis® (infliximab-abda) May 2017 Remicade® (infliximab) Available31

Cyltezo™ (adalimumab-adbm) August 2017 Humira® (adalimumab) Anticipated July 202332

Ixifi™ (infliximab-qbtx) December 2017 Remicade® (infliximab) Will not launch in U.S.33

Hyrimoz™ (adalimumab-adaz) October 2018 Humira® (adalimumab) Anticipated September 202334

Truxima® (rituximab-abbs) November 2018 Rituxan® (rituximab) Available35

Eticovo™ (etanercept-ykro) April 2019 Enbrel® (etanercept) TBD, pending patent litigation36

Ruxience™ (rituximab-pvvr) July 2019 Rituxan® (rituximab) Anticipated January 202037

Hadlima™ (adalimumab-bwwd) July 2019 Humira® (adalimumab) Anticipated June 202338

Abrilada™ (adalimumab-afzb) November 2019 Humira® (adalimumab) Anticipated 202339

Avsola™ (infliximab-axxq) December 2019 Remicade® (infliximab) TBD40

*Products may have additional indications not listed here.

8 | Magellan Rx Report | Spring 2020 Skyrizi™ (risankizumab-rzaa)

Skyrizi™ (risankizumab-rzaa) is an interleukin-23 (IL-23) inhibitor clinical trials achieved a 75% improvement in PASI (PASI 75) at that received FDA approval in April 2019 for the treatment of mod- week 12.16, 19, 45, 46 erate to severe plaque psoriasis in adults who are candidates for systemic therapy or phototherapy.16, 44 Risankizumab-rzaa is administered at a dose of 150 mg delivered in two subcutaneous Rinvoq™ (upadacitinib) injections every 12 weeks following two initial doses at weeks 0 and 4.44 The approval of risankizumab-rzaa was supported by In August 2019, the FDA approved RinvoqTM (upadacitinib), an oral the results from the global phase three program, which evalu- Janus kinase (JAK) inhibitor, for the treatment of moderate to se- ated the safety and efficacy of risankizumab-rzaa in adults with vere rheumatoid arthritis in adults who have had an inadequate moderate to severe plaque psoriasis across four randomized, con- response or intolerance to methotrexate.25, 47 The FDA approval of trolled trials that included either placebo or active-comparator upadacitinib was supported by data from the phase three regis- groups (ultIMMa-1, ultIMMa-2, IMMhance, and IMMvent).16, 44 The trational SELECT program, which is one of the largest clinical pro- co-primary efficacy endpoints across all studies were a 90% grams in rheumatoid arthritis, with 4,400 patients enrolled across improvement in the Psoriasis Area and Severity Index (PASI 90) the five studies.47 The studies evaluated the safety and efficacy of and static Physician Global Assessment (sPGA) score of clear or upadacitinib across a variety of patient populations, including almost clear (sPGA=0 or 1) at 16 weeks compared to placebo.16, 44 those who failed or were intolerant to biologic DMARDs and those who were naïve to or had an inadequate response to methotrexate, UltIMMA-1 Results:16, 44 although it is not indicated for methotrexate-naïve patients at this time. The SELECT program also evaluated whether patients treated » 75% of patients on risankizumab-rzaa achieved PASI 90 at with upadacitinib achieved clinical remission, defined as no dis- 16 weeks, compared with 5% of placebo patients (p<0.001). ease activity and symptoms, even without methotrexate.47 All pri- » 36% of patients on risankizumab-rzaa achieved PASI 100 at mary and ranked secondary endpoints were met across all SELECT 16 weeks, compared with 0% of placebo patients (p<0.001). phase three studies.25, 47 » 82% of patients on risankizumab-rzaa achieved PASI 90 and 56% achieved PASI 100 at 52 weeks (p<0.001). SELECT Results: » 88% of patients on risankizumab-rzaa who achieved PASI 90 at week 16 maintained the response at week 52, according » SELECT-EARLY: 52% of patients who were methotrexate-naïve to an integrated analysis of the two studies. and treated with upadacitinib achieved a 50% improvement in American College of Rheumatology score (ACR50), com- UltIMMA-2 Results:16, 44 pared with 28% of patients treated with methotrexate alone at week 12. » 75% of patients on risankizumab-rzaa achieved PASI 90 at » SELECT-MONOTHERAPY: 68% of patients who had an in- 16 weeks, compared to 2% of placebo patients (p<0.001). adequate response to methotrexate and were treated with » 51% of patients on risankizumab-rzaa achieved PASI 100 at upadacitinib achieved ACR20, compared with 41% of patients 16 weeks, compared with 2% of placebo patients (p<0.001). treated with methotrexate alone at week 14. » 81% of patients on risankizumab-rzaa achieved PASI 90 and » SELECT-COMPARE: Similar results were found in patients treat- 60% achieved PASI 100 at 52 weeks (p<0.001). ed with upadacitinib compared with those treated with place- » 80% of patients on risankizumab-rzaa who achieved PASI 90 bo plus methotrexate. 30% of patients achieved clinical remis- at week 16 maintained the response at week 52, according sion at week 12 with upadacitinib plus methotrexate and 41% to an integrated analysis of the two studies. achieved clinical remission at weeks 24 and 26. » SELECT-NEXT and SELECT-BEYOND: 64% of patients who had There are currently three IL-23 inhibitors on the market, in- an inadequate response to DMARD and 65% of patients who cluding Skyrizi™ (risankizumab-rzaa), Tremfya® (guselkumab), had an inadequate response to the biologic, respectively, went and Ilumya™ (tildrakizumab-asmn).15, 16, 19 While a lack of on to achieve ACR20 with upadacitinib treatment. head-to-head clinical trials precludes direct comparisons between products, 73% of patients treated with guselkumab There are currently three JAK inhibitors on the market, including in clinical trials achieved PASI 90 at week 16, and 61% Rinvoq™ (upadacitinib), Olumiant™ (baricitinib), and Xeljanz® to 64% of patients treated with tildrakizumab-asmn in (tofacitinib).23-25 While a lack of head-to-head clinical trials and

Visit us online at www.magellanrx.com | 9 AUTOIMMUNE DISEASES | Continued

interferons are implicated in the inflammatory pathways, and between 60% and 80% of adults with SLE have an increased type I The National Institutes of Health interferon gene signature, which correlates with disease activity.50 have estimated the annual direct The safety and efficacy of anifrolumab in SLE are being evaluated in the pivotal TULIP clinical program, which consists of two phase healthcare costs for autoimmune three trials, TULIP 1 and TULIP 2.50 Both trials enrolled patients with moderately to severely active autoantibody-positive SLE who were disease at approximately $100 receiving standard of care treatment.50 In September 2018, top- line data from TULIP-1 was announced, indicating that the primary billion. Since this estimate was endpoint was not met, failing to achieve a statistically significant reported nearly five years ago, reduction in disease activity in patients with SLE, as measured by the SLE Responder Index 4 at 12 months.51 movement and advances in the In TULIP-2 (N=373), patients were randomized to a fixed-dose in- autoimmune space have likely travenous infusion of anifrolumab 300 mg or placebo every four weeks for 48 weeks.52 The primary endpoint was the British Isles led to an increase in direct Lupus Assessment Group (BILAG)-based Composite Lupus Assess- ment (BICLA) response at week 52. BICLA response requires reduc- healthcare costs. tion in any moderate to severe baseline disease activity and no worsening in nine organ systems in the BILAG index, no worsening on the SLE Disease Activity Index, no increase of 0.3 points or more slight differences between patient populations in the clinical trials in the score on the Physician Global Assessment of disease activity, precludes direct comparison between products, 61.8% of patients no discontinuation of the trial intervention, and no use of medica- in the ORAL Scan trial who were treated with tofacitinib 10 mg and tions restricted by the protocol.52 At week 52, 47.8% of patients had an inadequate response to methotrexate achieved ACR20 at treated with anifrolumab achieved a BICLA response, compared six months.48 In the RA-BUILD study that included patients who with 31.5% in the placebo group (95% confidence interval 6.3 were biologic-naïve and had an inadequate response to at least to 26.3, p=0.001).52 BICLA responses were similar among patients one conventional DMARD, 62% of patients treated with baricitinib with high and low interferon gene signatures.52 4 mg daily achieved ACR20 response at week 12.49 Based on the favorable results from the TULIP-2 trial, the manufacturer intends to file for FDA approval in the second half of 2020.53 Autoimmune Disease Pipeline If approved, anifrolumab would be the second medication specifically approved for SLE, following Benlysta (belimumab).51 Despite the number of agents approved for psoriasis, rheumatoid arthritis, Crohn’s disease, and ulcerative colitis, a significant unmet Larazotide need remains across a number of other autoimmune diseases.1, 2 Ac- cording to a 2016 PhRMA report on medicines in development for Larazotide, an investigational agent in a new class of drugs referred autoimmune diseases, more than 300 medicines and vaccines are in to as tight junction regulators, is currently being studied for the development for a variety of autoimmune diseases, including 76 for treatment of celiac disease.54 In patients without celiac disease, autoimmune forms of arthritis, 58 for inflammatory bowel disease, tight junctions, which are located in the bowel, remain closed. In 39 for lupus, 34 for Type 1 diabetes, and 32 for multiple sclerosis.2 patients with celiac disease, gluten causes tight junctions to remain open, causing inflammation that results in intestinal dam- Anifrolumab age.54 When taken prior to a meal, larazotide may help keep tight junctions closed, diminishing the inflammatory response caused Anifrolumab is an investigational, fully human, monoclonal anti- by gluten.54 In a phase two study of larazotide in patients with ce- body currently being studied for the treatment of systemic lupus liac disease who were maintained on a gluten-free diet, patients erythematosus (SLE).50 Anifrolumab exerts its effect by binding to experienced fewer symptoms with larazotide than with placebo.55 subunit 1 of the type I interferon receptor, blocking the activity In August 2019, the manufacturer announced that the first patient of all type I interferons, including IFN-α, IFN-β, and IFN-Ω.50 Type I had been dosed in the first phase three clinical trial for patients

10 | Magellan Rx Report | Spring 2020 with celiac disease.56 CeD LA 3001 is a phase three multicenter, members may benefit from targeted case management to evaluate double-blind, placebo-controlled, randomized, parallel-group trial whether there is an opportunity to discontinue therapy in favor of that is expected to enroll 600 patients. Similar to the phase two an alternative. Similarly, completion of functional assessments could trial, the primary objective is to evaluate larazotide as an adjunct be built into initial and renewal criteria to evaluate treatment effi- therapy for patients who still experience symptoms despite being cacy. Not only would this help to address a gap in practice, but ob- on a gluten-free diet.56 jective data obtained via completion of an assessment could also be helpful in evaluating the efficacy of a current treatment and, if appropriate, getting the member on the right treatment sooner rath- Managed Care Implications er than later.

Autoimmune diseases carry a significant economic burden in the With millions of patients in need of effective treatments, there U.S. The National Institutes of Health have reported the most cur- are several strategies around formulary management that man- rent estimate for the annual direct healthcare costs for autoimmune aged care organizations can consider for managing the growing disease at approximately $100 billion.57 Since this estimate was use and cost of biologics. Because treatment options for auto- reported nearly five years ago, movement and advances in the au- immune diseases will likely fall on both the medical and pharmacy toimmune space have likely led to an increase in direct healthcare benefits, a holistic formulary management strategy incorporating both costs, meaning updated cost estimates are necessary to more clearly categories can help identify all areas of opportunity. Site-of-service reflect the current market. In comparison, direct costs for cancer are programs may be an approach for medical benefit drugs. Because approximately $57 billion and for heart disease and stroke are $200 these medications are administered by clinicians and billed under the billion.57 The cost attributed to autoimmune diseases is, in part, be- medical benefit, identifying cost-effective sites for members to receive ing driven by the cost of the biologics being used.3 In 2015, three of their doses could offer payers potential savings while still delivering the top six best-selling prescription drugs were biologics indicated quality care to members. for the treatment of autoimmune disorders, and 20% of all specialty drug spending was for autoimmune disorder drugs.3 According to Some payers are also turning to indication-based formulary manage- the Magellan Rx Management 2018 Medical Pharmacy Trend Report, ment strategies. Indication-based formulary design allows health plans biologic drugs accounted for a double-digit increase in both com- to tailor their formulary and negotiate coverage of drugs based on spe- mercial and Medicare per member per month (PMPM) costs (21% cific indications.63 For example, a drug could be on the plan formulary and 13%, respectively).58 Biologics in the autoimmune category are for one indication but not on the plan formulary for another. In August also forecasted to increase and have the highest potential for cat- 2018, the Centers for Medicare & Medicaid Services announced that egory growth; the Trend Report forecasts PMPM autoimmune drug an indication-based formulary design would be permissible for Part D costs to increase 90% (from $1.40 to $2.66) from 2017 to 2022.58 plan sponsors beginning in contract year 2020.63 While other health plans and pharmacy benefit managers have already begun exploring In the case of patients who have been stable on therapy and are indication-based management strategies, the announcement from the either in remission or have demonstrated low disease activity, there CMS may help to accelerate this shift in mindset for payers, manufac- may be an opportunity for providers to attempt downwards dose turers, and members.64 titration for certain members, depending on the diagnosis and the biologic being prescribed. Multiple studies support the conclusion There may be an opportunity for managed care organizations to en- that many stable members can have their doses tapered success- courage the use of biosimilars currently on the market; step therapy fully while maintaining clinical response.59, 60, 61 Doses can be adjust- requirements can influence prescribing habits and drive members ed either via a lower dose per administration or extension of each toward the less-expensive treatment. Specifically, criteria can be lev- dosing interval, depending on the drug and on patient and provider eraged to place a step therapy requirement for providers to first pre- preferences.60, 62 Such an approach is supported in rheumatoid ar- scribe a biosimilar for treatment-naïve members when the biosimilar thritis treatment guidelines published by the American College of is approved for the same indication as the reference biologic. With the Rheumatology. number of autoimmune disease drugs on the market with overlapping indications, coupling indication-based management strategies with If members do not qualify for this approach because their disease benefit structure changes that incentivize the member and/or provid- activity remains moderate or severe despite optimization of a bi- er to use preferred, more-cost-effective products may allow payers to ologic, this could create an opening for conversations focused on prefer the most effective drug for each specific indication based on promoting consistent use of functional assessments to evaluate dis- clinical data — and may allow for more strategic contract negotiations ease progression. Given the multitude of products available, these with manufacturers.

Visit us online at www.magellanrx.com | 11 AUTOIMMUNE DISEASES | Continued

References

1. “Autoimmune Disease List.” American Autoimmune Related 25. Rinvoq™ [package insert]. North Chicago, IL: AbbVie; 2019. Diseases Association, Inc., 2018, https://www.aarda.org/ 26. Orencia® [package insert]. Princeton, NJ: Bristol-Myers Squibb; diseaselist/. 2019. 2. “Medicines in Development for Autoimmune Diseases 2016 27. “Biosimilar Product Information.” U.S. Food and Drug Administration, Report.” PhRMA, Sept. 12, 2016, https://www.phrma.org/en/ Nov. 15, 2019, https://www.fda.gov/drugs/biosimilars/biosimilar- Report/Medicines-in-Development-for-Autoimmune-Diseases- product-information. 2016-Report. 28. “Pfizer announces the U.S. availability of biosimilar Inflectra® 3. McCain, Jack. “The Disease Burden of the Most Common (infliximab-dyyb).” Oct. 17, 2016, https://www.pfizer.com/news/ Autoimmune Diseases.” Managed Care, July 19, 2016, https:// press-release/press-release-detail/pfizer_announces_the_u_s_ www.managedcaremag.com/archives/2016/7/disease-burden- availability_of_biosimilar_inflectra_infliximab_dyyb. most-common-autoimmune-diseases. 29. “Sandoz will appeal District Court of New Jersey ruling in biosimilar 4. “Autoimmune Disease.” U.S. Pharmacist, June 16, 2016, https:// Erelzi® (etanercept-szzs) US patent case.” GlobeNewswire, www.uspharmacist.com/article/autoimmune-disease. Aug. 9, 2019, https://www.globenewswire.com/news- 5. Wyant, Tim et al. “An Overview of the Mechanism of Action of the release/2019/08/09/1900111/0/en/Sandoz-will-appeal-District- Monoclonal Antibody Vedolizumab.” Journal of Crohn’s and Colitis, Court-of-New-Jersey-ruling-in-biosimilar-Erelzi-etanercept-szzs-US- Dec. 2016, https://www.ncbi.nlm.nih.gov/pubmed/27252400. patent-case.html. 6. “Targeted Immune Modulators for Rheumatoid Arthritis: 30. “Product Profile: Adalimumab-atto (Amjevita).” BR&R Biosimilars Effectiveness & Value Evidence Report.” Institute for Clinical Review & Report, 2019, https://biosimilarsrr.com/product-profile- and Economic Review, April 7, 2017, https://icer-review.org/ amjevita-2-2-2/. wp-content/uploads/2016/08/NE_CEPAC_RA_Evidence_Report_ 31. Gifford, C. Nichole. “Samsung Bioepis and Merck Launch Renflexis® FINAL_040717.pdf. in the US.” Rothwell Figg, 2018, https://www.biosimilarsip. 7. Humira® [package insert]. North Chicago, IL: AbbVie; 2019. com/2017/08/09/samsung-bioepis-merck-launch-renflexis-u-s/. 8. Cimzia® [package insert]. Smyrna, GA: UCB; 2019. 32. “Boehringer Ingelheim announces resolution of Cyltezo® patent litigation.” Boehringer Ingelheim, May 14, 2019, https://www. 9. Enbrel® [package insert]. Thousand Oaks, CA: Amgen; 2018. boehringer-ingelheim.us/press-release/boehringer-ingelheim- 10. Simponi® [package insert]. Horsham, PA: Janssen Pharmaceutica; announces-resolution-cyltezo-patent-litigation. 2019. 33. Stanton, Dan. “Pfizer: ‘No plans to launch second approved Remicade 11. Remicade® [package insert]. Horsham, PA: Janssen Pharmaceutica; biosimilar in US’.” BioPharma Reporter, Dec. 14, 2017, updated Nov. 2018. 16, 2018, https://www.biopharma-reporter.com/Article/2017/12/14/ Pfizer-No-plans-to-launch-second-infliximab-biosimilar-in-US. 12. Rituxan® [package insert]. South San Francisco, CA: Genentech; 2019. 34. “FDA Approves Sandoz’s Biosimilar Adalimumab, Hyrimoz.” The Center for Biosimilars, Oct. 31, 2018, https://www. 13. Siliq™ [package insert]. Bridgewater, NJ: Bausch Health; 2017. centerforbiosimilars.com/news/fda-approves-sandozs-biosimilar- 14. Taltz® [package insert]. Indianapolis, IN: Eli Lilly; 2019. adalimumab-hyrimoz. 15. Tremfya® [package insert]. Horsham, PA: Janssen Pharmaceutica; 35. Davio, Kelly. “First Rituximab Biosimilar, Truxima, Launches in the 2019. United States.” The Center for Biosimilars, Nov. 7, 2019, https://www. centerforbiosimilars.com/news/first-rituximab-biosimilar-truxima- 16. Skyrizi™ [package insert]. North Chicago, IL: AbbVie; 2019. launches-in-the-united-states. ® 17. Kevzara [package insert]. Bridgewater, NJ: Sanofi/Regeneron; 36. Holt, Benjamin R. “Another Biosimilar Receives FDA Approval and 2018. Is Confronted with Litigation.” Rothwell Figg, 2019, https://www. 18. Actemra® [package insert]. South San Francisco, CA: Genentech, biosimilarsip.com/2019/05/28/another-biosimilar-receives-fda- Inc; 2019. approval-and-is-confronted-with-litigation/. 19. Ilumya™ [package insert]. Whitehouse Station, NJ: Merck & Co; 37. Davio, Kelly. “Pfizer Announces Launch Dates for 2 More Anticancer 2018. Biosimilars: Ruxience and Trazimera.” The Center for Biosimilars, Oct. 29, 2019, https://www.centerforbiosimilars.com/news/ ® 20. Cosentyx [package insert]. East Hanover, NJ: Novartis; 2018. pfizer-announces-launch-dates-for-2-more-anticancer-biosimilars- 21. Stelara® [package insert]. Horsham, PA: Janssen Pharmaceutica; ruxience-and-trazimera. 2019. 38. “FDA Approves Samsung Bioepis’ HADLIMA™ (adalimumab-bwwd).” 22. Entyvio® [package insert]. Deerfield, IL: Takeda; 2019. BioSpace, July 24, 2019, https://www.biospace.com/article/releases/ fda-approves-samsung-bioepis-hadlima-adalimumab-bwwd-/. 23. Olumiant® [package insert]. Indianapolis, IN: Eli Lilly; 2019. 24. Xeljanz® [package insert]. New York, NY: Pfizer; 2019.

12 | Magellan Rx Report | Spring 2020 References (cont.)

39. “FDA approves Pfizer’s biosimilar, ABRILADA™ (adalimumab- 52. Morand, Eric F. et al. “Trial of Anifrolumab in Active Systemic Lupus afzb) for multiple inflammatory conditions.” Pfizer, Nov. 18, 2019, Erythematosus.” The New England Journal of Medicine, Dec. 18, https://www.pfizer.com/news/press-release/press-release-detail/ 2019, https://www.nejm.org/doi/full/10.1056/NEJMoa1912196. fda_approves_pfizer_s_biosimilar_abrilada_adalimumab_afzb_for_ 53. Taylor, Nick Paul. “AstraZeneca plans 2020 filing for anifrolumab in multiple_inflammatory_conditions. lupus.” FierceBiotech, Nov. 12, 2019, https://www.fiercebiotech. 40. Davio, Kelly. “FDA approves Amgen’s Infliximab Biosimilar, com/biotech/astrazeneca-plans-2020-filing-for-anifrolumab-lupus. Avsola.” The Center for Biosimilars, Dec. 6, 2019, https://www. 54. “First Patient Dosed in First Ever Phase 3 Clinical Trial for Celiac centerforbiosimilars.com/news/fda-approves-amgens-infliximab- Disease.” Celiac Disease Foundation, Aug. 15, 2019, https://celiac. biosimilar-avsola. org/about-the-foundation/featured-news/2019/08/first-patient- 41. Wentworth, Simon. “Are we on the verge of a biosimilars dosed-in-first-ever-phase-3-clinical-trial-for-celiac-disease/. breakthrough in the USA?” The Pharma Letter, Aug. 22, 2017, 55. Leffler, D.A. et al. “Larazotide acetate for persistent symptoms of https://www.thepharmaletter.com/article/are-we-about-to-see-a- celiac disease despite a gluten-free diet: a randomized controlled biosimilars-breakthrough-in-the-usa. trial.” Gastroenterology, June 2015, https://www.ncbi.nlm.nih.gov/ 42. “How do Drugs and Biologics Differ?” Bio, 2018, https://www.bio. pubmed/25683116. org/articles/how-do-drugs-and-biologics-differ. 56. “Innovate Biopharmaceuticals, Inc. Announces First Patient 43. “Comparison of Biosimilars and Generic Drugs.” First Dosed in the First Phase 3 Clinical Trial for Patients with Celiac Report Managed Care, Oct. 16, 2013, https://www. Disease.” Innovate Biopharmaceuticals. GlobeNewsWire, managedhealthcareconnect.com/articles/comparison-biosimilars- Aug. 13, 2019, https://www.globenewswire.com/news- and-generic-drugs. release/2019/08/13/1901121/0/en/Innovate-Biopharmaceuticals- Inc-Announces-First-Patient-Dosed-in-the-First-Phase-3-Clinical- 44. “AbbVie Expands Immunology Portfolio in the U.S. with FDA Trial-for-Patients-with-Celiac-Disease.html. Approval of SKYRIZI™ (risankizumab-rzaa) for Moderate to Severe Plaque Psoriasis.” April 23, 2019, https://news.abbvie.com/news/ 57. “Autoimmune Disease Statistics.” American Autoimmune Related press-releases/abbvie-expands-immunology-portfolio-in-us-with- Diseases Association Inc., 2019, https://www.aarda.org/news- fda-approval-skyrizi-risankizumab-rzaa-for-moderate-to-severe- information/statistics/. plaque-psoriasis.htm. 58. “Medical Pharmacy Trend Report 2018 Ninth Edition.” Magellan 45. TREMFYA® (guselkumab). “Efficacy.” https://www.tremfyahcp.com/ Rx Management, 2018, https://www1.magellanrx.com/ efficacy/clinical-study-voyage-1. documents/2019/03/medical-pharmacy-trend-report_2018.pdf/. 46. ILUMYA® (tildrakizumab). “Results at week 12 are just the beginning 59. Singh, Jasvinder A. et al. “2015 American College of Rheumatology as demonstrated in reSURFACE 1 and 2.” https://www.ilumyapro. Guideline for the Treatment of Rheumatoid Arthritis.” American com/results/. College of Rheumatology. Arthritis & Rheumatology, January 2016, https://www.ncbi.nlm.nih.gov/pubmed/26545940. 47. “AbbVie Receives FDA Approval of RINVOQ™ (upadacitinib), an Oral JAK Inhibitor For The Treatment of Moderate to Severe Rheumatoid 60. Verhoef, L.M. et al. “Down-titration and discontinuation strategies Arthritis.” Aug. 16, 2019, https://news.abbvie.com/news/press- of tumor necrosis factor-blocking agents for rheumatoid arthritis releases/abbvie-receives-fda-approval-rinvoq-upadacitinib-an- in patients with low disease activity.” Cochrane Database of oral-jak-inhibitor-for-treatment-moderate-to-severe-rheumatoid- Systematic Reviews, May 24, 2019, https://www.ncbi.nlm.nih.gov/ arthritis.htm. pubmed/31125448. 48. “At a glance: The ORAL trials of tofacitinib for the treatment of RA.” 61. van den Bemt, B.J. et al. “Sustained effect after lowering high‐dose Medicine Matters rheumatology, April 8, 2017, upated April 2019, infliximab in patients with rheumatoid arthritis: a prospective dose https://rheumatology.medicinematters.com/rheumatoid-arthritis-/ titration study.” Annals of the Rheumatic Diseases, December 2008, tofacitinib/oral-trials-of-tofacitinib/13335124. https://www.ncbi.nlm.nih.gov/pubmed/18245109. 49. “At a glance: Trials evaluating baricitinib in RA.” Medicine Matters 62. van der Maas, A. et al. “Down titration and discontinuation of rheumatology, Dec. 9, 2017, updated January 2019, https:// infliximab in rheumatoid arthritis patients with stable low disease rheumatology.medicinematters.com/rheumatoid-arthritis-/jak- activity and stable treatment: an observational cohort study.” inhibitors/at-a-glance--trials-evaluating-baricitinib-in-ra/14224702. Annals of the Rheumatic Diseases, November, 2012, https://www. ncbi.nlm.nih.gov/pubmed/22504561. 50. “Anifrolumab Phase III trial meets primary endpoint in systemic lupus erythematosus.” AstraZeneca, Aug. 29, 2019, https://www. 63. “Indicated-Based Formulary Design Beginning in Contract Year (CY) astrazeneca.com/media-centre/press-releases/2019/anifrolumab- 2020.” Centers for Medicare & Medicaid Services, Aug. 29, 2018, phase-iii-trial-meets-primary-endpoint-in-systemic-lupus- https://www.cms.gov/newsroom/fact-sheets/indication-based- erythematosus-29082019.html. formulary-design-beginning-contract-year-cy-2020. 51. “AstraZeneca’s Lupus Drug Misses Primary Endpoint in Study.” Zacks 64. Spjut, Russ J. “Effects of indication-Based Formulary Design.” Equity Research. Yahoo! Finance, Sept. 3, 2018, https://finance.yahoo. First Report Managed Care, Sept. 27, 2018, https://www. com/news/astrazeneca-apos-lupus-drug-misses-134001878.html. managedhealthcareconnect.com/blog/effects-indication-based- formulary-design.

Visit us online at www.magellanrx.com | 13

Multiple Sclerosis: Therapy Recommendations and Treatment Advances The MS treatment landscape has been centered around disease-modifying therapies (DMTs), with more novel agents, biosimilars, bioequivalents, and generics coming to further saturate the market.

Multiple sclerosis (MS) is a chronic autoimmune inflammatory demyelinating disease of the central nervous system (CNS) with a largely unknown etiology.1 The clinical course begins with an immune-mediated attack on the CNS that leads to demyelination via destruction of oligodendrocytes, then degeneration of axons.1 Activation of both T-lymphocytes and B-lymphocytes are believed to be involved in the inflammation and damage that occurs within the CNS. Research suggests that the risk of developing MS is determined by genetic as well as environmental components,1 which may include low vitamin D levels, a history of Epstein-Barr virus, ultraviolet light exposure, and cigarette smoking.1 Currently, an estimated nearly one million people in the U.S. live with MS. Women are three times more likely than men to receive a diagnosis of MS.2

Sue Wilhelm, Patients diagnosed with MS are classified into two core phenotypes: relapsing-remitting and progressive B.S.Pharm., BCPS disease. Patients are then further classified into four clinical subtypes: Director of Pharmacy Security Health Plan • Clinically isolated syndrome (CIS). A CIS is the first clinical episode suggestive of an MS diagnosis.3 Patients with a CIS may or may not be diagnosed with MS at a later point in time.3 • Relapsing-remitting MS (RRMS). Accounting for approximately 85% of initial MS diagnoses, RRMS is the most common disease course and is defined by periods of attacks or relapses followed by periods of recovery or remission.3 • Primary progressive MS (PPMS). Approximately 15% of MS patients are diagnosed with PPMS, char- acterized by progression or worsening of neurologic function from the disease onset without periods of relapse and remission.3 • Secondary progressive MS (SPMS). SPMS is a progressive course with worsening neurologic function that follows an initially relapsing-remitting course.3 Most patients diagnosed with RRMS will progress to SPMS.

18 | Magellan Rx Report | Spring 2020 Treatment Guidelines

The following are the MS treatment guidelines set forth by the American Academy of Neurology (AAN) with recommendations for starting, switching, and stopping DMT.4

Table 1. Therapy Recommendations

Starting DMT Recommendations Evidence Level

Clinicians should counsel patients with newly diagnosed MS about specific treatment options with DMT at a dedicated Level B treatment visit. Clinicians must ascertain and incorporate/review preferences with patients with MS in terms of safety, route of administration, Level A lifestyle, cost, efficacy, common adverse effects (AEs), and tolerability in the choice of DMT.

Clinicians must engage patients with MS in an ongoing dialogue regarding treatment decisions throughout the disease course. Level A

Clinicians should counsel patients with MS that DMTs are prescribed to reduce relapses and new MRI lesion activity. DMTs are not Level B prescribed for symptom improvement in patients with MS.

Clinicians must counsel patients with MS on DMTs to notify the clinicians of new or worsening symptoms. Level A

Clinicians should evaluate readiness or reluctance to initiate DMT and counsel on its importance in patients with MS who are Level B candidates to initiate DMT. Clinicians should counsel patients with MS initiating DMTs about comorbid disease, adverse health behaviors, and potential Level B interactions of the DMT with concomitant medications.

Clinicians should evaluate barriers to adherence to DMT in patients with MS. Level B

Clinicians should counsel patients with MS initiating DMTs on the importance of adherence. Level B

Clinicians should discuss the benefits and risks of DMTs for patients with a single clinical demyelinating event with two or more Level B brain lesions that have imaging characteristics consistent with MS. After discussing the risks and benefits, clinicians should prescribe DMT to patients with a single clinical demyelinating event and Level B two or more brain lesions characteristic of MS who decide they want this therapy. Clinicians may recommend serial imaging at least annually for the first five years and close follow-up rather than initiating DMT in patients with CIS or relapsing forms of MS who are not on DMT, have not had relapses in the preceding two years, and do not have Level C active new MRI lesion activity on recent imaging.

Clinicians should offer DMTs to patients with relapsing forms of MS with recent clinical relapses or MRI activity. Level B

Clinicians should monitor patients with MS on DMTs for medication adherence, AEs, tolerability, safety, and effectiveness of Level B the therapy.

Clinicians should follow up with patients with MS on DMTs either annually or according to medication-specific REMS. Level B

Clinicians should monitor the reproductive plans and counsel regarding reproductive risks and use of birth control during DMT use Level B in women of childbearing potential who have MS. Clinicians should counsel men with MS on their reproductive plans regarding treatment implications before initiating treatment with Level B teriflunomide or cyclophosphamide. Because of the high frequency of severe AEs, clinicians should not prescribe mitoxantrone to patients with MS unless the potential Level B therapeutic benefits greatly outweigh the risks.

Clinicians should prescribe alemtuzumab, fingolimod, or natalizumab for patients with highly active MS. Level B

Clinicians may direct patients with MS who are candidates for DMTs to support programs. Level C

Clinicians may recommend azathioprine or cladribine for patients with relapsing forms of MS who do not have access to Level C approved DMTs. Clinicians may initiate natalizumab treatment in patients with MS with positive anti-JCV antibody indexes above 0.9 only when there is Level C a reasonable chance of benefit compared with the low but serious risk of progressive multifocal leukoencephalopathy (PML). Clinicians should offer ocrelizumab to patients with PPMS who are likely to benefit from this therapy unless there are risks of Level B treatment that outweigh the benefits.

Visit us online at www.magellanrx.com | 19 MULTIPLE SCLEROSIS | Continued

Table 1. Therapy Recommendations (cont.)

Switching DMT Recommendations Evidence Level

Clinicians should monitor MRI disease activity in patients with MS using DMT from the clinical onset of disease to detect the Level B accumulation of new lesions in order to inform treatment decisions.

Clinicians should recognize that relapses or new MRI-detected lesions may develop in patients with MS after initiation of a DMT and Level B before the treatment becomes effective.

Clinicians should discuss switching patients with MS from one DMT to another if they have been using one long enough for the treatment to take full effect and are adherent to their therapy but experience one or more relapses, two or more unequivocally new Level B MRI-detected lesions, or increased disability on examination over a one-year period.

Clinicians should evaluate the degree of disease activity, adherence, AE profiles, and mechanism of action of DMTs when switching Level B patients with MS with breakthrough disease activity during DMT use to another DMT.

Clinicians should discuss a change to noninjectable or less-frequently injectable DMTs with patients with MS on injectable DMTs Level B who report intolerable discomfort with the injections or injection fatigue.

Clinicians should ask patients with MS who are using a DMT about medication AEs and attempt to manage these AEs as appropriate. Level B

Clinicians should monitor laboratory abnormalities found on requisite laboratory surveillance (as outlined in the medication’s Level B package insert) in patients with MS who are using a DMT.

Clinicians should discuss switching DMT or reducing dosage or frequency (where there are data on different doses — e.g., Level B interferons, teriflunomide, azathioprine) when patients with MS exhibit persistent laboratory abnormalities.

Clinicians should counsel patients with MS considering natalizumab, fingolimod, rituximab, ocrelizumab, and dimethyl fumarate Level B about the PML risk associated with these agents.

Clinicians should discuss switching to a DMT with a lower PML risk with patients with MS taking natalizumab who are or become JCV Level B antibody-positive, especially those with anti-JCV antibody indexes above 0.9 while on therapy.

Clinicians should counsel patients with MS starting or using new DMTs without long-term safety data that they have an undefined Level B risk of malignancy and infection.

If a patient with MS develops a malignancy while using a DMT — especially azathioprine, methotrexate, mycophenolate, cyclophosphamide, fingolimod, teriflunomide, alemtuzumab, or dimethyl fumarate — clinicians should promptly discuss switching Level B to an alternate DMT.

Patients with MS with serious infections potentially linked to their DMT should switch DMTs (does not pertain to PML management Level B in patients with MS using DMT).

Clinicians should check for natalizumab antibodies in patients with MS who have infusion reactions before subsequent infusions or Level B experience breakthrough disease activity with natalizumab use.

Clinicians should switch patients with MS who have persistent natalizumab antibodies to a different DMT. Level B

Physicians must counsel patients with MS discontinuing natalizumab that there is an increased risk of MS relapse or MRI-detected Level A disease activity within six months of discontinuation.

Patients with MS choosing to switch from natalizumab to fingolimod should initiate treatment within eight to 12 weeks after Level B discontinuing natalizumab (for reasons other than pregnancy or pregnancy planning) to diminish the return of disease activity.

Clinicians should counsel women to stop their DMT before conception for planned pregnancies unless the risk of MS activity during Level B pregnancy outweighs the risk associated with the specific DMT during pregnancy.

Clinicians should discontinue DMTs during pregnancy if accidental exposure occurs, unless the risk of MS activity during pregnancy Level B outweighs the risk associated with the specific DMT during pregnancy.

Clinicians should not initiate DMTs during pregnancy unless the risk of MS activity during pregnancy outweighs the risk associated Level B with the specific DMT during pregnancy.

20 | Magellan Rx Report | Spring 2020 Table 1. Therapy Recommendations (cont.)

Stopping DMT Recommendations Evidence Level Clinicians should counsel patients with RRMS who are stable on DMT and want to discontinue DMT on the need for ongoing follow- Level B up and periodic reevaluation of the decision. Clinicians should advocate that patients with MS who are stable on DMT (that is, no relapses, no disability progression, stable Level B imaging) should continue their current DMT unless the patient and physician decide a trial off therapy is warranted. Clinicians should assess the likelihood of future relapse in patients with SPMS by assessing patient age, disease duration, relapse Level B history, and MRI-detected activity (e.g., frequency, severity, time since most recent relapse or gadolinium-enhanced lesion). Clinicians may advise discontinuation of DMT in patients with SPMS who do not have ongoing relapses (or gadolinium-enhanced Level C lesions on MRI activity) and have not been ambulatory (EDSS 7 or greater) for at least two years. *Definitions for evidence levels can be found within the American Academy of Neurology Guidelines for Disease-Modifying Therapies for Adults with Multiple Sclerosis.

Treatment Advances

The number of DMTs for MS has increased rapidly over the past sev- 47% lower in OPERA II 2 (0.16 versus 0.29; p<0.001).8 eral years, with a total of 15 medications currently available. New » In prespecified pooled analyses, the proportion of patients with agents released within the past few years include ocrelizumab confirmed disability progression was significantly lower with (Ocrevus®), siponimod (Mayzent®), and diroximel fumarate ocrelizumab than with interferon beta-1a — 9.1% versus 13.6% (Vumerity™). respectively (p<0.001) at 12 weeks and 6.9% versus 10.5% respectively (p=0.003) at 24 weeks.8 » The mean number of gadolinium-enhancing lesions was 94% lower in OPERA I with ocrelizumab (p<0.001) and 95% lower in The number of DMTs for MS OPERA II (p<0.001) than with interferon beta-1a.8 » The percentage of patients with serious infections was 1.3% of has increased rapidly over those treated with ocrelizumab and 2.9% of patients treated with interferon beta-1a. the past several years, with » In the ocrelizumab treatment group, 0.5% of the patients developed a neoplasm, compared with 0.2% of patients in the a total of 15 medications interferon beta-1a group.8 currently available. The safety and efficacy of ocrelizumab as the first DMT indicated for the treatment of PPMS were established in the ORATORIO trial.9 Ocrelizumab ORATORIO Results: Ocrelizumab was approved in 2017 based on the results from the OPERA I and II trials for patients with relapsing forms of MS.8 These » At 12 weeks, 32.9% of patients on ocrelizumab (p=0.03) had identically designed trials were randomized, double-blind, double- confirmed disability progression, compared with 39.3% of dummy, active comparator-controlled clinical trials.8 Included pa- placebo patients. tients had experienced at least one relapse within the prior year, or » At 24 weeks, 29.6% of patients on ocrelizumab had con- two relapses within the prior two years, and had an Expanded Dis- firmed disability progression, compared with 35.7% of pla- ability Status Scale (EDSS) score of 0 to 5.5.8 Patients with PPMS were cebo patients (p=0.04). excluded.8 Patients were randomized 1:1 to receive either ocrelizum- » At 120 weeks, performance on the timed 25-foot walk wors- ab 600 mg every 24 weeks or interferon beta-1a 44 mcg three times ened 38.9% in patients on ocrelizumab and 55.1% in place- weekly.8 bo patients (p=0.04). » Patients on ocrelizumab had a 3.4% decrease in total brain OPERA I and II Results: lesion volume on T2-weighted MRI, while placebo patients had a 7.4% increase (p<0.001). » The annualized relapse rate (ARR) was 46% lower with ocrelizumab » Patients on ocrelizumab had a brain-volume loss of 0.9%, compared to interferon beta-1a (0.16 versus 0.29; p<0.001), and compared with 1.09% in placebo patients (p=0.02).

Visit us online at www.magellanrx.com | 21 MULTIPLE SCLEROSIS | Continued

» Infusion-related reactions, upper respiratory tract infections, and oral herpes infections occurred more frequently in patients on ocrelizumab than in placebo patients. » Neoplasms occurred in 2.3% of patients on ocrelizumab and 0.8% of placebo patients. » The difference in the rates of serious adverse events and serious infections between groups was not clinically significant.

Siponimod

Siponimod (Mayzent®) was approved in March 2019, joining fingolimod (Gilenya®) in the class of sphingosine-1-phosphate receptor (S1P) modulators. Siponimod was designed to be » Serious AEs occurred in 18% of patients on siponimod and more selective than fingolimod and may have fewer risks.10 15% of placebo patients. Siponimod is also proven to be effective in patients with ac- » Lymphopenia, increased liver transaminase concentration, tive SPMS.10 Compared to fingolimod, which requires first-dose bradycardia and bradyarrhythmia at treatment initiation, monitoring for all patients, siponimod requires first-dose mon- macular edema, hypertension, varicella zoster reactiva- itoring only in patients with pre-existing heart conditions.10 tion, and convulsions occurred more frequently in the siponimod treatment group. The safety and efficacy of siponimod were established in » Cardiac first-dose effects were managed by the initial patients with SPMS in the EXPAND trial.11 This trial was a dose titration. randomized, double-blind, parallel-group, placebo- controlled, time-to-event study in patients with SPMS.11 In- Diroximel fumarate cluded patients were 18 to 60 years old, had evidence of disability progression in the previous two years, no relapse in the Diroximel fumarate was approved in November 2019 via the three months prior to study entry, and an EDSS score of 3.0 505(b)(2) pathway, meaning that at least a portion of the data to 6.5 at the time of study entry.11 Patients were randomized supporting its approval was derived from a reference product 2:1 to receive siponimod 2 mg once daily following an initial (dimethyl fumarate).12 Diroximel fumarate shares the same active dose titration or placebo for up to 3 years or until the metabolite as Tecfidera® (dimethyl fumarate), with potentially occurrence of a predetermined number of confirmed fewer side effects.13 Bioavailability studies comparing dimethyl disability progression events.11 The primary endpoint fumarate to diroximel fumarate in patients with relapsing forms was the time to 3-month continued disability progres- of MS and healthy subjects were used to establish the efficacy sion (CDP), which was defined as a ≥1-point increase of diroximel fumarate.12 in EDSS, or a ≥0.5-point increase for baseline EDSS ≥5.5, sustained for three months.11 The safety of diroximel fumarate is currently being evaluated in the EVOLVE-MS-1 trial, which is an ongoing open-label, phase EXPAND Results: three, long-term safety study.14 The ongoing EVOLVE-MS-2 trial is assessing the GI tolerability of diroximel fumarate versus dimethyl » 26% of patients on siponimod had confirmed disease pro- fumarate.15 gression, compared with 32% of placebo patients (p=0.013). » The ARR with siponimod was 0.071 versus 0.16 with placebo (relative reduction of 55%; p<0.01). Multiple Sclerosis Pipeline » While a significant difference in disability progression was found in patients with active SPMS, or those with a relapse Monomethyl Fumarate in the prior two years, the effect on patients with nonactive SPMS was not statistically significant. Monomethyl fumarate (Bafiertam™) is an immunomodulator » 82% of patients on siponimod and 78% of placebo patients and the active metabolite of dimethyl fumarate.16 Monomethyl completed the study. fumarate received tentative approval via the 505(b)(2) pathway » AEs occurred in 89% of patients on siponimod and 82% of as a bioequivalent of dimethyl fumarate (Tecfidera®).16 A por- placebo patients. tion of the data supporting its approval was derived from the

22 | Magellan Rx Report | Spring 2020 prodrug, dimethyl fumarate.16 A trial is currently ongoing to assess mon adverse events.21 Market entry is expected in late 2020.23 the GI tolerability of monomethyl fumarate compared to dimethyl fumarate.17 Market entry is expected in June 2020, pending the Ofatumumab patent expiration of Tecfidera®.16 Ofatumumab, an anti-CD20 antibody, is currently marketed under Ozanimod the trade name Arzerra® for the treatment of chronic lymphocytic leukemia (CLL).24 Ofatumumab acts by binding to the CD20 anti- Ozanimod, a selective S1P modulator, acts by blocking lympho- gen on B-cells leading to B-cell lysis.24 cytes from exiting the lymph nodes, decreasing the number of lymphocytes in the peripheral blood.18 Ozanimod is highly selec- The safety and efficacy of ofatumumab is currently being evaluat- tive for the S1P 1 and 5 subtypes.18 ed in the phase three ASCLEPIOS I and II studies, which are identically designed, flexible duration (up to 30 months), double-blind, The safety and efficacy were established in the phase three SUN- randomized, multicenter studies evaluating ofatumumab 20 mg BEAM and RADIANCE trials.18, 19 The SUNBEAM trial and the RA- monthly versus teriflunomide 14 mg once daily in adults with re- DIANCE trial studied the efficacy of ozanimod versus interferon lapsing MS.24 beta-1a over 12 months and 24 months respectively.18, 19 ASCLEPIOS I and II Results: SUNBEAM and RADIANCE Results: » The ARR was 0.11 for patients on ofatumumab, compared with » In the SUNBEAM trial, adjusted ARR were 0.35 with interferon 0.22 for patients on teriflunomide (relative reduction 50.5%, beta-1a, 0.18 with ozanimod 1 mg, and 0.24 with ozanimod p<0.001). 0.5 mg. There were no clinically significant reports of brady- » The ARR was 0.10 for patients on ofatumumab, compared with cardia or second-degree or third-degree atrioventricular block 0.25 for patients on teriflunomide (relative reduction 58.5%, related to the first dose of ozanimod.19 p<0.001.) » In the RADIANCE trial, adjusted ARR were 0.28 with interferon » Significant suppression of new inflammatory activity with beta-1a, 0.17 with ozanimod 1 mg, and 0.22 with ozanimod ofatumumab compared to teriflunomide was demonstrated 0.5 mg.18 by a suppression of gadolinium (Gd)-enhancing T1 lesions. » In both trials, fewer patients treated with ozanimod discontin- » In prespecified pooled analyses, ofatumumab demonstrat- ued treatment due to adverse events than did those treated ed relative risk reductions of 34.4% (p=0.002) and 32.5% with interferon beta-1a.18, 19 (p=0.012) in 3- and 6-month confirmed disease progression, » There were no reports of bradycardia or second-degree or respectively, compared with teriflunomide.24 third-degree atrioventricular block related to ozanimod in ei- » Market entry is expected in late 2020.23 ther trial.18, 19 » Approval is currently pending, and market entry is expected Ublituximab March 25, 2020.20 Ublituximab is an anti-CD20 antibody. Phase two trials showed Ponesimod annualized relapse rate of 0.07, with 93% of patients relapse-free at week 48.25 T1 Gd-enhancing lesions were eliminated by ub- Ponesimod is another S1P modulator.21 It was studied in patients lituximab at week 24 and complete elimination was maintained with relapsing forms of MS in the Oral Ponesimod Versus Teriflun- at week 48.25 Ublituximab was well-tolerated overall, and rapid omide In Relapsing Multiple Sclerosis (OPTIMUM) trial, a phase infusion as low as one hour was also well-tolerated.25 The ULTI- three multicenter, randomized, double-blind, parallel-group, ac- MATE 1 and 2 trials are currently two ongoing phase three, ran- tive-controlled, superiority study.22 domized, multicenter, double-blinded, active-controlled trials comparing ublituximab to teriflunomide in patients with relaps- The study was completed May 16, 2019, and early data showed ing MS.25 Market entry is expected in 2021.23 statistically significant reduction of the ARR by 30.5% at week 108 with ponesimod versus teriflunomide (ARR=0.202 for ponesimod Natalizumab (Tysabri®) 20 mg versus 0.290 for teriflunomide 14 mg, p=0.0003).21, 22 Na- sopharyngitis, headache, upper respiratory tract infections, and Polpharma is currently recruiting participants for a phase three an increase in alanine amino transferase (ALT) were the most com- trial to establish efficacy and similarity of safety with biosimilar

Visit us online at www.magellanrx.com | 23 MULTIPLE SCLEROSIS | Continued

PB006 compared to Tysabri® in patients with relapsing-remitting that siponimod exceeds the commonly cited thresholds of cost- MS.26, 27 The estimated study completion date is August 2021.27 effectiveness.31 The report recommended that the manufacturer Market entry is to be determined. lower the current price of siponimod in order to better align with the value that this therapy provides to patients.31 Dimethyl fumarate Managed Care Implications Several generic manufacturers have submitted ANDAs for generic dimethyl fumarate.28 Market entry is expected in June 2020 pend- The MS treatment guidelines recommend initiation of DMT early ing the patient expiration of Tecfidera®.29 in the disease course of MS patients to delay the progression. As a result, the treatment landscape is becoming increasingly centered around these DMTs. As many novel agents, biosimilars, bioequiva- Effectiveness and Value of Disease lents, and generics come to the market, and the therapeutic class Modifying Therapies becomes more saturated, formulary management and selection of preferred agents are likely to become the focus for payers. The Institute for Clinical and Economic Review (ICER) published a final evidence report in 2017, “Disease-Modifying Therapies for Relapsing-Remitting and Primary-Progressive Multiple Sclerosis: Effectiveness and Value,” as well as “Siponimod for the Treatment References of Secondary Progressive Multiple Sclerosis: Effectiveness and Val- 30, 31 1. “About MS.” National Multiple Sclerosis Society, https://www. ue” in 2019. These reports outline the clinical effectiveness of nationalmssociety.org/For-Professionals/Clinical-Care/About-MS. each therapy as well as the cost effectiveness and value.30, 31 2. Wallin, Mitchell T. et al. “The prevalence of MS in the United States: A population-based estimate using health claims data.” Neurology, The 2017 report determined that the most effective DMTs for March 5, 2019, https://www.ncbi.nlm.nih.gov/pubmed/30770430/. reduction of relapses were alemtuzumab, natalizumab, and 3. Lublin, Fred D. et al. “Defining the clinical course of multiple ocrelizumab.30 The next-most effective therapies were fingolimod, sclerosis: the 2013 revisions.” Neurology, July 15, 2014, https:// rituximab, and dimethyl fumarate. The least effective therapies www.ncbi.nlm.nih.gov/pubmed/24871874. 30 were interferons, glatiramer acetate, and teriflunomide. The re- 4. Rae-Grant, Alex et al. “Practice guideline recommendations port also determined that for treating RRMS, there was moderate summary: Disease-modifying therapies for adults with multiple certainty of small to substantial net health benefit for alemtuzumab, sclerosis: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy natalizumab, and ocrelizumab, and moderate certainty of com- of Neurology.” Neurology, April 24, 2018, https://www.aan.com/ parable or better net health benefit for fingolimod and dimethyl Guidelines/Home/ByStatusOrType?status=all. fumarate, compared with the interferons and glatiramer acetate. 5. “Relapse Management.” National Multiple Sclerosis Society, https:// For the treatment of PPMS, the report concluded that, compared www.nationalmssociety.org/For-Professionals/Clinical-Care/ with best supportive care, there is moderate certainty of small Managing-MS/Relapse-Management. 30 to substantial net health benefit for ocrelizumab. Although the 6. Cortese, Irene et al. “Evidence-based guideline update: newer therapies are more effective, they also have greater risks Plasmapheresis in neurologic disorders: report of the Therapeutics of life-threatening infections and serious AEs compared with and Technology Assessment Subcommittee of the American Academy of Neurology.” Neurology, Jan. 18, 2011, https://www. interferons and glatiramer acetate.30 ICER calculated the incremental ncbi.nlm.nih.gov/pubmed/21242498. cost-effectiveness ratio using the cost per additional quality- 7. Ocrevus® [package insert]. South San Francisco, CA; Genentech; adjusted life year (QALY) for each DMT compared with best sup- November 2019. portive care and determined that alemtuzumab had good value with a cost per QALY of $38,000.30 The other DMTs were above 8. Hauser, Stephen L. et al. “Ocrelizumab versus Interferon Beta- 1a in Relapsing Multiple Sclerosis.” New England Journal of the range of reasonable value, $100,000-$150,000, meaning that Medicine, Jan. 19, 2017, https://www.nejm.org/doi/full/10.1056/ these therapies have poor long-term value for money.30 The report NEJMoa1601277. recommended that launch prices of new DMTs be better aligned 9. Montalban, Xavier et al. “Ocrelizumab versus Placebo in with the value they provide to the patients.30 Primary Progressive Multiple Sclerosis.” New England Journal of Medicine, Jan. 19, 2017, https://www.nejm.org/doi/full/10.1056/ The 2019 report concluded with high certainty that siponimod NEJMoa1606468. provides at least a small net benefit in patients with active SPMS, compared to placebo. However, economic analyses concluded

24 | Magellan Rx Report | Spring 2020 References (cont.)

10. “FDA Approves Siponimod - Brand named Mayzent® - for Relapsing 22. “Oral Ponesimod Versus Teriflunomide In Relapsing Multiple Forms of MS Including Active Secondary Progressive MS UPDATE.” Sclerosis (OPTIMUM).” Clinical Trial NCT02425644, April 24, 2015, National Multiple Sclerosis Society, March 27, 2019, https://www. https://clinicaltrials.gov/ct2/show/NCT02425644. nationalmssociety.org/About-the-Society/News/FDA-Approves- 23. Kish, Troy. “Promising Multiple Sclerosis Agents In Late-Stage Siponimod-Brand-named-Mayzent%C2%AE-for-Re. Development.” P&T Community, December 2018, https://www. 11. Kappos, L et al. “Siponimod versus placebo in secondary ptcommunity.com/journal/article/full/2018/12/750/promising- progressive multiple sclerosis (EXPAND): a double-blind, multiple-sclerosis-agents-late-stage-development. randomised, phase 3 study.” The Lancet, March 31, 2018, 24. “Novartis Phase III ASCLEPIOS trials demonstrate robust efficacy of https://www.thelancet.com/journals/lancet/article/PIIS0140- ofatumumab in patients with relapsing multiple sclerosis.” Novartis, 6736(18)30475-6/fulltext. Sept. 13, 2019, https://www.novartis.com/news/media-releases/ 12. Vumerity™ [package insert]. Cambridge, MA; Biogen; October 2019. novartis-phase-iii-asclepios-trials-demonstrate-robust-efficacy- ofatumumab-patients-relapsing-multiple-sclerosis. 13. “FDA Approves Oral Vumerity™ (Diroximel Fumarate), Similar to Tecfidera®, for Relapsing MS.” National Multiple Sclerosis 25. “TG Therapeutics, Inc. Announces Final Phase 2 Multiple Sclerosis Society, Oct. 30, 2019, https://www.nationalmssociety.org/About- Data Presentation at the Americas Committee for Treatment and the-Society/News/FDA-Approves-Oral-Vumerity™-(Diroximel- Research in Multiple Sclerosis (ACTRIMS) Annual Meeting.” TG Fumarate),. Therapeutics, March 1, 2019, http://ir.tgtherapeutics.com/news- releases/news-release-details/tg-therapeutics-inc-announces-final- 14. “A Study of ALKS 8700 in Adults With Relapsing Remitting Multiple phase-2-multiple-sclerosis-1. Sclerosis (MS) EVOLVE-MS-1.” Clinical Trial NCT02634307, https:// clinicaltrials.gov/ct2/show/NCT02634307. 26. Davio, Kelly. “Sandoz to Commercialize Biosimilar of MS Drug, Natalizumab.” Sept. 3, 2019, https://www.centerforbiosimilars.com/ 15. “A Tolerability Study of ALKS 8700 in Subjects With Relapsing news/sandoz-to-commercialize-biosimilar-of-ms-drug-natalizumab. Remitting Multiple Sclerosis (RRMS) EVOLVE-MS-2.” Clinical Trial NCT03093324, https://clinicaltrials.gov/ct2/show/ 27. “Efficacy and Safety of the Biosimilar Natalizumab PB006 in NCT03093324?term=ALKS+8700&draw=1&rank=2. Comparison to Tysabri® (Antelope).” Clinical Trial NCT04115488, Oct. 4, 2019, https://www.clinicaltrials.gov/ct2/show/ 16. “Banner Receives FDA Tentative Approval for BAFIERTAM for the NCT04115488?term=PB006&draw=2&rank=1. Treatment of Relapsing Forms of Multiple Sclerosis.” Banner Life Sciences. Business Wire, Jan. 2, 2019, https://www.businesswire. 28. “Drugs@FDA: FDA-Approved Drugs.” U.S. Food and Drug com/news/home/20190102005088/en/Banner-Receives-FDA- Administration, https://www.accessdata.fda.gov/scripts/cder/daf/ Tentative-Approval-BAFIERTAM-Treatment. index.cfm. 17. “Study to Compare GI Tolerability Following Oral Administration 29. “Glenmark Pharmaceuticals Receives Tentative ANDA Approval for of Bafiertam™ or Tecfidera to Healthy Volunteers.” Clinical Trial Dimethyl Fumarate Delayed-Release Capsules, 120 mg and 240 NCT04022473, https://clinicaltrials.gov/ct2/show/NCT04022473. mg.” Glenmark Pharmaceuticals Ltd., Oct. 9, 2019, https://www. prnewswire.com/in/news-releases/glenmark-pharmaceuticals- 18. Cohen, Jeffrey A. et al. “Safety and efficacy of ozanimod versus receives-tentative-anda-approval-for-dimethyl-fumarate-delayed- interferon beta-1a in relapsing multiple sclerosis (RADIANCE): a release-capsules-120-mg-and-240-mg-880935531.html. multicentre, randomised, 24-month, phase 3 trial.” The Lancet Neurology, November 2019, https://www.thelancet.com/article/ 30. Tice, Jeffrey A. et al. “Disease-Modifying Therapies for Relapsing- S1474-4422(19)30238-8/fulltext. Remitting and Primary-Progressive Multiple Sclerosis: Effectiveness and Value.” Institute for Clinical and Economic Review, March 6, 19. Comi, Giancarlo et al. “Safety and efficacy of ozanimod versus 2017, https://icer-review.org/wp-content/uploads/2016/08/CTAF_ interferon beta-1a in relapsing multiple sclerosis (SUNBEAM): a MS_Final_Report_030617.pdf. multicentre, randomised, minimum 12-month, phase 3 trial.” The Lancet Neurology, November 2019, https://www.thelancet.com/ 31. Sharaf, Ravi N. et al. “Siponimod for the Treatment of Secondary journals/laneur/article/PIIS1474-4422(19)30239-X/fulltext. Progressive Multiple Sclerosis: Effectiveness and Value.” Institute for Clinical and Economic Review, June 20, 2019, https:// 20. Payesko, Jenna. “FDA Accepts Ozanimod NDA for Treatment of icer-review.org/wp-content/uploads/2018/10/ICER_MS_Final_ Relapsing Forms of Multiple Sclerosis.” Neurology Live, June 6, Evidence_Report_062019.pdf. 2019, https://www.neurologylive.com/clinical-focus/fda-accepts- ozanimod-nda-for-treatment-of-relapsing-forms-of-multiple- sclerosis. 21. “New Head-to-Head Phase 3 Study Data Show Ponesimod Superiority Versus Aubagio® (teriflunomide) 14 mg in Adults with Relapsing Multiple Sclerosis (MS).” Johnson & Johnson, Sept. 11, 2019, https://www.jnj.com/new-head-to-head-phase-3-study-data- show-ponesimod-superiority-versus-aubagio-teriflunomide-14-mg- in-adults-with-relapsing-multiple-sclerosis-ms.

Visit us online at www.magellanrx.com | 25

Introducing MRx Navigate: Whole Patient Care Meets Digital Innovation

The new medical management program MRx Navigate offers integrated high-touch and high-tech solutions to enhance and simplify the healthcare experience for health plans and their members.

In October 2019, Magellan Rx Management (MRx) introduced a new multifaceted, holistic medical management program, MRx Navigate, to support MRx pharmacy benefit manager, employer, and government clients by providing an integrated view of the member and to offer standalone services for other clients.

Through MRx Navigate, members have access to a coach or care manager when they are newly diagnosed with a health condition, recently discharged from the hospital, interested in making a lifestyle change, or have questions about healthcare decisions. After an initial connection is made, MRx Navigate staff will proactively reach out to members and provide comprehensive education and adherence programs to improve healthcare decision-making and engagement. Caroline Carney, M.D., M.Sc., FAPM, CPHQ MRx Navigate eliminates gaps in care and improves adherence through digital tools, online resources, Chief Medical Officer and apps — and by leveraging analytics that identify members at risk for nonadherence or ineffective Magellan Rx Management medical and pharmacy utilization. Driven by data-led, evidence-based algorithms, the program uses data from multiple sources to identify members in need of care-management or disease-management outreach and determine the intensity of intervention needed. Additionally, utilization-management support is provided for medical and behavioral health requests for services.

MRx Navigate is a comprehensive program including four different programs to cover multiple facets of care management.

1. Navigate Change

With the objective of assisting members on their road to recovery, Navigate Change connects members with nurses, behavioral health professionals, and clinical pharmacists. The Navigate Change team works to ensure members receive the proper medications, education, and network resources that will

26 | Magellan Rx Report | Spring 2020 help them avoid a return visit to the hospital. Care managers take customized approaches based on members’ individual needs, assessing impacts to quality of life and financial costs. Clinical pharmacists are available to assist members with medications Informed by data analytics, by reviewing compliance, side effects, interactions, and any Navigate PopHealth questions or concerns raised by a member. Navigate Change has targeted disease states for transitions in both care and care identifies members who management (Table 1). Internal data suggests that access to a collaborative team of a pharmacist and care manager can reduce have chronic health hospital readmissions by 50%. conditions and who may

Table 1. Targeted Disease States be at risk of nonadherence,

Transitions in Care Care Management coordinates care, and Asthma/COPD Cancer reviews social determinants Behavioral Health High-Risk Pregnancy Congestive Heart Failure Pain Management of health that may be CVA/Stroke Transplants Diabetes Dialysis impacting health outcomes. Heart Disease Large Claims Readmissions Multiple ER Visits Out-of-Network identified for gaps in care and/or nonadherence, member engagement is initiated by an appropriate care manager (nurse, 2. Navigate PopHealth pharmacist, or behavioral health specialist). Once outreach is initiated, the care manager and member agree to a scheduled The population health management program Navigate contact cycle where the care plan goals and challenges will be PopHealth reviews for gaps in care and implements a care plan reviewed and discussed. Through Navigate PopHealth, members to reduce or eliminate identified gaps. Informed by data ana- will also have access to educational materials and resources to lytics, Navigate PopHealth identifies members who have chron- make the best healthcare decisions. ic health conditions and who may be at risk of nonadherence, coordinates care, and reviews social determinants of health Members with specific conditions (Figure 1) will have access that may be impacting health outcomes. Once members are to a variety of resources. Nurses, pharmacists, and behavioral

Figure 1. PopHealth Chronic Health Conditions

Osteoporosis Kidney Disease Congestive Heart Chronic Obstructive Hypertension Failure Pulminary Disease

Cerebrovascular Behavioral Health Diabetes Heart Disease Asthma Accident/Stroke

Visit us online at www.magellanrx.com | 27 MRX NAVIGATE | Continued

health professionals consult with members to help them consistent with the standards required under the program’s manage their chronic conditions and can assist in discussions certification by the National Committee for Quality Assurance. A with members’ physicians. standard suite of reports to track trends and identify opportunities is regularly reviewed with clients.

3. Navigate Wellness Objectives and Commitments:

Navigate Wellness aims to identify diseases and increase members’ • Prevent fraud, waste, and abuse quality of life through educational tools and resources. Onsite • Refer members into care management biometric screenings, flu shot clinics, and mobile mammograms • Minimize readmission through transition of care educate members about their health and wellness and keep them • Provide medically necessary care based on nationally healthy by preventing more serious and costly complications. recognized clinical guidelines Onsite programs, challenges, educational resources, webinars, and • Efficiently manage turnaround times wellness coaches help members set and achieve their wellness • Provide comprehensive peer-to-peer review goals. Navigate Wellness helps members focus on a healthier lifestyle, which impacts their day-to-day activities both at work and at home.

Where offered, wellness programs have had a positive impact on employees. At worksites offering a wellness program, a higher rate of employees exercised regularly and actively managed their weight.

Onsite programs include flu shot clinics, mobile mammograms, biometric screenings, wellness seminars, and health fairs. Navigate Wellness also provides access to virtual resources, including personal wellness coaches, wellness challenges, videos, newsletters, blog posts, health risk assessments, nutritional assessments, and sleep tips.

4. Navigate UM

The utilization management program Navigate UM focuses on ensuring members receive the proper medical and behavioral healthcare. The program covers prior authorization for medical and behavioral services, concurrent review of inpatient admissions, transition of care assessment, and appeal management. It documents requests for review in an integrated platform connected to available care-management services and utilizes industry- leading evidence-based care guidelines. The Navigate UM team of intake specialists, nurses, and physicians perform these services

Unlock the Possibilities for Better Care To learn more about how Magellan Rx Management and MRx Navigate can help your organization, contact us at [email protected] or visit magellanrx.com.

28 | Magellan Rx Report | Spring 2020 IN ADVANCED FIBROSIS DUE TO NASH HOW CLOSE ARE PATIENTS TO THE TIPPING POINT™?

Visit www.nashtippingpoint.com to learn more

Use of the “UK traffic sign: risk of falling rocks ahead” is licensed under the Open Government Licence version 1.0 (https://NationalArchives.gov.uk/doc/open-government-licence/version/1/) (OGL v1.0). Tipping Point and NASH Tipping Point are trademarks of Intercept Pharmaceuticals, Inc. The Intercept logo is a registered trademark of Intercept Pharmaceuticals, Inc. New York, NY 10001 | T: 844-782-ICPT | F: 646-747-1001 © 2020 Intercept Pharmaceuticals, Inc. All rights reserved. US-PP-NAS-0476 02/20

Gene Therapy: Changing Market Landscape and Pipeline As more gene therapies for larger patient populations enter the pipeline, payers must meet the immense challenge of how to fund the coverage.

Once just a pipe dream, gene therapy has become a reality. Several groundbreaking gene therapies have received FDA approval since 2017,1 offering significant treatment advancements and, in some cases, even cure. While gene therapy has been a long time coming, there will certainly be a learning curve for patients, payers, and providers as these innovative therapies are incorporated into clinical practice.

Gene Therapy: 101

To best understand the complexities of gene therapy in clinical development and, ultimately, in clinical practice, it is critical to understand how gene therapy works. Gene therapy is essentially the use of genet- 2-4 Natalie A. Tate, ic material to manipulate a patient’s cells in order to treat an inherited or acquired genetic disease. The PharmD, MBA, BCPS genetic material that is inserted directly into the cell is typically nonfunctional and may include nucleic Vice President, Pharmacy acids, viruses, or genetically engineered microorganisms. This genetically engineered vector is used to BlueCross BlueShield of deliver the gene to the desired location. Viruses, one of the most efficient vectors utilized, insert genetic Tennessee material into the cell by infecting the cell, but modifications prevent that virus from causing disease in the human host.2-4 Commonly utilized viruses include retroviruses, which integrate their genetic material into chromosomes in the human cell, and adenoviruses, which introduce deoxyribonucleic acid (DNA) into the nucleus of the cell but not into the chromosome.2-4

Currently Available Gene Therapies

Luxturna® (voretigene neparvovec-rzyl)

Luxturna® received FDA approval in December 2017, making it the first directly administered gene therapy approved in the U.S. that targets disease caused by mutations in a specific gene.5 Lead- ing up to the approval, the FDA granted Luxturna® the Priority Review, Breakthrough Therapy, and

30 | Magellan Rx Report | Spring 2020 Orphan Drug designations, and, following approval, the manufacturer, Spark Therapeutics, received a Rare Pediatric Dis- ease Priority Review Voucher.6 Specifically, Luxturna® was approved for the treatment of children and adult patients with confirmed biallelic retinal pigment epithelium (RPE65) mutation-associated retinal dystrophy — an inherited form of vision loss that may cause complete blindness in certain patients.5, 6 The RPE65 gene encodes an enzyme that is essential for normal vision; mutations in the RPE65 gene result in reduced or absent RPE65 activity, inhibiting the visual cycle and resulting in visual impairment. For individuals with biallelic RPE65 mutation-associated retinal dystrophy, progressive deterioration of vision occurs over time, typically during childhood or adolescence, and progresses to complete blindness. Biallelic RPE65 mutation-associated retinal dystrophy affects somewhere between 1,000 and 2,000 individuals in the U.S.5, 6

Luxturna® utilizes an adeno-associated viral (AAV) vector to deliver a normal copy of the human RPE65 gene to the retinal cells in order to restore vision.6 These retinal cells are then able to produce normal protein that converts light to an electrical signal within the form of SMA.9 As with Luxturna®, the FDA granted Zolgensma® the retina.6, 7 As such, Luxturna® should only be given to patients who Fast Track, Breakthrough Therapy, and Priority Review designations have viable retinal cells. Luxturna® is administered via subretinal leading up to approval, and awarded the manufacturer, Novartis, a injection into each eye separately, with a minimum of six days be- Rare Pediatric Disease Priority Review Voucher.10 tween injections. Patients are also given a course of oral predni- sone to mitigate any potential immune reactions.6, 7 SMA is a rare genetic disease that represents the leading genetic cause of infant mortality.11 SMA is caused by a mutation in the The safety and efficacy of Luxturna® was evaluated in a clinical survival motor neuron 1 (SMN1) gene, which encodes the surviv- program that included 41 patients between the ages of 4 and 44 al motor neuron (SMN) protein essential for the maintenance and years.8 In the phase three trial (n=31), 20 patients were randomly function of motor neurons in the brain and spinal cord that con- assigned to treatment with Luxturna®.8 At baseline, patients had trol muscle movement throughout the body.10, 11 When functional best corrected visual acuity of 20/60 or worse in each eye or vi- SMN protein is lacking, motor neurons die, resulting in debilitating sual field less than 20 degrees in any meridian, or both, with suf- and potentially fatal muscle weakness. Zolgensma® is approved for ficient viable retina and the ability to perform standardized multi- infantile-onset SMA. Infants with this form of SMA typically display luminance mobility testing (MLMT) within the luminance range symptoms between birth and six months of age; these may include evaluated.8 The MLMT is a test that evaluates a patient’s ability to problems holding their head up, swallowing, and breathing. Unfor- maneuver through an obstacle course at various light levels. One tunately, affected children are not expected to survive past early year after treatment, the mean bilateral MLMT change score was childhood.10, 11 1.8 light levels in the intervention group, compared to 0.2 light levels in the control group (difference 1.6; 95% confidence interval Zolgensma® is an AAV vector-based gene therapy that works by deliv- 0.72 to 2.41; p=0.0013). Of the patients treated with Luxturna®, ering a fully functional copy of the human SMN gene into the target 65% successfully passed the MLMT at the lowest luminance level motor neuron cells.10, 12 A single intravenous administration promotes tested (one lux, equivalent to a moonless night), demonstrating the the expression of the SMN protein in the patient’s motor neurons, maximum possible improvement.8 improving both muscle function and the patient’s survival.10

Zolgensma® (onasemnogene abeparvovec-xioi) The efficacy and safety of Zolgensma® was evaluated in an ongoing clinical trial as well as a completed clinical trial that included 36 In May 2019, the FDA approved the second gene therapy, pediatric patients with infantile-onset SMA between the ages of Zolgensma®, for the treatment of spinal muscular atrophy (SMA) two weeks and eight months at study entry.10, 12 All patients had in children less than two years of age, who get the most severe genetically-confirmed biallelic SMN1 gene deletions, two copies

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Current Market Landscape With the advancement of gene therapy technology, there has been With the advancement of an explosion of activity within the gene therapy pipeline. Accord- ing to the Alliance for Regenerative Medicine’s first-quarter report gene therapy technology, for 2019, there were 372 clinical trials for gene therapy in progress, 58% of which were phase two and 9% of which were phase there has been an three.14 Notably, the number of clinical trials increased 17% year- over-year from the 319 trials that were ongoing in the first three explosion of activity months of 2018.14 Following the approval of the first gene therapy, within the pipeline. Luxturna®, former FDA Commissioner Scott Gottlieb stated that “we’re at a turning point when it comes to this novel form of therapy,” and that he believes “gene therapy will become a mainstay in treating, and maybe curing, many of our most devastating and intractable diseases.”6 With excitement around gene therapy and the robustness of the pipeline, the FDA anticipates approving 10 to 20 cell and gene therapies per year starting in 2025.9 of the SMN2 gene, and absence of the c.859G>C modification in exon 7 of the SMN2 gene, which predicts a milder phenotype.12 The primary efficacy data included in the package insert was based on Gene Therapy Pipeline data from 21 patients enrolled in the ongoing clinical trial. The efficacy of Zolgensma® was established on the basis of survival and Valoctocogene Roxaparvovec achievement of developmental motor milestones such as sitting without support.12 As of the March 2019 data cutoff, 19 of 21 pa- There are hundreds of gene therapies currently in early-stage de- tients enrolled in the trial were alive without permanent ventilation, velopment, and a few that may receive FDA approval within the which was considered event-free survival. Of the two patients no next year.14 One such product, valoctocogene roxaparvovec by longer enrolled, one patient died at age 7.8 months due to disease BioMarin, is an investigational AAV-based gene therapy currently progression and one patient withdrew from the study at age 11.9 being studied for adults with hemophilia A.15 Hemophilia A, also months.12 By the data cutoff, 13 of the 19 patients continuing in the known as Factor VIII deficiency, is an X-linked genetic disorder trial had reached 14 months of age without permanent ventilation. caused by missing or defective Factor VIII, which is an essential Furthermore, 10 of the 21 patients initially enrolled (47.6%) were clotting protein. Individuals with the most severe form — which able to sit without support for 30 seconds or more between 9.2 and approximately 60% of those with hemophilia A have — may ex- 16.9 months of age (mean, 12.1 months).12 Comparatively, based perience spontaneous, painful bleeds into the muscle tissue or on the natural history of disease in SMA, only 25% of these pa- joints.16 The current standard of care for hemophilia A includes a tients would be expected to survive without permanent ventilation prophylactic regimen of replacement Factor VIII infusions admin- beyond 14 months of age. It is important to note that Zolgensma® istered intravenously two to three times per week. Unfortunately, does have a boxed warning for acute serious liver injury and ele- affected individuals may continue to experience bleeds and pro- vated aminotransferases.12 gressive, debilitating joint damage.15

Zolgensma® appears to offer a transformative approach to the Valoctocogene roxaparvovec works by delivering a functional copy treatment of a form of SMA that impacts 450 to 500 infants born of the B-domain-deleted Factor VIII gene, and it is given as a single each year. It quickly became the most expensive drug in the world, dose.16 Three-year follow-up data from an ongoing phase one/two at a staggering $2,125,000 per patient.9 Novartis does offer a study was presented at the 2019 Congress of the International So- payment plan that divides the total cost of the one-time treat- ciety on Thrombosis and Haemostasis.17 The phase one/two study ment into five yearly installments of $425,000.9 Although the cost was an open-label, dose-escalation study that enrolled 13 men. Pa- seems extreme, the existing SMA competitor product, Spinraza® tients were included in the study if they had severe hemophilia A (nusinersen), costs $750,000 for the first year and $375,000 annu- with residual Factor VIII levels ≤1 IU/dL and were exposed to Factor ally thereafter for the patient’s lifetime.9, 13 After five years, Spinraza®, VIII concentrates or cryoprecipitate for at least 150 days.17 All study which offers a temporary fix to the genetic mutations in SMA, subjects received a single dose of valoctocogene roxaparvovec, at costs $2,175,000, which is similar in cost to the potentially cura- 6 x 1013 v/kg (n=6) or 4 x 1013 vg/kg (n=6). After three years of tive gene therapy.9, 13 follow-up, subjects in both dose groups required fewer infusions

32 | Magellan Rx Report | Spring 2020 A to reach the market, there are a handful of competitors in late- stage development in what has become one of the most competi- tive therapeutic areas in the emerging field of gene therapy.18 Ad- ditional gene therapies in development for hemophilia A include SPK-8011 from Spark Therapeutics and SB-525 from Sangamo and Pfizer. While SB-525 is the furthest out, Sangamo and Pfizer announced promising phase one/two data that demonstrated that patients who received the highest dose of SB-525 were sustaining normal levels of Factor VIII clotting protein at the interim analysis.18 As excitement for new gene therapies in hemophilia builds, a survey of 25 doctors who treated approximately 3,000 patients with hemophilia in the U.S. and Europe found that 28% intend to prescribe valoctocogene roxaparvovec to eligible patients within two years of launch, and 39% would prescribe within five years.18 While the cost is not yet known, it will likely be substantial — some studies have estimated that the average cost of managing a patient with hemophilia in the U.S. is approximately $140,000 to $155,000 annually.19-22 For patients who develop inhibitors and require more Factor VIII concentrate, the cost of management can jump to $697,000 to $1 million per year.19-22 It is important to note that these estimates are based on current treatment and management of hemophilia and are likely much lower than the cost of managing hemophilia with emerging gene therapies. In an interview, the CEO of BioMarin drew comparisons between valoctocogene of Factor VIII per year, with reductions from baseline of 96% in roxaparvovec and Zolgensma®, with each product competing the 6 x 1013 v/kg dose group and 97% in the 4 x 1013 v/kg dose against a current standard of care.23 He stated that it may “be diffi- group.17 Of note, the Factor VIII expression reached a plateau at cult for payers to pay more” for the gene therapy than the equiva- approximately 20% at year three, and the study investigators not- lent cost of five years of hemophilia care, which may suggest that ed that Factor VIII expression levels were expected to decline over there are plans to utilize a similar five-year payment strategy for time.17 The investigators noted that current projections conserva- valoctocogene roxaparvovec.23 tively estimate the persistence of bleeding control for at least eight years post-administration, and longer if the Factor VIII expression Zynteglo® (formerly known as LentiGlobin®) plateaus are maintained.17 Zynteglo® is an investigational gene therapy from Bluebird Bio In addition to improvements in Factor VIII expression, study sub- being studied for the treatment of transfusion-dependent β jects in both groups experienced significant reductions in the an- thalassemia (TDT).24 β thalassemia, an inherited genetic disease, nualized bleeding rate.17 In the year prior to treatment, subjects in results in defective red blood cells that are unable to carry ox- the 6 x 1013 v/kg dose group experienced a mean of 16.3 bleeds, ygen appropriately. Severe cases require frequent blood trans- compared to 0.9 bleeds in the first year post-treatment, 0.2 bleeds fusions, which may be associated with a toxic accumulation of in the second year, and 0.7 in the third year (p-value not report- iron in the blood.24 ed).17 This represents a 96% reduction in mean annualized bleeding rates. Similar reductions in annualized bleeding rate were ob- Zynteglo® works by delivering functional copies of a modified form served in the 4 x 1013 v/kg dose group.17 of the beta-globin gene into a patient’s own hematopoietic stem cells (HSC).25 Once a patient has the functional gene, they have the Valoctocogene roxaparvovec has been awarded the Breakthrough potential to produce HbAT87Q, which is gene therapy-derived he- Therapy and Orphan Drug designations by the FDA, and in De- moglobin, at levels that eliminate or drastically reduce the need for cember 2019, BioMarin announced the submission of a Biolog- transfusions of donor HSC.25 ics License Application to the FDA, initially seeking accelerated approval based on phase one/two data.15 While valoctocogene The efficacy and safety of Zynteglo® were evaluated in a completed roxaparvovec is likely to be the first gene therapy for hemophilia phase one/two study, as well as two ongoing phase three studies.25

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The phase one/two study enrolled 18 patients, including 10 who did not have a β0/β0 genotype and eight who did have a β0/β0 genotype. After completion of the two-year study, all 18 patients With each new therapy enrolled in a long-term follow-up study.25 Of the 10 patients who did not have a β0/β0 genotype, eight achieved transfusion inde- that is approved, the pendence (no transfusion for at least 12 months and maintenance of weighted hemoglobin ≥9 g/dL).25 Of the patients with a β0/β0 question of how much the genotype, three of the eight achieved transfusion independence and maintained a median weighted average hemoglobin ranging market is willing to pay for from 9.5 to 10.1 g/dL for a median duration of 16.4 months.25 innovation arises. In March 2019, Zynteglo® received regulatory approval in the EU and set a price of $1.8 million USD.26 Bluebird Bio has told their investors to expect a regulatory submission to the FDA by the end tions around the efficacy and the durability of effect remain. Man- of 2019. Although they haven’t announced their intentions with ufacturers of gene therapy products justify their hefty price tags pricing in the U.S., they did suggest that the product has an “intrin- by arguing that these therapies offer potentially curative effects; sic value” of $2.1 million.26 however, many are concerned about those patients who fail to respond and, for those that do respond, whether those effects will truly last 10 years and beyond. For those patients who lose effect Managed Care Implications after several years, will it be possible to treat them again, and will it be financially feasible? Undoubtedly, gene therapy has and will continue to make waves in the managed care world. With each new therapy that is approved, With all these challenges and unanswered questions facing payers, the question of how much the market is willing to pay for innova- it will be imperative to take a proactive approach, staying abreast of tion arises. It seems obvious that curative therapies for devastat- the gene therapy pipeline and the data supporting these products. ing, deadly diseases would be covered; however, with upfront costs Many gene therapies target patients with specific characteristics exceeding $2 million per patient, funding this coverage becomes such as mutations. Given the cost and the fact that gene therapies a major challenge. While many gene therapies may actually save may only work for patients with certain characteristics, access to money in the long term, the initial payer may never accrue those patient screening is essential to ensure that only the appropriate savings due to the rate at which patients change health insurer. patients receive treatment. In light of the questions around efficacy This could disincline payers from providing coverage from such and durability, value-based contracting will likely gain new traction costly therapies, thus limiting access for patients. A payer survey in the gene therapy arena, as payers seek contracts that reimburse showed that four out of five national payers and nine out of 16 for gene therapy that does not maintain its effect or does not work regional payers reported “very high” concern with regard to man- at all. As we have already seen to some degree, manufacturers are aging the potential financial risk and impact of gene therapies.27 also getting creative in the pricing of their gene therapies, offering In the same survey, nearly one-third of small-employer third-party payment plans in lieu of larger, upfront payments. Despite these administrators and managed Medicaid plans indicated they were efforts, payers and manufacturers will need to continue working likely to exclude coverage for gene therapies due to the associated together to identify solutions that can bring these innovative ther- financial challenges.27 Naturally, this could lead to a disparity in ac- apies to the patients who need them. cess for patients based on their specific payer, resulting in patients shopping for payers with more favorable criteria for these emerging therapies.

Furthermore, in the not-so-distant past, payers only had to worry about the one or two patients in their plan with a rare disease who may be candidates for gene therapy. Now, as the gene therapy pipeline expands to a greater number of therapeutic areas, including genetic diseases that impact more people, the potential pool of patients is ever-increasing. In addition to the growing treatment pool, there are several other challenges with gene therapy. Ques-

34 | Magellan Rx Report | Spring 2020 References

1. “Approved Cellular and Gene Therapy Products.” U.S. Food and Drug 16. “Hemophilia A.” National Hemophilia Foundation, 2020, https:// Administration, March 29, 2019, https://www.fda.gov/vaccines- www.hemophilia.org/Bleeding-Disorders/Types-of-Bleeding- blood-biologics/cellular-gene-therapy-products/approved-cellular- Disorders/Hemophilia-A. and-gene-therapy-products. 17. “Valoctocogene Roxaparvovec Continues to Improve Bleeding 2. “Gene therapy vs. cell therapy.” American Society of Gene & Cell Outcomes in Patients With Hemophilia A.” ASH Clinical News, Therapy, https://annualmeeting.asgct.org/about_gene_therapy/ Sept. 1, 2019, https://www.ashclinicalnews.org/on-location/ genevscell.php. other-meetings/valoctocogene-roxaparvovec-continues-improve- bleeding-outcomes-patients-hemophilia/. 3. “Guidance for Industry: Gene Therapy Clinical Trials — Observing Subjects for Delayed Adverse Events.” U.S. Food and Drug 18. Bell, Jacob. “BioMarin confirms timeline for hemophilia gene Administration, Nov. 4, 2015, https://www.fda.gov/media/72225/ therapy, putting pressure on rivals.” BioPharma Dive, July 8, download. 2019, https://www.biopharmadive.com/news/biomarin-confirms- timeline-for-hemophilia-gene-therapy-putting-pressure- 4. “How does gene therapy work?” Genetics Home Reference, Aug. 15, on/558279/. 2017, http://ghr.nlm.nih.gov/primer/therapy/procedures 19. Chen, S. L. “Economic costs of hemophilia and the impact of 5. Darrow, J.J. “Luxturna: FDA documents reveal the value of a costly prophylactic treatment on patient management.” American gene therapy.” Drug Discovery Today, April 2019, https://www.ncbi. Journal of Managed Care, April 2016, https://www.ncbi.nlm.nih. nlm.nih.gov/pubmed/30711576. gov/pubmed/27266809. 6. “FDA approves novel gene therapy to treat patients with a rare form 20. Escobar, M. “Health economics in haemophilia: a review from the of inherited vision loss.” U.S. Food and Drug Administration, Dec. clinician’s perspective.” Haemophilia, May 2010, https://www. 18, 2017, https://www.fda.gov/news-events/press-announcements/ ncbi.nlm.nih.gov/pubmed/20586799. fda-approves-novel-gene-therapy-treat-patients-rare-form- inherited-vision-loss. 21. Guh, S. et al. “Healthcare expenditures for males with haemophilia and employer-sponsored insurance in the United States, 2008.’ 7. Luxturna® [package insert], Philadelphia, PA, Spark Therapeutics, Haemophilia, March 2012, https://www.ncbi.nlm.nih.gov/ 2017. pubmed/22151000. 8. Russell, S. et al. “Efficacy and safety of voretigene neparvovec 22. Chen, S. L. “Economic costs of hemophilia and the impact of (AAV2-hRPE65v2) in patients with RPE65-mediated inherited prophylactic treatment on patient management.” American retinal dystrophy: a randomised controlled, open-label, phase Journal of Managed Care, April 2016, https://www.ncbi.nlm.nih. 3 trial.” The Lancet, Aug. 2017, https://www.ncbi.nlm.nih.gov/ gov/pubmed/27266809. pubmed/28712537. 23. Lash, Alex. “With Sliver of Data, BioMarin to Seek OK for 9. Cross, Ryan. “FDA approves second gene therapy, Zolgensma, to Hemophilia Gene Therapy.” Xconomy, May 28, 2019, https:// treat spinal muscular atrophy in infants.” Chemical & Engineering xconomy.com/san-francisco/2019/05/28/with-sliver-of-data- News, May 30, 2019, https://cen.acs.org/business/FDA-approves- biomarin-to-seek-ok-for-hemophilia-gene-therapy/. second-gene-therapy/97/i22. 24. Terry, Mark. “BlueBird Bio presents more data on its $1.8 million 10. “FDA approves innovative gene therapy to treat pediatric patients gene therapy Zynteglo.” BioSpace, June 14, 2019, https://www. with spinal muscular atrophy, a rare disease and leading genetic biospace.com/article/bluebird-bio-presents-more-data-on-its-1- cause of infant mortality.” U.S. Food and Drug Administration, May 8-million-gene-therapy-zynteglo/. 24, 2019, https://www.fda.gov/news-events/press-announcements/ fda-approves-innovative-gene-therapy-treat-pediatric-patients- 25. “bluebird bio presents long-term efficacy and safety data from spinal-muscular-atrophy-rare-disease. clinical studies of LentiGlobin® gene therapy for transfusion- dependent β-thalassemia (TDT) at 24th European Hematology 11. “About SMA.” Cure SMA, 2019, https://www.curesma.org/about- Association (EHA) Congress.” BusinessWire, June 14, 2019, https:// sma/ www.businesswire.com/news/home/20190614005119/en/ 12. Zolgensma® [package insert], Bannockburn, IL, AveXis, Inc, 2019. bluebird-bio-Presents-Long-Term-Efficacy-Safety-Data. 13. Spinraza® [package insert], Cambridge, MA, Biogen, 2019. 26. Weintraub, Arlene. “bluebird tees up its first gene therapy approval with Zynteglo thumbs-up in EU.” FiercePharma, March 14. Philippidis, Alex. “25 Up-and-Coming Gene Therapies of 2019.” 29, 2019, https://www.fiercepharma.com/pharma/europe-sets- Genetic Engineering & Biotechnology News, May 20, 2019, https:// up-first-bluebird-gene-therapy-approval-thumbs-up-thalassemia- www.genengnews.com/a-lists/25-up-and-coming-gene-therapies- treatment. of-2019/. 27. Ciarametaro, Michael et al. “Are Payers Ready to Address 15. “BioMarin Submits Biologics License Application to U.S. Food and the Financial Challenges Associated With Gene Therapy?” Drug Administration for Valoctocogene Roxaparvovec to Treat HealthAffairs, June 28, 2018, https://www.healthaffairs.org/ Hemophilia A.” BioSpace, Dec. 23, 2019, https://investors.biomarin. do/10.1377/hblog20180626.330036/full/. com/2019-12-23-BioMarin-Submits-Biologics-License-Application- to-U-S-Food-and-Drug-Administration-for-Valoctocogene- Roxaparvovec-to-Treat-Hemophilia-A.

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Rare Liver Disease Update: Nonalcoholic Steatohepatitis

As the prevalence of NASH approaches that of Type 2 diabetes, new therapies to address chronic liver disease will soon reshape the treatment landscape for liver disease patients.

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the world and the precursor to nonalcoholic steatohepatitis (NASH). NASH is a progressive form of NAFLD and can potentially lead to cirrhosis and the mortality associated with it. NASH has also quickly become a leading cause of liver transplantation and hepatocellular carcinoma.1

In the U.S., economic models estimate that 6.7 million adults live with NASH. 2017 saw 232,000 in- cident cases, and total estimated lifetime costs for NASH patients totaled $222.6 billion, with advanced-stage patients costing $95.4 billion.1

Lester Lachuk, Pharm.D., MBA Cause and Pathogenesis of NASH VP, Corporate Pharmacy BlueCross BlueShield of Steatosis (infiltration of liver cells by fat) causes damage to the liver and leads to progressive liver fibro- Western New York sis. NASH causes greater liver damage than isolated steatosis and often leads to liver-related illness and death. An analysis of over 8.5 million persons from 22 countries showed that over 80% of persons with NASH are overweight or obese, 72% have dyslipidemia, and 44% have received a diagnosis of Type 2 diabetes. Because of this, NASH is considered to be a hepatic form of metabolic syndrome, a systemic disorder associated with visceral adiposity.2

NASH is closely linked to liver fibrosis, which results in scarring. The level or degree of fibrosis is determined by biopsy and staged from F0 to F4. The stages of fibrosis scoring are as follows: F0 — no fibrosis, F1 — portal fibrosis without septa, F2 — portal fibrosis with few septa, F3 — bridging septa between central and portal veins, and F4 — cirrhosis. Studies show that a quarter of NASH patients have stage F2 fibrosis or higher when diagnosed.2 A certain level of fibrosis is expected in NASH patients, as it remains after liver wounds heal. Septa in the liver are made up of collagen and connecting tissue and reorganize the structure of the liver, decreasing its ability to function properly.

36 | Magellan Rx Report | Spring 2020 Progression of fibrosis in the liver is variable. A cohort of patients was studied by looking at sequential biopsies over a period of decades. Findings showed that patients progressed at a rate of one stage per decade, meaning a patient in stage F2 could progress to Management of metabolic cirrhosis within 20 years. Variations in this rate of progression were seen among patients in whom healing of NASH had taken place, syndrome and screening creating the possibility of a nonlinear prediction of progression in for cancer in patients with some cases.2 NASH and cirrhosis need The cause of NASH has been linked to inherited and environmental factors. Factors contributing to the development of NASH in- to be incorporated early clude inflammation, hyperinsulinemia — or insulin resistance — and changes in lipid homeostasis. Genetic studies indicate certain on in treatment. polymorphisms in phospholipase can promote the development of NASH and related liver damage. Gene expression changes can be seen without altering the DNA code itself. Studies have observed this area to determine if models seen in mice can be used to guide families with a history of adult-onset obesity to look at alterations providers on the treatment of humans using therapies such as anti- that dysregulate metabolic pathways controlling adiposity, insulin biotics, probiotics, or prebiotics to prevent or treat NASH. sensitivity, and tissue generation or regeneration. Studies continue to investigate these factors to determine if there is a link to devel- Sleep patterns and an increased risk of hepatic steatosis are oping NASH. also being studied in mice. Prolonged disruption of the circadian rhythms in mice with fatty livers has shown disruption in two nuclear hormone receptors, leading to development of NASH. This Environmental Factors may be relevant in patients with a history of shift work, which dis- rupts ideal sleep habits. It is believed that liver health is dependent Modifiable internal and external risk factors are also being eval- on metabolic responses working together as a network to regulate uated for any link to NASH. Early studies in genetically modified energy supply and demand. obese mice with metabolic syndrome and fatty livers revealed an abnormal microbiome with hepatic inflammatory signals leading to insulin resistance, hepatic steatosis, and NASH. Work continues in Diagnosis and Current Treatment Options

The differentiation between patients with hepatic steatosis and patients with NASH is critical when considering a course of treatment. Staging of liver fibrosis is the first diagnostic tool used to determine severity of disease, and accurate staging is necessary because the development of NASH is closely related to a diagnosis of F2 or higher. The risk of death increases 50% to 80% as fibrosis increases from F2 to F3 or F4.2

Patients at risk for fatty liver and subsequent NASH typically include individuals who are overweight, over the age of 45, have metabolic syndrome, and are insulin-resistant. Because liver fibrosis severity can vary within the liver, multiple samples may be needed to determine the level of disease. Less-invasive diagnostic tests are available to diagnose cirrhosis and exclude a diagnosis of NASH. Patients will be worked up for presence of steatosis by ultrasound and then other disorders — e.g. hepatitis, alcohol consumption, etc. — will be excluded. The only way to definitively diagnose NASH today is by visualizing ballooning and inflammation by biopsy. Physicians will diagnose NASH based on risk factors and

Visit us online at www.magellanrx.com | 37 RARE LIVER DISEASE UPDATE | Continued

exclusion of other disorders, then use noninvasive techniques to determine level of fibrosis. Less-invasive tests to diagnose NASH are being developed and may include panels of serum biomarkers, As some patients transition imaging tests, and dynamic tests of liver function. through multiple stages of Management of metabolic syndrome and screening for cancer in patients with NASH and cirrhosis need to be incorporated early on liver disease to NASH and, in treatment. Lifestyle modifications are typically the first line of treatment to reduce the risk of liver fibrosis progressing to NASH. potentially, to carcinoma, For overweight or obese patients, weight-loss goals of 7% of current body weight, limiting consumption of fructose-enriched bev- the burden of disease and erages, limiting consumption of alcohol (less than one drink per associated costs can be day for women and less than two drinks per day for men), and drinking two or more caffeinated cups of coffee a day are recom- substantial. After assessing the mended lifestyle modifications that can aid in reducing this risk. Caffeinated coffee reduces the risk of liver fibrosis in several liver costs for this type of progression diseases including nonalcoholic fatty liver disease.2 of liver disease, researchers In terms of pharmacologic treatments, clinical trials have been un- derway for many years to find a drug to treat NASH. There are ther- concluded that advanced apies in phase two or phase three development designed to work NASH is associated with higher within the liver to decrease metabolic stress and reduce inflammation and the degree of fibrosis (Table 1). lifetime economic burden.

Table 1. Pharmacotherapies for Nonalcoholic Steatohepatitis Evaluated in Phase Two or Phase Three Clinical Trials2 focusing on already-FDA-approved therapies indicated for other Pharmacologic Agent Therapeutic Target conditions. Other studies also focus on disease states in combi- Metabolic Pharmacalogic Agent Stress Inflammation Fibrosis nation with NASH, such as Type 2 diabetes, osteoarthritis, obesity, and hyperlipidemia. These other disease states fall in line with the Vitamin E † Yes Yes No correlation of metabolic syndrome and inflammation as a precur- Pioglitazone (PPAR-γ agonist) † Yes Yes Yes sor to NASH. Obeticholic acid (FXR agonist) † Yes Yes Yes Chemokine receptor 2 and 5 antagonists No Yes Yes Two studies looking at obeticholic acid (Ocaliva®) for the treatment PPAR-α and PPAR-Δ agonists Yes Yes Yes of NASH have progressed through successful phase three trials. Lysyl oxidase-like 2 inhibitor Yes Yes Yes The REGENERATE study looked at adult patients with a diagnosis Galectin-3 No No Yes of NASH and a fibrosis stage of F2 to F3, or F1 with at least one Bovine milk colostrum No Yes Yes accompanying comorbidity. The study ran for 18 months and the primary endpoints included were fibrosis improvement (>1 stage) Stress-activated kinase 1 inhibitor Yes Yes Yes with no worsening of NASH or NASH resolution with no worsening FGF-21 Yes Yes Yes of fibrosis; the study was considered successful if either endpoint FGF-19-like agent Yes Yes Yes was met.3, 4 †This agent was superior to placebo in a randomized clinical trial. Abbreviations: FGF=fibroblast growth factor; FXR=farnesoid X receptor; PPAR= The analysis was performed as an intention to treat, with patients peroxisome proliferator-activated receptor receiving at least one dose of treatment during the study period. Presently, there are at least 700 trials in various stages, from not A total of 1,968 patients with F1 to F3 fibrosis were enrolled be- yet recruiting to withdrawn to completed. Currently, seven stud- tween December 2015 and October 2018. Patients were stratified ies have been withdrawn, 42 have terminated, with or without into three groups: placebo, obeticholic acid 10 mg, or obeticholic results, and 301 have been completed. There are also 98 studies acid 25 mg. An improvement endpoint was achieved by 12% of in research phases three and four. Many of these clinical trials are patients in the placebo arm, 18% of patients in the obeticholic

38 | Magellan Rx Report | Spring 2020 acid 10 mg arm, and 23% of patients in the obeticholic acid 25 As therapies are still in the approval process, it is hard to determine mg arm. The most common adverse effect across all three groups what the cost of treatment will look like. Since it is known that was pruritus, ranging from 19% in the placebo arm to 51% in the NASH is related to the metabolic syndrome, lifestyle modifications obeticholic acid 25 mg arm.3 The primary endpoint of improving should be discussed early on as a treatment option, and additional fibrosis with no worsening of NASH in patients with F2 or F3 fibro- comorbidities of increased weight and lipid levels should be ad- sis at 18 months was met by obeticholic acid 25 mg. Based on the dressed early. As pharmaceutical agents become available to treat FDA efficacy endpoints for NASH, which is improvement of fibrosis NASH, improved and more-effective management presents the op- by at least one stage with no worsening of NASH, obeticholic acid portunity for the associated economic and health burden to stabi- is likely predictive of clinical benefit. The FDA has not issued fi- lize over time. nal guidance on Intercept’s obeticholic acid as of yet, which would include the dosing to treat NASH; additional guidance is expect- Patient-support programs are available to help patients better ed from the FDA in summer 2020.4 Additional therapies, though manage their health. These programs may include personalized further from FDA approval, can be found in the NASH therapeutic coaching to improve health through engagement, motivational in- pipeline (Table 2). terviewing, and targeted education. In some instances, programs may include a suite of digital products focusing on specialty medication education, disease-management strategies, personalized Table 2. NASH Therapeutic Pipeline care plans and treatment goals, and improved care coordination. Other types of programs focus on overall wellness or targeted dis- Generic Mechanism of Oral Company Route Stage ease states, including diabetes, heart disease, and cancer. Name Action Tobira cenicrivi- Phase TBR-652 Takeda Oral Entry inhibitor As the prevalence of NASH approaches that of Type 2 diabetes roc Three Allergan and the direct costs to treat NAFLD exceed $100 billion, it is es- Galmed Stearoyl-CoA sential that all stakeholders understand more about this disease Phase Aramchol™ TBD Pharma- Oral desaturase-1 Three state. Research has shown a connection to metabolic disease and ceuticals (SCD-1) inhibitor inflammation and fibrosis of the liver. With this knowledge, thera- Peroxisome pro- pies to target the underlying cause of fibrosis in the liver, to slow elafibra- liferator-activated Phase GFT505 Genfit Oral or stop progression, and to heal fibrotic areas have gained traction nor receptor (PPAR) Three agonist over the last few years. New therapies should be available soon to Madrigal change the course of therapy for patients with NASH and undoubt- resmeti- Pharma- Thyroid hormone Phase edly reshape the treatment landscape for these patients. MGL-3196 Oral rom ceuticals receptor agonist Three Inc. Cirius Thiazolidinedi- Phase MSDC-0602K TBD Thera- Oral ones Three peutics References

1. Younossi, Zobair M. et al. “Burden of Illness and Economic Model Impact on Payers and Managed Care for Patients With Nonalcoholic Steatohepatitis in the United States.” Hepatology, Jan. 8, 2019, https://www.ncbi.nlm.nih.gov/ pubmed/30180285. As some patients transition through multiple stages of liver dis- 2. Diehl, Anna M., M.D., and Christopher Day, M.D. “Cause, ease to NASH and, potentially, to carcinoma, the burden of disease Pathogenesis, and Treatment of Nonalcoholic Steatohepatitis.” New and associated costs can be substantial. After assessing the costs England Journal of Medicine, Nov. 23, 2017, https://www.nejm.org/ for this type of progression of liver disease, researchers concluded doi/full/10.1056/NEJMra1503519. that advanced NASH is associated with higher lifetime economic 3. Younossi, Zobair M. et al. “Obeticholic acid for the treatment of burden.1 It is estimated that a patient with NASH will have a life- non-alcoholic steatohepatitis: interim analysis from a multicentre, time cost of $77,000 for disease treatment alone, which does not randomised, placebo-controlled phase 3 trial.” The Lancet, Dec. 14, include cost for a liver transplant if necessary.1 The prevalence of 2019, https://www.ncbi.nlm.nih.gov/pubmed/31813633. NASH is expected to grow by 10.8 million cases by 2060, with a 4. Neuschwander-Tetri, Brent A. et al. “Farnesoid X nuclear total cost burden of $359 billion.1 Initiating treatment at the ap- receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo- propriate time of disease progression can have a positive impact controlled trial.” The Lancet, Nov. 6, 2014, https://www.thelancet. on patients’ quality of life while possibly decreasing cost to payers. com/journals/lancet/article/PIIS0140-6736(14)61933-4/fulltext.

Visit us online at www.magellanrx.com | 39 WHEN IT COMES TO LOSING WEIGHT AND KEEPING IT OFF WE HAVE THE NOW YOU CAN GIVE US THE

Give them the power to choose a way forward by adding Saxenda®. To manage the chronic disease of obesity, willpower alone isn’t enough. Combined with a reduced-calorie meal plan and increased physical activity, Saxenda® can help patients lose weight and keep it off.1

When patients with obesity lose weight, one response of their bodies involves an increase in the hunger hormone, and a decrease in satiety hormones including glucagon-like peptide (GLP-1)—undermining their People living with obesity want you ability to lose weight and keep it off.2 to ask them about their weight-loss attempts. Saxenda®, which is 97% similar to the native gut hormone GLP-1, activates receptors in the braina to increase satiety and thereby reduce food intake.1,a Tell them how adding Saxenda® can help them lose weight and keep it off. Half of patients taking Saxenda® who achieved ≥5% body weight loss at 1 year maintained it at 3 years in a 3-year study (vs 25% and 10% for placebo, respectively).1,b —————— In a cardiovascular outcomes (CVOT) trial, NO increased risk of MACE observed with liraglutide 1.8 mg in patients with type 2 diabetes and cardiovascular disease.1,c Rate of primary component MACE endpoints was 1302 (608 [13.0%] with liraglutide 1.8 mg and 694 [14.9%] with placebo). Efficacy of doses below 3 mg has not been established for chronic weight management.

aShown in animal models.1 b Not actual patients. A 160-week, randomized, double-blind, placebo-controlled study that evaluated the percentage of patients who achieved ≥5% weight loss at both 1 and 3 years. Adults with pre-diabetes and a BMI of ≥30 or ≥27 with at least one weight-related comorbidity were randomized to receive once-daily Saxenda® (n=1,505) or placebo (n=749), added to lifestyle intervention, including increased physical activity and a 500-kcal/day-deficit diet. Study included: 4 weeks of dose escalation; 156 weeks at full dose; and 12-week off-drug observational period. Mean baseline body weight was 233.9 lb; mean BMI was 38.3. 817 Saxenda® patients vs 182 on placebo, and 391 patients on Saxenda® and 74 on placebo lost ≥5% at 1 and 3 years, respectively.1,3 c Major Adverse Cardiovascular Event (MACE) defined as: cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke. Results from a randomized Indications and Usage trial of 9340 patients with inadequately controlled type 2 diabetes and cardiovascular disease treated with liraglutide 1.8 mg or placebo in addition to standard of care treatments for type 2 diabetes for a median duration of 3.5 years. Patients either were 50 years of age or older with established, stable cardiovascular, Saxenda® (liraglutide) injection 3 mg is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management 2 2 cerebrovascular, peripheral vascular disease, chronic renal failure or chronic heart failure (80% of patients), or were 60 years of age or older and had other specified in adult patients with an initial body mass index (BMI) of 30 kg/m or greater (obesity) or 27 kg/m or greater (overweight) in the presence of at least one risk factors of vascular disease (20% of patients). The primary endpoint was the time from randomization to first occurrence of a major adverse cardiovascular event. weight-related comorbid condition (eg, hypertension, type 2 diabetes mellitus, or dyslipidemia) 96.8% of the patients completed the trial.1 Limitations of Use • Saxenda® is not indicated for the treatment of type 2 diabetes Important Safety Information (cont’d) • Saxenda® and Victoza® both contain the same active ingredient, liraglutide, and therefore should not be used together. Saxenda® should not be used in combination • Risk of Hypoglycemia with Concomitant Use of Anti-Diabetic Therapy: When Saxenda® is used with an insulin secretagogue (eg, a sulfonylurea) serious with any other GLP-1 receptor agonist hypoglycemia can occur. Consider lowering the dose of the insulin secretagogue to reduce the risk of hypoglycemia. Monitor blood glucose parameters prior to • Saxenda® has not been studied in patients taking insulin. Saxenda® and insulin should not be used together starting Saxenda® and during treatment and adjust anti-diabetic drugs as needed • The safety and efficacy of Saxenda® in combination with other products for weight loss, including prescription drugs, over-the-counter drugs, and herbal preparations, • Heart Rate Increase: Mean increases in resting heart rate of 2 to 3 beats per minute (bpm) were observed in patients treated with Saxenda®. Monitor heart rate at have not been established regular intervals and inform patients to report palpitations or feelings of a racing heartbeat while at rest during treatment with Saxenda®. Discontinue Saxenda® in patients who experience a sustained increase in resting heart rate Important Safety Information • Renal Impairment: Acute renal failure and worsening of chronic renal failure, which may sometimes require hemodialysis, have been reported, usually in ® WARNING: RISK OF THYROID C-CELL TUMORS association with nausea, vomiting, diarrhea, or dehydration. Use caution when initiating or escalating doses of Saxenda in patients with renal impairment • Hypersensitivity Reactions: Serious hypersensitivity reactions (eg, anaphylaxis and angioedema) have been reported in patients treated with liraglutide. If a Liraglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors at clinically relevant exposures in both genders of rats and ® ® hypersensitivity reaction occurs, patients should stop taking Saxenda and promptly seek medical advice mice. It is unknown whether Saxenda causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as the human relevance of ® ® • Suicidal Behavior and Ideation: In clinical trials, 9 (0.3%) of 3,384 patients treated with Saxenda and 2 (0.1%) of the 1,941 treated with placebo reported liraglutide-induced rodent thyroid C-cell tumors has not been determined. Saxenda is contraindicated in patients with a personal or family history of MTC ® ® and in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Counsel patients regarding the potential risk of MTC with use of Saxenda® suicidal ideation; one of the patients treated with Saxenda attempted suicide. Monitor patients on Saxenda for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Discontinue treatment if patients experience suicidal thoughts or behaviors. and inform them of symptoms of thyroid tumors (eg, a mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum ® calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with Saxenda®. Avoid Saxenda in patients with a history of suicidal attempts or active suicidal ideation Adverse Events Contraindications • The most common adverse reactions, reported in ≥5% are: nausea, hypoglycemia, diarrhea, constipation, vomiting, headache, decreased appetite, dyspepsia, Saxenda® is contraindicated in: fatigue, dizziness, abdominal pain, and increased lipase • Patients with a personal or family history of MTC or MEN 2 Drug Interactions • Patients with a prior serious hypersensitivity reaction to liraglutide or to any of the product components • Saxenda® causes a delay of gastric emptying, and has the potential to impact the absorption of concomitantly administered oral medications. Monitor for potential • Pregnancy consequences of delayed absorption of oral medications concomitantly administered with Saxenda® Warnings and Precautions Use in Specific Populations • Risk of Thyroid C-cell Tumors: If serum calcitonin is measured and found to be elevated, the patient should be further evaluated. Patients with thyroid nodules • There are no data on the presence of liraglutide in human breast milk; liraglutide was present in the milk of lactating rats noted on physical examination or neck imaging should also be further evaluated • Saxenda® has not been studied in patients below 18 years of age and is not recommended for use in pediatric patients • Acute Pancreatitis: Acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, has been observed in patients treated with liraglutide • Saxenda® slows gastric emptying. Saxenda® has not been studied in patients with preexisting gastroparesis postmarketing. Observe patients carefully for signs and symptoms of pancreatitis (persistent severe abdominal pain, sometimes radiating to the back with or without ® vomiting). If pancreatitis is suspected, discontinue Saxenda® promptly and if pancreatitis is confirmed, do not restart Please see Brief Summary of Information about Saxenda on the following pages. • Acute Gallbladder Disease: Substantial or rapid weight loss can increase the risk of cholelithiasis; however, the incidence of acute gallbladder disease was greater References ® in patients treated with Saxenda than with placebo even after accounting for the degree of weight loss. If cholelithiasis is suspected, gallbladder studies and 1. Saxenda® [package insert]. Plainsboro, NJ: Novo Nordisk Inc; 2018. appropriate clinical follow-up are indicated 2. Sumithran P, Prendergast LA, Delbridge E, et al. Long-term persistence of hormonal adaptations to weight loss. N Engl J Med. 2011;365(17):1597-1604. 3. le Roux CW, Astrup A, Fujioka K, et al; for the SCALE Obesity and Prediabetes NN8022-1839 Study Group. 3 years of liraglutide versus placebo for type 2 diabetes risk reduction and weight management in individuals with prediabetes: a randomised, double-blind trial [published online February 22, 2017]. Lancet. doi:10.1016/S0140-6736(17)30069-7.

Saxenda® and Victoza® are registered trademarks of Novo Nordisk A/S. Novo Nordisk is a registered trademark of Novo Nordisk A/S. © 2020 Novo Nordisk Printed in the U.S.A. US20SX00016 March 2020 Visit us online at www.magellanrx.com | 41 Saxenda® (liraglutide) injection trials, 2.2% of Saxenda-treated patients reported adverse events of cholelithiasis controlled 160-week period instead, followed by a 12-week off-treatment follow-up. reported as “hypoglycemia” in 92 (3.1%) Saxenda-treated patients and 13 (0.8%) ® Rx Only versus 0.8% of placebo-treated patients. The incidence of cholecystitis was 0.8% in For those participating in this 160-week period, patients received Saxenda for a placebo-treated patients. Gastrointestinal Adverse Reactions: In the clinical trials, Saxenda-treated patients versus 0.4% in placebo-treated patients. The majority of mean treatment duration of 110 weeks (median, 159 weeks). For all trials, dosing approximately 68% of Saxenda-treated patients and 39% of placebo-treated patients BRIEF SUMMARY. Please consult package insert for full prescribing Saxenda-treated patients with adverse events of cholelithiasis and cholecystitis was initiated and increased weekly to reach the 3 mg dose. In clinical trials, 9.8% of reported gastrointestinal disorders; the most frequently reported was nausea (39% information. required cholecystectomy. Substantial or rapid weight loss can increase the risk of patients treated with Saxenda® and 4.3% of patients treated with placebo prematurely and 14% of patients treated with Saxenda® and placebo, respectively). The cholelithiasis; however, the incidence of acute gallbladder disease was greater in discontinued treatment as a result of adverse reactions. The most common adverse percentage of patients reporting nausea declined as treatment continued. Other WARNING: RISK OF THYROID C-CELL TUMORS: Liraglutide causes Saxenda-treated patients than in placebo-treated patients even after accounting for reactions leading to discontinuation were nausea (2.9% versus 0.2% for Saxenda ® common adverse reactions that occurred at a higher incidence among Saxenda- dose-dependent and treatment-duration-dependent thyroid C-cell the degree of weight loss. If cholelithiasis is suspected, gallbladder studies and and placebo, respectively), vomiting (1.7% versus less than 0.1%), and diarrhea treated patients included diarrhea, constipation, vomiting, dyspepsia, abdominal tumors at clinically relevant exposures in both genders of rats ® appropriate clinical follow-up are indicated. Risk for Hypoglycemia with (1.4% versus 0%). Adverse reactions reported in greater than or equal to 2% of pain, dry mouth, gastritis, gastroesophageal reflux disease, flatulence, eructation and mice. It is unknown whether Saxenda causes thyroid C-cell Concomitant Use of Anti-Diabetic Therapy: The risk for serious hypoglycemia Saxenda-treated patients and more frequently than in placebo-treated patients are and abdominal distension. Most episodes of gastrointestinal events were mild or tumors, including medullary thyroid carcinoma (MTC), in humans, is increased when Saxenda® is used in combination with insulin secretagogues (for shown in Table 3. moderate and did not lead to discontinuation of therapy (6.2% with Saxenda® versus as the human relevance of liraglutide-induced rodent thyroid C-cell example, sulfonylureas) in patients with type 2 diabetes mellitus. Therefore, patients 0.8% with placebo discontinued treatment as a result of gastrointestinal adverse tumors has not been determined [see Warnings and Precautions]. Table 3. Adverse Reactions Reported in Greater Than or Equal to 2% of ® may require a lower dose of sulfonylurea (or other concomitantly administered insulin Saxenda-treated Patients and More Frequently than with Placebo* reactions). There have been reports of gastrointestinal adverse reactions, such as Saxenda is contraindicated in patients with a personal or family secretagogues) in this setting [see Adverse Reactions]. Saxenda® should not be used nausea, vomiting, and diarrhea, associated with volume depletion and renal history of MTC and in patients with Multiple Endocrine Neoplasia in patients taking insulin. Saxenda® can lower blood glucose. Monitor blood glucose Placebo Saxenda impairment [see Warnings and Precautions]. Asthenia, Fatigue, Malaise, Dysgeusia syndrome type 2 (MEN 2). Counsel patients regarding the potential parameters prior to starting Saxenda® and during Saxenda ® treatment in patients N = 1941 N = 3384 and Dizziness: Events of asthenia, fatigue, malaise, dysgeusia and dizziness were risk of MTC with use of Saxenda® and inform them of symptoms with type 2 diabetes. If needed, adjust co-administered anti-diabetic drugs based on % % mainly reported within the first 12 weeks of treatment with Saxenda ® and were often of thyroid tumors (e.g., a mass in the neck, dysphagia, dyspnea, glucose monitoring results and risk of hypoglycemia. Heart Rate Increase: Mean Gastrointestinal Disorders co-reported with gastrointestinal events such as nausea, vomiting, and diarrhea. persistent hoarseness). Routine monitoring of serum calcitonin or increases in resting heart rate of 2 to 3 beats per minute (bpm) were observed with Nausea 13.8 39.3 Immunogenicity: Patients treated with Saxenda ® may develop anti-liraglutide using thyroid ultrasound is of uncertain value for early detection routine clinical monitoring in Saxenda-treated patients compared to placebo in Diarrhea 9.9 20.9 antibodies. Anti-liraglutide antibodies were detected in 42 (2.8%) of 1505 Saxenda- of MTC in patients treated with Saxenda® [see Contraindications, clinical trials. More patients treated with Saxenda®, compared with placebo, had treated patients with a post-baseline assessment. Antibodies that had a neutralizing Warnings and Precautions]. Constipation 8.5 19.4 changes from baseline at two consecutive visits of more than 10 bpm (34% versus Vomiting 3.9 15.7 effect on liraglutide in an in vitro assay occurred in 18 (1.2%) of 1505 Saxenda- 19%, respectively) and 20 bpm (5% versus 2%, respectively). At least one resting treated patients. Presence of antibodies may be associated with a higher incidence of INDICATIONS AND USAGE: Saxenda® is indicated as an adjunct to a reduced- Dyspepsia 2.7 9.6 heart rate exceeding 100 bpm was recorded for 6% of Saxenda-treated patients calorie diet and increased physical activity for chronic weight management in adult injection site reactions and reports of low blood glucose. In clinical trials, these compared with 4% of placebo-treated patients, with this occurring at two consecutive Abdominal Pain 3.1 5.4 patients with an initial body mass index (BMI) of 30 kg/m2 or greater (obese), or events were usually classified as mild and resolved while patients continued on study visits for 0.9% and 0.3%, respectively. Tachycardia was reported as an adverse Upper Abdominal Pain 2.7 5.1 27 kg/m2 or greater (overweight) in the presence of at least one weight-related treatment. The detection of antibody formation is highly dependent on the sensitivity reaction in 0.6% of Saxenda-treated patients and in 0.1% of placebo-treated patients. Gastroesophageal Reflux Disease 1.7 4.7 comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). and specificity of the assay. Additionally, the observed incidence of antibody In a clinical pharmacology trial that monitored heart rate continuously for 24 hours, Limitations of Use: Saxenda® is not indicated for the treatment of type 2 diabetes Abdominal Distension 3.0 4.5 (including neutralizing antibody) positivity in an assay may be influenced by several Saxenda® treatment was associated with a heart rate that was 4 to 9 bpm higher than mellitus. Saxenda® and Victoza® both contain the same active ingredient, liraglutide, Eructation 0.2 4.5 factors including assay methodology, sample handling, timing of sample collection, that observed with placebo. Heart rate should be monitored at regular intervals and therefore should not be used together. Saxenda® should not be used in Flatulence 2.5 4.0 concomitant medications, and underlying disease. For these reasons, the incidence consistent with usual clinical practice. Patients should inform health care providers of antibodies to Saxenda® cannot be directly compared with the incidence of combination with any other GLP-1 receptor agonist. Saxenda ® has not been studied Dry Mouth 1.0 2.3 of palpitations or feelings of a racing heartbeat while at rest during Saxenda® antibodies of other products. Allergic Reactions: Urticaria was reported in 0.7% of in patients taking insulin. Saxenda® and insulin should not be used together [see Metabolism and Nutrition Disorders ® treatment. For patients who experience a sustained increase in resting heart rate Saxenda-treated patients and 0.5% of placebo-treated patients. Anaphylactic Warnings and Precautions]. The safety and effectiveness of Saxenda in combination 1 while taking Saxenda®, Saxenda® should be discontinued. Renal Impairment: In Hypoglycemia in T2DM 12.7 23.0 with other products intended for weight loss, including prescription drugs, over-the- reactions, asthma, bronchial hyperreactivity, bronchospasm, oropharyngeal patients treated with GLP-1 receptor agonists, including Saxenda ®, there have been Decreased Appetite 2.3 10.0 counter drugs, and herbal preparations, have not been established. swelling, facial swelling, angioedema, pharyngeal edema, type IV hypersensitivity reports of acute renal failure and worsening of chronic renal failure, sometimes Nervous System Disorders reactions have been reported in patients treated with liraglutide in clinical trials. ® is contraindicated in: Patients with a personal CONTRAINDICATIONS: Saxenda requiring hemodialysis [see Adverse Reactions]. Some of these events were reported Headache 12.6 13.6 Cases of anaphylactic reactions with additional symptoms such as hypotension, or family history of medullary thyroid carcinoma (MTC) or patients with Multiple in patients without known underlying renal disease. A majority of the reported events Dizziness 5.0 6.9 palpitations, dyspnea, and edema have been reported with marketed use of liraglutide. Endocrine Neoplasia syndrome type 2 (MEN 2) [see Warnings and Precautions]; occurred in patients who had experienced nausea, vomiting, or diarrhea leading to Anaphylactic reactions may potentially be life-threatening. Injection Site Reactions: Patients with a prior serious hypersensitivity reaction to liraglutide or to any of the volume depletion. Some of the reported events occurred in patients receiving one or General Disorders and Administration Site Conditions Injection site reactions were reported in approximately 13.9% of Saxenda-treated product components [see Warnings and Precautions]; Pregnancy [see Use in Specific more medications known to affect renal function or volume status. Altered renal Fatigue 4.6 7.5 patients and 10.5% of placebo-treated patients. The most common reactions, each Populations]. function has been reversed in many of the reported cases with supportive treatment Injection Site Erythema 0.2 2.5 reported by 1% to 2.5% of Saxenda-treated patients and more commonly than by WARNINGS AND PRECAUTIONS: Risk of Thyroid C-cell Tumors: Liraglutide and discontinuation of potentially causative agents, including liraglutide. Use caution Injection Site Reaction 0.6 2.5 placebo-treated patients, included erythema, pruritus, and rash at the injection site. ® causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors when initiating or escalating doses of Saxenda in patients with renal impairment Asthenia 0.8 2.1 0.6% of Saxenda-treated patients and 0.5% of placebo-treated patients discontinued ® (adenomas and/or carcinomas) at clinically relevant exposures in both genders of [see Use in Specific Populations]. Hypersensitivity Reactions: There have been Infections and Infestations treatment due to injection site reactions. Breast Cancer: In Saxenda clinical trials, reports of serious hypersensitivity reactions (e.g., anaphylactic reactions and breast cancer confirmed by adjudication was reported in 17 (0.7%) of 2379 Saxenda- rats and mice. Malignant thyroid C-cell carcinomas were detected in rats and mice. It Gastroenteritis 3.2 4.7 is unknown whether Saxenda® will cause thyroid C-cell tumors, including medullary angioedema) in patients treated with liraglutide [see Contraindications and Adverse treated women compared with 3 (0.2%) of 1300 placebo-treated women, including Urinary Tract Infection 3.1 4.3 thyroid carcinoma (MTC), in humans, as the human relevance of liraglutide-induced Reactions]. If a hypersensitivity reaction occurs, the patient should discontinue invasive cancer (13 Saxenda- and 2 placebo-treated women) and ductal carcinoma in ® rodent thyroid C-cell tumors has not been determined. Cases of MTC in patients Saxenda and other suspect medications and promptly seek medical advice. Viral Gastroenteritis 1.6 2.8 situ (4 Saxenda- and 1 placebo-treated woman). The majority of cancers were treated with liraglutide have been reported in the postmarketing period; the data in Anaphylaxis and angioedema have been reported with other GLP-1 receptor agonists. Investigations estrogen- and progesterone-receptor positive. There were too few cases to determine these reports are insufficient to establish or exclude a causal relationship between Use caution in a patient with a history of anaphylaxis or angioedema with another Increased Lipase 2.2 5.3 whether these cases were related to Saxenda®. In addition, there are insufficient data MTC and liraglutide use in humans. Saxenda® is contraindicated in patients with a GLP-1 receptor agonist because it is unknown whether such patients will be to determine whether Saxenda® has an effect on pre-existing breast neoplasia. ® Psychiatric Disorders personal or family history of MTC or in patients with MEN 2. Counsel patients predisposed to these reactions with Saxenda . Suicidal Behavior and Ideation: Papillary Thyroid Cancer: In Saxenda ® clinical trials, papillary thyroid carcinoma ® Insomnia 1.7 2.4 ® In Saxenda clinical trials, 9 (0.3%) of 3384 Saxenda-treated patients and 2 (0.1%) confirmed by adjudication was reported in 8 (0.2%) of 3291 Saxenda-treated patients regarding the potential risk for MTC with the use of Saxenda and inform them of Anxiety 1.6 2.0 symptoms of thyroid tumors (e.g., a mass in the neck, dysphagia, dyspnea, persistent of the 1941 placebo-treated patients reported suicidal ideation; one of these compared with no cases among 1843 placebo-treated patients. Four of these ® 1 hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of Saxenda-treated patients attempted suicide. Patients treated with Saxenda should Documented symptomatic (defined as documented symptoms of hypoglycemia papillary thyroid carcinomas were less than 1 cm in greatest diameter and 4 were uncertain value for early detection of MTC in patients treated with Saxenda®. Such be monitored for the emergence or worsening of depression, suicidal thoughts or in combination with a plasma glucose less than or equal to 70 mg/dL) in patients diagnosed in surgical pathology specimens after thyroidectomy prompted by ® monitoring may increase the risk of unnecessary procedures, due to low test behavior, and/or any unusual changes in mood or behavior. Discontinue Saxenda in with type 2 diabetes (Study 2). See text below for further information regarding findings identified prior to treatment. Colorectal Neoplasms: In Saxenda ® clinical ® specificity for serum calcitonin and a high background incidence of thyroid disease. patients who experience suicidal thoughts or behaviors. Avoid Saxenda in patients hypoglycemia in patients with and without type 2 diabetes. T2DM = type 2 trials, benign colorectal neoplasms (mostly colon adenomas) confirmed by Significantly elevated serum calcitonin may indicate MTC, and patients with MTC with a history of suicidal attempts or active suicidal ideation. diabetes mellitus adjudication were reported in 20 (0.6%) of 3291 Saxenda-treated patients compared usually have calcitonin values greater than 50 ng/L. If serum calcitonin is measured ADVERSE REACTIONS: The following serious adverse reactions are described * Adverse reactions for trials with treatment period up to 56 weeks with 7 (0.4%) of 1843 placebo-treated patients. Six positively adjudicated cases of and found to be elevated, the patient should be further evaluated. Patients with below or elsewhere in the prescribing information: Risk of Thyroid C-Cell Tumors Hypoglycemia: Saxenda® can lower blood glucose. In a clinical trial involving malignant colorectal neoplasms were reported in 5 Saxenda-treated patients (0.2%, thyroid nodules noted on physical examination or neck imaging should also be [see Warnings and Precautions]; Acute Pancreatitis [see Warnings and Precautions]; patients with type 2 diabetes mellitus and overweight or obesity, severe hypoglycemia mostly adenocarcinomas) and 1 in a placebo-treated patient (0.1%, neuroendocrine further evaluated. Acute Pancreatitis: Based on spontaneous postmarketing Acute Gallbladder Disease [see Warnings and Precautions]; Risk for Hypoglycemia (defined as requiring the assistance of another person) occurred in 3 (0.7%) of 422 tumor of the rectum). Cardiac Conduction Disorders: In Saxenda® clinical trials, 11 reports, acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing with Concomitant Use of Anti-Diabetic Therapy [see Warnings and Precautions]; Saxenda-treated patients and in none of the 212 placebo-treated patients. Each of (0.3%) of 3384 Saxenda-treated patients compared with none of the 1941 placebo- pancreatitis, has been observed in patients treated with liraglutide. After initiation of Heart Rate Increase [see Warnings and Precautions]; Renal Impairment [see Warnings these 3 Saxenda-treated patients was also taking a sulfonylurea. In the same trial, treated patients had a cardiac conduction disorder, reported as first degree Saxenda®, observe patients carefully for signs and symptoms of pancreatitis and Precautions]; Hypersensitivity Reactions [see Warnings and Precautions]; among patients taking a sulfonylurea, documented symptomatic hypoglycemia atrioventricular block, right bundle branch block, or left bundle branch block. (including persistent severe abdominal pain, sometimes radiating to the back and Suicidal Behavior and Ideation [see Warnings and Precautions]. Clinical Trials (defined as documented symptoms of hypoglycemia in combination with a plasma Hypotension: Adverse reactions related to hypotension (that is, reports of which may or may not be accompanied by vomiting). If pancreatitis is suspected, Experience: Because clinical trials are conducted under widely varying conditions, glucose less than or equal to 70 mg/dL) occurred in 48 (43.6%) of 110 Saxenda- hypotension, orthostatic hypotension, circulatory collapse, and decreased blood Saxenda® should promptly be discontinued and appropriate management should be adverse reaction rates observed in the clinical trials of a drug cannot be directly treated patients and 15 (27.3%) of 55 placebo-treated patients. The doses of pressure) were reported more frequently with Saxenda ® (1.1%) compared with initiated. If pancreatitis is confirmed, Saxenda® should not be restarted. In Saxenda® compared to rates in the clinical studies of another drug and may not reflect the sulfonylureas were reduced by 50% at the beginning of the trial per protocol. The placebo (0.5%) in Saxenda® clinical trials. Systolic blood pressure decreases to less clinical trials, acute pancreatitis was confirmed by adjudication in 9 (0.3%) of 3291 rates observed in practice. Saxenda® was evaluated for safety in 5 double-blind, frequency of hypoglycemia may be higher if the dose of sulfonylurea is not reduced. than 80 mmHg were observed in 4 (0.1%) Saxenda-treated patients compared with Saxenda-treated patients and 2 (0.1%) of 1843 placebo-treated patients. In addition, placebo controlled trials that included 3384 overweight or obese patients treated Among patients not taking a sulfonylurea, documented symptomatic hypoglycemia no placebo-treated patients. One of the Saxenda-treated patients had hypotension there were 2 cases of acute pancreatitis in Saxenda-treated patients who prematurely with Saxenda® for a treatment period up to 56 weeks (3 trials), 52 weeks (1 trial), occurred in 49 (15.7%) of 312 Saxenda-treated patients and 12 (7.6%) of 157 associated with gastrointestinal adverse reactions and renal failure [see Warnings withdrew from these clinical trials, occurring 74 and 124 days after the last dose. and 32 weeks (1 trial). All patients received study drug in addition to diet and placebo-treated patients. In Saxenda® clinical trials involving patients without type 2 and Precautions]. Laboratory Abnormalities: Liver Enzymes: Increases in alanine There were 2 additional cases in Saxenda-treated patients, 1 during an off-treatment exercise counseling. In these trials, patients received Saxenda® for a mean treatment diabetes mellitus, there was no systematic capturing or reporting of hypoglycemia, aminotransferase (ALT) greater than or equal to 10 times the upper limit of normal follow-up period within 2 weeks of discontinuing Saxenda®, and 1 that occurred in a duration of 46 weeks (median, 56 weeks). Baseline characteristics included a mean as patients were not provided with blood glucose meters or hypoglycemia diaries. were observed in 5 (0.15%) Saxenda-treated patients (two of whom had ALT greater patient who completed treatment and was off-treatment for 106 days. Liraglutide has age of 47 years, 71% women, 85% white, 39% with hypertension, 15% with type 2 Spontaneously reported symptomatic episodes of unconfirmed hypoglycemia were than 20 and 40 times the upper limit of normal) compared with 1 (0.05%) placebo- been studied in a limited number of patients with a history of pancreatitis. It is diabetes, 34% with dyslipidemia, 29% with a BMI greater than 40 kg/m2, and 9% reported by 46 (1.6%) of 2962 Saxenda-treated patients and 19 (1.1%) of 1729 treated patient during the Saxenda ® clinical trials. Because clinical evaluation to unknown if patients with a history of pancreatitis are at higher risk for development of with cardiovascular disease. In one of the 56-week trials, a subset of patients (with placebo-treated patients. Fasting plasma glucose values obtained at routine clinic exclude alternative causes of ALT and aspartate aminotransferase (AST) increases pancreatitis on Saxenda®. Acute Gallbladder Disease: In Saxenda ® clinical abnormal glucose measurements at randomization) were enrolled for a placebo- visits less than or equal to 70 mg/dL, irrespective of hypoglycemic symptoms, were was not done in most cases, the relationship to Saxenda® is uncertain. Some 42 | Magellan Rx Report | Spring 2020 Saxenda® (liraglutide) injection trials, 2.2% of Saxenda-treated patients reported adverse events of cholelithiasis controlled 160-week period instead, followed by a 12-week off-treatment follow-up. reported as “hypoglycemia” in 92 (3.1%) Saxenda-treated patients and 13 (0.8%) ® Rx Only versus 0.8% of placebo-treated patients. The incidence of cholecystitis was 0.8% in For those participating in this 160-week period, patients received Saxenda for a placebo-treated patients. Gastrointestinal Adverse Reactions: In the clinical trials, Saxenda-treated patients versus 0.4% in placebo-treated patients. The majority of mean treatment duration of 110 weeks (median, 159 weeks). For all trials, dosing approximately 68% of Saxenda-treated patients and 39% of placebo-treated patients BRIEF SUMMARY. Please consult package insert for full prescribing Saxenda-treated patients with adverse events of cholelithiasis and cholecystitis was initiated and increased weekly to reach the 3 mg dose. In clinical trials, 9.8% of reported gastrointestinal disorders; the most frequently reported was nausea (39% information. required cholecystectomy. Substantial or rapid weight loss can increase the risk of patients treated with Saxenda® and 4.3% of patients treated with placebo prematurely and 14% of patients treated with Saxenda® and placebo, respectively). The cholelithiasis; however, the incidence of acute gallbladder disease was greater in discontinued treatment as a result of adverse reactions. The most common adverse percentage of patients reporting nausea declined as treatment continued. Other WARNING: RISK OF THYROID C-CELL TUMORS: Liraglutide causes Saxenda-treated patients than in placebo-treated patients even after accounting for reactions leading to discontinuation were nausea (2.9% versus 0.2% for Saxenda ® common adverse reactions that occurred at a higher incidence among Saxenda- dose-dependent and treatment-duration-dependent thyroid C-cell the degree of weight loss. If cholelithiasis is suspected, gallbladder studies and and placebo, respectively), vomiting (1.7% versus less than 0.1%), and diarrhea treated patients included diarrhea, constipation, vomiting, dyspepsia, abdominal tumors at clinically relevant exposures in both genders of rats ® appropriate clinical follow-up are indicated. Risk for Hypoglycemia with (1.4% versus 0%). Adverse reactions reported in greater than or equal to 2% of pain, dry mouth, gastritis, gastroesophageal reflux disease, flatulence, eructation and mice. It is unknown whether Saxenda causes thyroid C-cell Concomitant Use of Anti-Diabetic Therapy: The risk for serious hypoglycemia Saxenda-treated patients and more frequently than in placebo-treated patients are and abdominal distension. Most episodes of gastrointestinal events were mild or tumors, including medullary thyroid carcinoma (MTC), in humans, is increased when Saxenda® is used in combination with insulin secretagogues (for shown in Table 3. moderate and did not lead to discontinuation of therapy (6.2% with Saxenda® versus as the human relevance of liraglutide-induced rodent thyroid C-cell example, sulfonylureas) in patients with type 2 diabetes mellitus. Therefore, patients 0.8% with placebo discontinued treatment as a result of gastrointestinal adverse tumors has not been determined [see Warnings and Precautions]. Table 3. Adverse Reactions Reported in Greater Than or Equal to 2% of ® may require a lower dose of sulfonylurea (or other concomitantly administered insulin Saxenda-treated Patients and More Frequently than with Placebo* reactions). There have been reports of gastrointestinal adverse reactions, such as Saxenda is contraindicated in patients with a personal or family secretagogues) in this setting [see Adverse Reactions]. Saxenda® should not be used nausea, vomiting, and diarrhea, associated with volume depletion and renal history of MTC and in patients with Multiple Endocrine Neoplasia in patients taking insulin. Saxenda® can lower blood glucose. Monitor blood glucose Placebo Saxenda impairment [see Warnings and Precautions]. Asthenia, Fatigue, Malaise, Dysgeusia syndrome type 2 (MEN 2). Counsel patients regarding the potential parameters prior to starting Saxenda® and during Saxenda ® treatment in patients N = 1941 N = 3384 and Dizziness: Events of asthenia, fatigue, malaise, dysgeusia and dizziness were risk of MTC with use of Saxenda® and inform them of symptoms with type 2 diabetes. If needed, adjust co-administered anti-diabetic drugs based on % % mainly reported within the first 12 weeks of treatment with Saxenda ® and were often of thyroid tumors (e.g., a mass in the neck, dysphagia, dyspnea, glucose monitoring results and risk of hypoglycemia. Heart Rate Increase: Mean Gastrointestinal Disorders co-reported with gastrointestinal events such as nausea, vomiting, and diarrhea. persistent hoarseness). Routine monitoring of serum calcitonin or increases in resting heart rate of 2 to 3 beats per minute (bpm) were observed with Nausea 13.8 39.3 Immunogenicity: Patients treated with Saxenda ® may develop anti-liraglutide using thyroid ultrasound is of uncertain value for early detection routine clinical monitoring in Saxenda-treated patients compared to placebo in Diarrhea 9.9 20.9 antibodies. Anti-liraglutide antibodies were detected in 42 (2.8%) of 1505 Saxenda- of MTC in patients treated with Saxenda® [see Contraindications, clinical trials. More patients treated with Saxenda®, compared with placebo, had treated patients with a post-baseline assessment. Antibodies that had a neutralizing Warnings and Precautions]. Constipation 8.5 19.4 changes from baseline at two consecutive visits of more than 10 bpm (34% versus Vomiting 3.9 15.7 effect on liraglutide in an in vitro assay occurred in 18 (1.2%) of 1505 Saxenda- 19%, respectively) and 20 bpm (5% versus 2%, respectively). At least one resting treated patients. Presence of antibodies may be associated with a higher incidence of INDICATIONS AND USAGE: Saxenda® is indicated as an adjunct to a reduced- Dyspepsia 2.7 9.6 heart rate exceeding 100 bpm was recorded for 6% of Saxenda-treated patients calorie diet and increased physical activity for chronic weight management in adult injection site reactions and reports of low blood glucose. In clinical trials, these compared with 4% of placebo-treated patients, with this occurring at two consecutive Abdominal Pain 3.1 5.4 patients with an initial body mass index (BMI) of 30 kg/m2 or greater (obese), or events were usually classified as mild and resolved while patients continued on study visits for 0.9% and 0.3%, respectively. Tachycardia was reported as an adverse Upper Abdominal Pain 2.7 5.1 27 kg/m2 or greater (overweight) in the presence of at least one weight-related treatment. The detection of antibody formation is highly dependent on the sensitivity reaction in 0.6% of Saxenda-treated patients and in 0.1% of placebo-treated patients. Gastroesophageal Reflux Disease 1.7 4.7 comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). and specificity of the assay. Additionally, the observed incidence of antibody In a clinical pharmacology trial that monitored heart rate continuously for 24 hours, Limitations of Use: Saxenda® is not indicated for the treatment of type 2 diabetes Abdominal Distension 3.0 4.5 (including neutralizing antibody) positivity in an assay may be influenced by several Saxenda® treatment was associated with a heart rate that was 4 to 9 bpm higher than mellitus. Saxenda® and Victoza® both contain the same active ingredient, liraglutide, Eructation 0.2 4.5 factors including assay methodology, sample handling, timing of sample collection, that observed with placebo. Heart rate should be monitored at regular intervals and therefore should not be used together. Saxenda® should not be used in Flatulence 2.5 4.0 concomitant medications, and underlying disease. For these reasons, the incidence consistent with usual clinical practice. Patients should inform health care providers of antibodies to Saxenda® cannot be directly compared with the incidence of combination with any other GLP-1 receptor agonist. Saxenda ® has not been studied Dry Mouth 1.0 2.3 of palpitations or feelings of a racing heartbeat while at rest during Saxenda® antibodies of other products. Allergic Reactions: Urticaria was reported in 0.7% of in patients taking insulin. Saxenda® and insulin should not be used together [see Metabolism and Nutrition Disorders ® treatment. For patients who experience a sustained increase in resting heart rate Saxenda-treated patients and 0.5% of placebo-treated patients. Anaphylactic Warnings and Precautions]. The safety and effectiveness of Saxenda in combination 1 while taking Saxenda®, Saxenda® should be discontinued. Renal Impairment: In Hypoglycemia in T2DM 12.7 23.0 with other products intended for weight loss, including prescription drugs, over-the- reactions, asthma, bronchial hyperreactivity, bronchospasm, oropharyngeal patients treated with GLP-1 receptor agonists, including Saxenda ®, there have been Decreased Appetite 2.3 10.0 counter drugs, and herbal preparations, have not been established. swelling, facial swelling, angioedema, pharyngeal edema, type IV hypersensitivity reports of acute renal failure and worsening of chronic renal failure, sometimes Nervous System Disorders reactions have been reported in patients treated with liraglutide in clinical trials. ® is contraindicated in: Patients with a personal CONTRAINDICATIONS: Saxenda requiring hemodialysis [see Adverse Reactions]. Some of these events were reported Headache 12.6 13.6 Cases of anaphylactic reactions with additional symptoms such as hypotension, or family history of medullary thyroid carcinoma (MTC) or patients with Multiple in patients without known underlying renal disease. A majority of the reported events Dizziness 5.0 6.9 palpitations, dyspnea, and edema have been reported with marketed use of liraglutide. Endocrine Neoplasia syndrome type 2 (MEN 2) [see Warnings and Precautions]; occurred in patients who had experienced nausea, vomiting, or diarrhea leading to Anaphylactic reactions may potentially be life-threatening. Injection Site Reactions: Patients with a prior serious hypersensitivity reaction to liraglutide or to any of the volume depletion. Some of the reported events occurred in patients receiving one or General Disorders and Administration Site Conditions Injection site reactions were reported in approximately 13.9% of Saxenda-treated product components [see Warnings and Precautions]; Pregnancy [see Use in Specific more medications known to affect renal function or volume status. Altered renal Fatigue 4.6 7.5 patients and 10.5% of placebo-treated patients. The most common reactions, each Populations]. function has been reversed in many of the reported cases with supportive treatment Injection Site Erythema 0.2 2.5 reported by 1% to 2.5% of Saxenda-treated patients and more commonly than by WARNINGS AND PRECAUTIONS: Risk of Thyroid C-cell Tumors: Liraglutide and discontinuation of potentially causative agents, including liraglutide. Use caution Injection Site Reaction 0.6 2.5 placebo-treated patients, included erythema, pruritus, and rash at the injection site. ® causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors when initiating or escalating doses of Saxenda in patients with renal impairment Asthenia 0.8 2.1 0.6% of Saxenda-treated patients and 0.5% of placebo-treated patients discontinued ® (adenomas and/or carcinomas) at clinically relevant exposures in both genders of [see Use in Specific Populations]. Hypersensitivity Reactions: There have been Infections and Infestations treatment due to injection site reactions. Breast Cancer: In Saxenda clinical trials, reports of serious hypersensitivity reactions (e.g., anaphylactic reactions and breast cancer confirmed by adjudication was reported in 17 (0.7%) of 2379 Saxenda- rats and mice. Malignant thyroid C-cell carcinomas were detected in rats and mice. It Gastroenteritis 3.2 4.7 is unknown whether Saxenda® will cause thyroid C-cell tumors, including medullary angioedema) in patients treated with liraglutide [see Contraindications and Adverse treated women compared with 3 (0.2%) of 1300 placebo-treated women, including Urinary Tract Infection 3.1 4.3 thyroid carcinoma (MTC), in humans, as the human relevance of liraglutide-induced Reactions]. If a hypersensitivity reaction occurs, the patient should discontinue invasive cancer (13 Saxenda- and 2 placebo-treated women) and ductal carcinoma in ® rodent thyroid C-cell tumors has not been determined. Cases of MTC in patients Saxenda and other suspect medications and promptly seek medical advice. Viral Gastroenteritis 1.6 2.8 situ (4 Saxenda- and 1 placebo-treated woman). The majority of cancers were treated with liraglutide have been reported in the postmarketing period; the data in Anaphylaxis and angioedema have been reported with other GLP-1 receptor agonists. Investigations estrogen- and progesterone-receptor positive. There were too few cases to determine these reports are insufficient to establish or exclude a causal relationship between Use caution in a patient with a history of anaphylaxis or angioedema with another Increased Lipase 2.2 5.3 whether these cases were related to Saxenda®. In addition, there are insufficient data MTC and liraglutide use in humans. Saxenda® is contraindicated in patients with a GLP-1 receptor agonist because it is unknown whether such patients will be to determine whether Saxenda® has an effect on pre-existing breast neoplasia. ® Psychiatric Disorders personal or family history of MTC or in patients with MEN 2. Counsel patients predisposed to these reactions with Saxenda . Suicidal Behavior and Ideation: Papillary Thyroid Cancer: In Saxenda ® clinical trials, papillary thyroid carcinoma ® Insomnia 1.7 2.4 ® In Saxenda clinical trials, 9 (0.3%) of 3384 Saxenda-treated patients and 2 (0.1%) confirmed by adjudication was reported in 8 (0.2%) of 3291 Saxenda-treated patients regarding the potential risk for MTC with the use of Saxenda and inform them of Anxiety 1.6 2.0 symptoms of thyroid tumors (e.g., a mass in the neck, dysphagia, dyspnea, persistent of the 1941 placebo-treated patients reported suicidal ideation; one of these compared with no cases among 1843 placebo-treated patients. Four of these ® 1 hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of Saxenda-treated patients attempted suicide. Patients treated with Saxenda should Documented symptomatic (defined as documented symptoms of hypoglycemia papillary thyroid carcinomas were less than 1 cm in greatest diameter and 4 were uncertain value for early detection of MTC in patients treated with Saxenda®. Such be monitored for the emergence or worsening of depression, suicidal thoughts or in combination with a plasma glucose less than or equal to 70 mg/dL) in patients diagnosed in surgical pathology specimens after thyroidectomy prompted by ® monitoring may increase the risk of unnecessary procedures, due to low test behavior, and/or any unusual changes in mood or behavior. Discontinue Saxenda in with type 2 diabetes (Study 2). See text below for further information regarding findings identified prior to treatment. Colorectal Neoplasms: In Saxenda ® clinical ® specificity for serum calcitonin and a high background incidence of thyroid disease. patients who experience suicidal thoughts or behaviors. Avoid Saxenda in patients hypoglycemia in patients with and without type 2 diabetes. T2DM = type 2 trials, benign colorectal neoplasms (mostly colon adenomas) confirmed by Significantly elevated serum calcitonin may indicate MTC, and patients with MTC with a history of suicidal attempts or active suicidal ideation. diabetes mellitus adjudication were reported in 20 (0.6%) of 3291 Saxenda-treated patients compared usually have calcitonin values greater than 50 ng/L. If serum calcitonin is measured ADVERSE REACTIONS: The following serious adverse reactions are described * Adverse reactions for trials with treatment period up to 56 weeks with 7 (0.4%) of 1843 placebo-treated patients. Six positively adjudicated cases of and found to be elevated, the patient should be further evaluated. Patients with below or elsewhere in the prescribing information: Risk of Thyroid C-Cell Tumors Hypoglycemia: Saxenda® can lower blood glucose. In a clinical trial involving malignant colorectal neoplasms were reported in 5 Saxenda-treated patients (0.2%, thyroid nodules noted on physical examination or neck imaging should also be [see Warnings and Precautions]; Acute Pancreatitis [see Warnings and Precautions]; patients with type 2 diabetes mellitus and overweight or obesity, severe hypoglycemia mostly adenocarcinomas) and 1 in a placebo-treated patient (0.1%, neuroendocrine further evaluated. Acute Pancreatitis: Based on spontaneous postmarketing Acute Gallbladder Disease [see Warnings and Precautions]; Risk for Hypoglycemia (defined as requiring the assistance of another person) occurred in 3 (0.7%) of 422 tumor of the rectum). Cardiac Conduction Disorders: In Saxenda® clinical trials, 11 reports, acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing with Concomitant Use of Anti-Diabetic Therapy [see Warnings and Precautions]; Saxenda-treated patients and in none of the 212 placebo-treated patients. Each of (0.3%) of 3384 Saxenda-treated patients compared with none of the 1941 placebo- pancreatitis, has been observed in patients treated with liraglutide. After initiation of Heart Rate Increase [see Warnings and Precautions]; Renal Impairment [see Warnings these 3 Saxenda-treated patients was also taking a sulfonylurea. In the same trial, treated patients had a cardiac conduction disorder, reported as first degree Saxenda®, observe patients carefully for signs and symptoms of pancreatitis and Precautions]; Hypersensitivity Reactions [see Warnings and Precautions]; among patients taking a sulfonylurea, documented symptomatic hypoglycemia atrioventricular block, right bundle branch block, or left bundle branch block. (including persistent severe abdominal pain, sometimes radiating to the back and Suicidal Behavior and Ideation [see Warnings and Precautions]. Clinical Trials (defined as documented symptoms of hypoglycemia in combination with a plasma Hypotension: Adverse reactions related to hypotension (that is, reports of which may or may not be accompanied by vomiting). If pancreatitis is suspected, Experience: Because clinical trials are conducted under widely varying conditions, glucose less than or equal to 70 mg/dL) occurred in 48 (43.6%) of 110 Saxenda- hypotension, orthostatic hypotension, circulatory collapse, and decreased blood Saxenda® should promptly be discontinued and appropriate management should be adverse reaction rates observed in the clinical trials of a drug cannot be directly treated patients and 15 (27.3%) of 55 placebo-treated patients. The doses of pressure) were reported more frequently with Saxenda ® (1.1%) compared with initiated. If pancreatitis is confirmed, Saxenda® should not be restarted. In Saxenda® compared to rates in the clinical studies of another drug and may not reflect the sulfonylureas were reduced by 50% at the beginning of the trial per protocol. The placebo (0.5%) in Saxenda® clinical trials. Systolic blood pressure decreases to less clinical trials, acute pancreatitis was confirmed by adjudication in 9 (0.3%) of 3291 rates observed in practice. Saxenda® was evaluated for safety in 5 double-blind, frequency of hypoglycemia may be higher if the dose of sulfonylurea is not reduced. than 80 mmHg were observed in 4 (0.1%) Saxenda-treated patients compared with Saxenda-treated patients and 2 (0.1%) of 1843 placebo-treated patients. In addition, placebo controlled trials that included 3384 overweight or obese patients treated Among patients not taking a sulfonylurea, documented symptomatic hypoglycemia no placebo-treated patients. One of the Saxenda-treated patients had hypotension there were 2 cases of acute pancreatitis in Saxenda-treated patients who prematurely with Saxenda® for a treatment period up to 56 weeks (3 trials), 52 weeks (1 trial), occurred in 49 (15.7%) of 312 Saxenda-treated patients and 12 (7.6%) of 157 associated with gastrointestinal adverse reactions and renal failure [see Warnings withdrew from these clinical trials, occurring 74 and 124 days after the last dose. and 32 weeks (1 trial). All patients received study drug in addition to diet and placebo-treated patients. In Saxenda® clinical trials involving patients without type 2 and Precautions]. Laboratory Abnormalities: Liver Enzymes: Increases in alanine There were 2 additional cases in Saxenda-treated patients, 1 during an off-treatment exercise counseling. In these trials, patients received Saxenda® for a mean treatment diabetes mellitus, there was no systematic capturing or reporting of hypoglycemia, aminotransferase (ALT) greater than or equal to 10 times the upper limit of normal follow-up period within 2 weeks of discontinuing Saxenda®, and 1 that occurred in a duration of 46 weeks (median, 56 weeks). Baseline characteristics included a mean as patients were not provided with blood glucose meters or hypoglycemia diaries. were observed in 5 (0.15%) Saxenda-treated patients (two of whom had ALT greater patient who completed treatment and was off-treatment for 106 days. Liraglutide has age of 47 years, 71% women, 85% white, 39% with hypertension, 15% with type 2 Spontaneously reported symptomatic episodes of unconfirmed hypoglycemia were than 20 and 40 times the upper limit of normal) compared with 1 (0.05%) placebo- been studied in a limited number of patients with a history of pancreatitis. It is diabetes, 34% with dyslipidemia, 29% with a BMI greater than 40 kg/m2, and 9% reported by 46 (1.6%) of 2962 Saxenda-treated patients and 19 (1.1%) of 1729 treated patient during the Saxenda ® clinical trials. Because clinical evaluation to unknown if patients with a history of pancreatitis are at higher risk for development of with cardiovascular disease. In one of the 56-week trials, a subset of patients (with placebo-treated patients. Fasting plasma glucose values obtained at routine clinic exclude alternative causes of ALT and aspartate aminotransferase (AST) increases pancreatitis on Saxenda®. Acute Gallbladder Disease: In Saxenda ® clinical abnormal glucose measurements at randomization) were enrolled for a placebo- visits less than or equal to 70 mg/dL, irrespective of hypoglycemic symptoms, were was not done in most cases, the relationship to Saxenda® is uncertain. Some Visit us online at www.magellanrx.com | 43 increases in ALT and AST were associated with other confounding factors (such as humans at the MRHD of 3 mg/day at all doses, based on plasma AUC comparison. gallstones). Serum Calcitonin: Calcitonin, a biological marker of MTC, was measured Liraglutide decreased fetal weight and dose-dependently increased the incidence of throughout the clinical development program [see Warnings and Precautions]. More total major fetal abnormalities at all doses. The incidence of malformations exceeded patients treated with Saxenda® in the clinical trials were observed to have high concurrent and historical controls at 0.01 mg/kg/day (kidneys, scapula), greater than calcitonin values during treatment, compared with placebo. The proportion of or equal to 0.01 mg/kg/day (eyes, forelimb), 0.025 mg/kg/day (brain, tail and sacral patients with calcitonin greater than or equal to 2 times the upper limit of normal at the vertebrae, major blood vessels and heart, umbilicus), greater than or equal to 0.025 end of the trial was 1.2% in Saxenda-treated patients and 0.6% in placebo-treated mg/kg/day (sternum) and at 0.05 mg/kg/day (parietal bones, major blood vessels). patients. Calcitonin values greater than 20 ng/L at the end of the trial occurred in Irregular ossification and/or skeletal abnormalities occurred in the skull and jaw, 0.5% of Saxenda-treated patients and 0.2% of placebo-treated patients; among vertebrae and ribs, sternum, pelvis, tail, and scapula; and dose-dependent minor patients with pre-treatment serum calcitonin less than 20 ng/L, none had calcitonin skeletal variations were observed. Visceral abnormalities occurred in blood vessels, elevations to greater than 50 ng/L at the end of the trial. Serum Lipase and Amylase: lung, liver, and esophagus. Bilobed or bifurcated gallbladder was seen in all treatment Serum lipase and amylase were routinely measured in the Saxenda® clinical trials. groups, but not in the control group. In pregnant female rats given subcutaneous Among Saxenda-treated patients, 2.1% had a lipase value at anytime during treatment doses of 0.1, 0.25 and 1 mg/kg/day liraglutide from gestation day 6 through weaning of greater than or equal to 3 times the upper limit of normal compared with 1.0% of or termination of nursing on lactation day 24, estimated systemic exposures were placebo-treated patients. 0.1% of Saxenda-treated patients had an amylase value at 0.8-, 3-, and 11-times exposure in obese humans at the MRHD of 3 mg/day, based on anytime in the trial of greater than or equal to 3 times the upper limit of normal versus plasma AUC comparison. A slight delay in parturition was observed in the majority 0.1% of placebo-treated patients. The clinical significance of elevations in lipase or of treated rats. Group mean body weight of neonatal rats from liraglutide-treated amylase with Saxenda® is unknown in the absence of other signs and symptoms of dams was lower than neonatal rats from control group dams. Bloody scabs and pancreatitis [see Warnings and Precautions]. Post-Marketing Experience: The agitated behavior occurred in male rats descended from dams treated with 1 mg/ following adverse reactions have been reported during post-approval use of kg/day liraglutide. Group mean body weight from birth to postpartum day 14 trended liraglutide, the active ingredient of Saxenda®. Because these reactions are reported lower in F2 generation rats descended from liraglutide-treated rats compared to F 2 voluntarily from a population of uncertain size, it is not always possible to reliably generation rats descended from controls, but differences did not reach statistical estimate their frequency or establish a causal relationship to drug exposure. significance for any group. Lactation: Risk Summary: There are no data on the Neoplasms: Medullary thyroid carcinoma [see Warnings and Precautions]; presence of liraglutide in human milk, the effects on the breastfed infant, or effects Gastrointestinal Disorders: Acute pancreatitis, hemorrhagic and necrotizing on milk production. Liraglutide was present in the milk of lactating rats (see Data). pancreatitis, sometimes resulting in death [see Warnings and Precautions]; The developmental and health benefits of breastfeeding should be considered along ® Metabolism and Nutrition Disorders: Dehydration resulting from nausea, vomiting with the mother’s clinical need for Saxenda and any potential adverse effects on ® and diarrhea [see Adverse Reactions]; Renal and Urinary Disorders: Increased serum the breastfed infant from Saxenda or from the underlying maternal condition. creatinine, acute renal failure or worsening of chronic renal failure, sometimes Data: In lactating rats, liraglutide was present unchanged in milk at concentrations requiring hemodialysis [see Warnings and Precautions]; General Disorders and approximately 50% of maternal plasma concentrations. Pediatric Use: Safety and effectiveness of Saxenda® have not been established in pediatric patients. Saxenda® Administration Site Conditions: Allergic reactions: rash and pruritus [see Adverse ® Reactions]; Immune System Disorders: Angioedema and anaphylactic reactions [see is not recommended for use in pediatric patients. Geriatric Use: In the Saxenda Warnings and Precautions]; Hepatobiliary Disorders: Elevations of liver enzymes, clinical trials, 232 (6.9%) of the Saxenda-treated patients were 65 years of age and hyperbilirubinemia, cholestasis and hepatitis [see Adverse Reactions] over, and 17 (0.5%) of the Saxenda-treated patients were 75 years of age and over. No overall differences in safety or effectiveness were observed between these patients DRUG INTERACTIONS: Oral Medications: Saxenda® causes a delay of gastric and younger patients, but greater sensitivity of some older individuals cannot be ruled emptying, and thereby has the potential to impact the absorption of concomitantly out. Renal Impairment: There is limited experience with Saxenda® in patients with administered oral medications. In clinical pharmacology trials, liraglutide did not mild, moderate, and severe renal impairment, including end-stage renal disease. affect the absorption of the tested orally administered medications to any clinically However, there have been postmarketing reports of acute renal failure and worsening relevant degree. Nonetheless, monitor for potential consequences of delayed of chronic renal failure with liraglutide, which may sometimes require hemodialysis absorption of oral medications concomitantly administered with Saxenda®. [see Warnings and Precautions and Adverse Reactions]. Saxenda® should be used USE IN SPECIFIC POPULATIONS: Pregnancy: Risk Summary: Saxenda® is with caution in this patient population. Hepatic Impairment: There is limited contraindicated during pregnancy because weight loss offers no potential benefit to experience in patients with mild, moderate, or severe hepatic impairment. Therefore, a pregnant woman and may result in fetal harm [see Clinical Considerations]. There Saxenda® should be used with caution in this patient population. Gastroparesis: are no available data with liraglutide in pregnant women to inform a drug associated Saxenda® slows gastric emptying. Saxenda ® has not been studied in patients with risk for major birth defects and miscarriage. Saxenda® should not be used during pre-existing gastroparesis. pregnancy. If a patient wishes to become pregnant, or pregnancy occurs, treatment OVERDOSAGE: Overdoses have been reported in clinical trials and post-marketing with Saxenda® should be discontinued. Animal reproduction studies identified use of liraglutide. Effects have included severe nausea and severe vomiting. In the increased adverse embryofetal developmental outcomes from exposure during event of overdosage, appropriate supportive treatment should be initiated according pregnancy. Liraglutide exposure was associated with early embryonic deaths and to the patient’s clinical signs and symptoms. an imbalance in some fetal abnormalities in pregnant rats administered liraglutide More detailed information is available upon request. during organogenesis at doses that approximate clinical exposures at the maximum recommended human dose (MRHD) of 3 mg/day. In pregnant rabbits administered liraglutide during organogenesis, decreased fetal weight and an increased incidence of major fetal abnormalities were seen at exposures below the human exposures at the MRHD [see Animal 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 defects and miscarriage of clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations: Disease-associated maternal and/or embryofetal risk: A minimum weight gain, and no weight loss, is recommended for all pregnant women, including those who are already overweight or obese, due to the necessary weight gain that occurs in maternal tissues during pregnancy. Animal Data: Liraglutide has been shown to be teratogenic in rats at or above 0.8-times systemic exposures in obese humans resulting from the maximum recommended human dose (MRHD) of 3 mg/day based on plasma area under the time-concentration curve (AUC) comparison. Liraglutide Version: 5 has been shown to cause reduced growth and increased total major abnormalities Saxenda® and Victoza® are registered trademarks of Novo Nordisk A/S. in rabbits at systemic exposures below exposure in obese humans at the MRHD based on plasma AUC comparison. Female rats given subcutaneous doses of 0.1, PATENT Information: http://novonordisk-us.com/patients/products/product- 0.25 and 1 mg/kg/day liraglutide beginning 2 weeks before mating through gestation patents.html day 17 had estimated systemic exposures 0.8-, 3-, and 11-times the exposure in Manufactured by: Novo Nordisk A/S, DK-2880 Bagsvaerd, Denmark obese humans at the MRHD based on plasma AUC comparison. The number of early For information about Saxenda® contact: embryonic deaths in the 1 mg/kg/day group increased slightly. Fetal abnormalities Novo Nordisk Inc., 800 Scudders Mill Road, Plainsboro, NJ 08536 and variations in kidneys and blood vessels, irregular ossification of the skull, and a 1-844-363-4448 more complete state of ossification occurred at all doses. Mottled liver and minimally © 2014-2018 Novo Nordisk kinked ribs occurred at the highest dose. The incidence of fetal malformations in US20SX00007 2/2020 liraglutide-treated groups exceeding concurrent and historical controls were misshapen oropharynx and/or narrowed opening into larynx at 0.1 mg/kg/day and umbilical hernia at 0.1 and 0.25 mg/kg/day. Pregnant rabbits given subcutaneous doses of 0.01, 0.025 and 0.05 mg/kg/day liraglutide from gestation day 6 through day 18 inclusive, had estimated systemic exposures less than the exposure in obese 44 | Magellan Rx Report | Spring 2020 increases in ALT and AST were associated with other confounding factors (such as humans at the MRHD of 3 mg/day at all doses, based on plasma AUC comparison. gallstones). Serum Calcitonin: Calcitonin, a biological marker of MTC, was measured Liraglutide decreased fetal weight and dose-dependently increased the incidence of throughout the clinical development program [see Warnings and Precautions]. More total major fetal abnormalities at all doses. The incidence of malformations exceeded patients treated with Saxenda® in the clinical trials were observed to have high concurrent and historical controls at 0.01 mg/kg/day (kidneys, scapula), greater than calcitonin values during treatment, compared with placebo. The proportion of or equal to 0.01 mg/kg/day (eyes, forelimb), 0.025 mg/kg/day (brain, tail and sacral patients with calcitonin greater than or equal to 2 times the upper limit of normal at the vertebrae, major blood vessels and heart, umbilicus), greater than or equal to 0.025 end of the trial was 1.2% in Saxenda-treated patients and 0.6% in placebo-treated mg/kg/day (sternum) and at 0.05 mg/kg/day (parietal bones, major blood vessels). patients. Calcitonin values greater than 20 ng/L at the end of the trial occurred in Irregular ossification and/or skeletal abnormalities occurred in the skull and jaw, 0.5% of Saxenda-treated patients and 0.2% of placebo-treated patients; among vertebrae and ribs, sternum, pelvis, tail, and scapula; and dose-dependent minor patients with pre-treatment serum calcitonin less than 20 ng/L, none had calcitonin skeletal variations were observed. Visceral abnormalities occurred in blood vessels, elevations to greater than 50 ng/L at the end of the trial. Serum Lipase and Amylase: lung, liver, and esophagus. Bilobed or bifurcated gallbladder was seen in all treatment Serum lipase and amylase were routinely measured in the Saxenda® clinical trials. groups, but not in the control group. In pregnant female rats given subcutaneous Among Saxenda-treated patients, 2.1% had a lipase value at anytime during treatment doses of 0.1, 0.25 and 1 mg/kg/day liraglutide from gestation day 6 through weaning of greater than or equal to 3 times the upper limit of normal compared with 1.0% of or termination of nursing on lactation day 24, estimated systemic exposures were placebo-treated patients. 0.1% of Saxenda-treated patients had an amylase value at 0.8-, 3-, and 11-times exposure in obese humans at the MRHD of 3 mg/day, based on anytime in the trial of greater than or equal to 3 times the upper limit of normal versus plasma AUC comparison. A slight delay in parturition was observed in the majority 0.1% of placebo-treated patients. The clinical significance of elevations in lipase or of treated rats. Group mean body weight of neonatal rats from liraglutide-treated amylase with Saxenda® is unknown in the absence of other signs and symptoms of dams was lower than neonatal rats from control group dams. Bloody scabs and pancreatitis [see Warnings and Precautions]. Post-Marketing Experience: The agitated behavior occurred in male rats descended from dams treated with 1 mg/ following adverse reactions have been reported during post-approval use of kg/day liraglutide. Group mean body weight from birth to postpartum day 14 trended liraglutide, the active ingredient of Saxenda®. Because these reactions are reported lower in F2 generation rats descended from liraglutide-treated rats compared to F 2 voluntarily from a population of uncertain size, it is not always possible to reliably generation rats descended from controls, but differences did not reach statistical estimate their frequency or establish a causal relationship to drug exposure. significance for any group. Lactation: Risk Summary: There are no data on the Neoplasms: Medullary thyroid carcinoma [see Warnings and Precautions]; presence of liraglutide in human milk, the effects on the breastfed infant, or effects Gastrointestinal Disorders: Acute pancreatitis, hemorrhagic and necrotizing on milk production. Liraglutide was present in the milk of lactating rats (see Data). pancreatitis, sometimes resulting in death [see Warnings and Precautions]; The developmental and health benefits of breastfeeding should be considered along ® Metabolism and Nutrition Disorders: Dehydration resulting from nausea, vomiting with the mother’s clinical need for Saxenda and any potential adverse effects on ® and diarrhea [see Adverse Reactions]; Renal and Urinary Disorders: Increased serum the breastfed infant from Saxenda or from the underlying maternal condition. Managing Obesity: creatinine, acute renal failure or worsening of chronic renal failure, sometimes Data: In lactating rats, liraglutide was present unchanged in milk at concentrations approximately 50% of maternal plasma concentrations. Pediatric Use: Safety and requiring hemodialysis [see Warnings and Precautions]; General Disorders and ® ® Administration Site Conditions: Allergic reactions: rash and pruritus [see Adverse effectiveness of Saxenda have not been established in pediatric patients. Saxenda ® Employer Weight-Management Programs and Gaps Reactions]; Immune System Disorders: Angioedema and anaphylactic reactions [see is not recommended for use in pediatric patients. Geriatric Use: In the Saxenda Warnings and Precautions]; Hepatobiliary Disorders: Elevations of liver enzymes, clinical trials, 232 (6.9%) of the Saxenda-treated patients were 65 years of age and hyperbilirubinemia, cholestasis and hepatitis [see Adverse Reactions] over, and 17 (0.5%) of the Saxenda-treated patients were 75 years of age and over. No overall differences in safety or effectiveness were observed between these patients in Strategies DRUG INTERACTIONS: Oral Medications: Saxenda® causes a delay of gastric and younger patients, but greater sensitivity of some older individuals cannot be ruled emptying, and thereby has the potential to impact the absorption of concomitantly out. Renal Impairment: There is limited experience with Saxenda® in patients with Obesity is the greatest contributor to the economic burden of chronic disease in the U.S. administered oral medications. In clinical pharmacology trials, liraglutide did not mild, moderate, and severe renal impairment, including end-stage renal disease. affect the absorption of the tested orally administered medications to any clinically However, there have been postmarketing reports of acute renal failure and worsening relevant degree. Nonetheless, monitor for potential consequences of delayed of chronic renal failure with liraglutide, which may sometimes require hemodialysis absorption of oral medications concomitantly administered with Saxenda®. ® should be used [see Warnings and Precautions and Adverse Reactions]. Saxenda Nearly 40% of adults in the U.S. suffer from obesity, a rate that continues to rise every year.1 In 2016, USE IN SPECIFIC POPULATIONS: Pregnancy: Risk Summary: Saxenda® is with caution in this patient population. Hepatic Impairment: There is limited contraindicated during pregnancy because weight loss offers no potential benefit to experience in patients with mild, moderate, or severe hepatic impairment. Therefore, 100.3 million and 80.2 million U.S. residents lived with obesity and overweight, respectively.2 Patients ® a pregnant woman and may result in fetal harm [see Clinical Considerations]. There Saxenda should be used with caution in this patient population. Gastroparesis: with obesity, a disease known to be chronic and progressive, have a higher prevalence of serious comor- are no available data with liraglutide in pregnant women to inform a drug associated Saxenda® slows gastric emptying. Saxenda ® has not been studied in patients with risk for major birth defects and miscarriage. Saxenda® should not be used during pre-existing gastroparesis. bid conditions — including Type 2 diabetes, hypertension, and cardiovascular disease — than those with pregnancy. If a patient wishes to become pregnant, or pregnancy occurs, treatment OVERDOSAGE: Overdoses have been reported in clinical trials and post-marketing normal body mass index (BMI).3, 4 The significance of the disease is compounded by its economic impact. ® with Saxenda should be discontinued. Animal reproduction studies identified use of liraglutide. Effects have included severe nausea and severe vomiting. In the Obesity accounts for 47.1% of the total cost of chronic diseases nationwide, making it the greatest con- increased adverse embryofetal developmental outcomes from exposure during event of overdosage, appropriate supportive treatment should be initiated according pregnancy. Liraglutide exposure was associated with early embryonic deaths and to the patient’s clinical signs and symptoms. tributor to the economic burden of chronic disease in the U.S.2 The estimated annual healthcare costs an imbalance in some fetal abnormalities in pregnant rats administered liraglutide More detailed information is available upon request. associated with obesity range from $147 to $210 billion.5 Weight-related complications associated with during organogenesis at doses that approximate clinical exposures at the maximum recommended human dose (MRHD) of 3 mg/day. In pregnant rabbits administered obesity and overweight (such as Type 2 diabetes, hypertension, and cardiovascular disease) accounted liraglutide during organogenesis, decreased fetal weight and an increased incidence for $480.7 billion in direct healthcare costs in 2016 alone, with another $1.24 trillion in indirect costs of major fetal abnormalities were seen at exposures below the human exposures at the 2 MRHD [see Animal Data]. The estimated background risk of major birth defects and Lindsay C. Speicher, J.D. due to lost economic productivity. Projections by health economists indicate that total annual health- miscarriage for the indicated populations is unknown. In the U.S. general population, Project Manager care costs attributable to obesity will be between $860.7 and $956.9 billion by the year 2030.3 Average the estimated background risk of major birth defects and miscarriage of clinically Magellan Method medical claims cost per 100 members with obesity ($51,019) is 7.3 times greater than for members recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations: Disease-associated maternal and/or embryofetal risk: A minimum weight gain, without obesity ($7,503).6 Indirect costs related to obesity include job absenteeism — which can range and no weight loss, is recommended for all pregnant women, including those who from $3.38 billion to $6.38 billion annually — and lower productivity, or presenteeism, estimated at are already overweight or obese, due to the necessary weight gain that occurs in 7, 8 maternal tissues during pregnancy. Animal Data: Liraglutide has been shown to $506 per worker with obesity per year. A study published in November 2019 reported that Ameri- be teratogenic in rats at or above 0.8-times systemic exposures in obese humans can employees with obesity cost $1,158 more per person per year than employees without obesity, resulting from the maximum recommended human dose (MRHD) of 3 mg/day based concluding that obesity was associated with high costs among employees across major U.S. industries.9 on plasma area under the time-concentration curve (AUC) comparison. Liraglutide Version: 5 has been shown to cause reduced growth and increased total major abnormalities Saxenda® and Victoza® are registered trademarks of Novo Nordisk A/S. in rabbits at systemic exposures below exposure in obese humans at the MRHD Costs associated with lost productivity and absenteeism, in addition to healthcare costs, result in a based on plasma AUC comparison. Female rats given subcutaneous doses of 0.1, PATENT Information: http://novonordisk-us.com/patients/products/product- 0.25 and 1 mg/kg/day liraglutide beginning 2 weeks before mating through gestation patents.html substantial financial burden for employers, incentivizing many to implement weight-management pro- day 17 had estimated systemic exposures 0.8-, 3-, and 11-times the exposure in Manufactured by: Novo Nordisk A/S, DK-2880 Bagsvaerd, Denmark grams to target obesity in their employee populations. A 2014 poll of large employers revealed that ® obese humans at the MRHD based on plasma AUC comparison. The number of early For information about Saxenda contact: 10 embryonic deaths in the 1 mg/kg/day group increased slightly. Fetal abnormalities Novo Nordisk Inc., 800 Scudders Mill Road, Plainsboro, NJ 08536 50% are focusing on weight management, with 20% reporting it would be their top priority in 2015. and variations in kidneys and blood vessels, irregular ossification of the skull, and a 1-844-363-4448 Employers have a variety of options when it comes to weight-management programs. Some include pro- more complete state of ossification occurred at all doses. Mottled liver and minimally © 2014-2018 Novo Nordisk viding access via employer-provided health insurance plans to lifestyle change agents such as wellness kinked ribs occurred at the highest dose. The incidence of fetal malformations in US20SX00007 2/2020 liraglutide-treated groups exceeding concurrent and historical controls were coaches to aid behavior modification; online tracking tools to aid in caloric “accounting”; onsite and/or misshapen oropharynx and/or narrowed opening into larynx at 0.1 mg/kg/day and digital behavior-modification classes through commercial weight-loss providers such as WW or online umbilical hernia at 0.1 and 0.25 mg/kg/day. Pregnant rabbits given subcutaneous doses of 0.01, 0.025 and 0.05 mg/kg/day liraglutide from gestation day 6 through day 18 inclusive, had estimated systemic exposures less than the exposure in obese Visit us online at www.magellanrx.com | 45 MANAGING OBESITY | Continued

and progressive nature of obesity is taken into account. Consider- ing that more than 60% of Americans are insured through their A study published in employers, this presents a substantial barrier to the healthcare that employees with obesity or overweight need.14 Overall, lack of November 2019 reported coverage by employer-provided health plans for weight loss treatments — such as medical visits for overweight or obesity treat- that employees with ment, behavioral health intervention, anti-obesity pharmacologic treatment, and bariatric surgery — is a major obstacle in effectively obesity cost $1,158 more targeting and managing obesity and overweight in employee populations.15 Employers are in an optimal position to improve obesi- per person per year than ty- and overweight-related management and treatment by increas- employees without obesity, ing access to appropriate care via benefit design.15 concluding that obesity was associated with high costs Current Weight-Management Programs Less than 20% of employers in a 2016 poll agreed that their cur- among employees across rent strategy promoting healthy weight was effective.16 Employee engagement is a major challenge cited by nearly 60% of employ- major U.S. industries. ers, and about half of employers report a rate of only 10% for employee participation in weight-management programs.10, 17 These low rates of engagement could be attributed to the nature and focus of many employer-provided weight-management programs. One study showed that most employers (more than 80%) provided coverage for bariatric surgery, yet most did not cover weight loss weight-control programs; healthy alternative food options onsite; medications.16 While bariatric surgery is a proven effective treat- and referrals to weight-management content, including education ment of obesity for eligible patients, Magellan Rx explored the on nutrition and better healthy dietary choices, through an employ- structure of employer-provided benefit designs focusing largely er-provided insurer website.11 These programs largely mirror each on bariatric surgery and the associated gap in care for overweight other in offerings, focusing on tracking food and calorie intake and or obese patients who are not eligible for or not interested in this behavior modification. However, the returns seen through offering type of intervention. employees weight-management resources are highly variable; few lead to a meaningful improvement in outcomes, largely due to the heterogeneity of the composition of these programs.

Under the Affordable Care Act, employers are permitted to impose penalties and rewards on employees in accordance with specific health-related outcomes, including BMI, blood pressure, and cholesterol; however, only about 5% of large employers utilized this type of program in 2015.12, 13 An online study conducted in 2013 showed 16% of employees reporting that their respective employers require participation in wellness programs to receive full health benefits. The same study showed that while most employees reported that reduced weight is the most common target with outcomes-based incentives in employer wellness programs, which typically rely on often inaccurate self-reporting to track weight change, most of those employees also reported they did not have access to evidence-based, comprehensive obesity treatment in their employer-provided health plan.3 Lack of access to evidence-based obesity treatment is significant when the chronic

46 | Magellan Rx Report | Spring 2020 Benefit structures that focus on bariatric surgery can potentially discourage patients from losing weight or first trying effective treatment alternatives that are much less costly and invasive. In Ultimately, a benefit design many benefit designs, access to bariatric surgery is conditional upon a specified length — usually three to 12 months — of weight that is reliant on surgery loss and counseling prior to surgery.16 This additional effort and challenge may present a burden employees are unwilling to over- precludes employees from come, thus precluding them from eligibility. Additionally, many employees may not fully participate for the prescribed length of time preventively addressing in an effort to avoid too much weight loss, which may render them ineligible for bariatric surgery. It is important to note that patients obesity. No other chronic with other diseases are not treated with this strategy; for example, disease is treated this way. a patient with breast cancer would not be expected to attempt to shrink a tumor on their own prior to being eligible for mastectomy. The patient would initially be offered chemotherapy plus surgery to address the medical condition immediately.

The approach to successful employer weight-management pro- efit design. With this benefit-structured focus, employer-provided grams should incorporate resources for all employees that could or -supported weight-management interventions are likely to be benefit from weight loss, not exclusively employees qualifying for considered only once an employee with obesity has reached a de- bariatric surgery. According to the American Association of Clini- gree at which he or she is considered as a candidate for bariatric cal Endocrinologists (AACE) guidelines, behavioral therapy is the surgery. Ultimately, a benefit design that is reliant upon bariatric cornerstone for treating overweight and obesity, and a structured surgery as the primary weight-loss intervention precludes employ- lifestyle intervention program consisting of a healthy meal plan, ees from preventively addressing weight gain, overweight, or obe- physical activity, and behavioral interventions should be available. sity with employer-sponsored initiatives. No other chronic disease AACE guidelines make clear that an effective approach to treating is treated this way, in which surgery is first. overweight and obesity includes a behavior-intervention package executed by a multidisciplinary team that includes dietitians, As such, current employer-provided weight-management offerings nurses, educators, physical activity trainers or coaches, and clin- usually fail to provide effective promotion of exercise and healthy ical psychologists, and that behavioral health specialists such as eating for a reasonable duration; typically, at least one year would psychologists or psychiatrists should participate in the treatment be considered an effective duration in order for meaningful results of underlying eating disorders, depression, anxiety, psychoses, to be achieved. They are likely to limit the opportunity to offer com- or other psychological issues that often attribute to overweight prehensively designed, tailored interventions to suit each individ- or obesity and can impair the effectiveness of lifestyle interven- ual’s clinical status. Ideally, weight-management programs should tion programs.19 Without proper behavioral health intervention, look beyond offering access to bariatric surgery and should provide approaches to obesity and overweight treatment or weight-loss access to pharmacotherapy options, behavioral health therapy, and programs often prove ineffective long-term. As AACE notes, oth- other appropriate therapies that are part of a customized treatment er people may need pharmacotherapy to assist in carrying out the plan based on patients’ weight status, history of weight loss, and reduced-calorie diet recommendations.19 obesity-related comorbidities.

Due to the complexity of the underlying causes of obesity, man- Gaps in Current Weight-Management agement and treatment must be multifaceted.20 Research shows Benefit Designs that adherence to a combination of treatment components can lead to greater weight loss, as well as improvement in related For most employers, the decision to commit to and offer access to health risks.21 A National Institute of Health (NIH) report stated: weight-management support programs becomes centered on the “Effective weight control involves multiple techniques and strate- decision to provide coverage for bariatric surgical interventions gies including dietary therapy, physical activity, behavior therapy, for employees meeting health plan-recommended, employer- pharmacotherapy, and surgery, as well as combinations of these supported criteria. Weight-management programs that focus on strategies.”22 There is a need for a multidisciplinary approach that surgical interventions are, as a result, based around medical ben- includes behavioral counseling, support, or education components

Visit us online at www.magellanrx.com | 47 MANAGING OBESITY | Continued

in the current weight-management approach taken by employer- provided benefits, whereas a more effective model would con- structively coordinate the medical benefit and pharmacy benefit and integrate within the broader employer-sponsored initiative. Lack of integration across the medical and pharmacy benefits and the employer-sponsored programs presents a significant gap.

Evidence of this gap is found when assessing employer-based programs that focus on the prescription drug benefit and access to pharmacologic therapies to support weight-loss efforts. Prescrip- tion drug benefit policies governing access to these therapies are not widely available and are typically restrictive; in many cases, pharmacotherapies are not even available as part of the standard pharmacy benefit. When included in the pharmacy benefit drug formulary, weight-loss drugs are likely to require nearly insur- mountable prior authorization review and approval processes or have high out-of-pocket costs.

Patients with obesity need access to behavioral health support. Growing evidence suggests that offering bariatric surgery as the primary solution to obesity can be ineffective, as it does not address the behavioral health of employees with obesity. Studies show 20% of patients experience substantial weight regain after surgery.23 Post-surgery weight regain can often be attributed to addictive behaviors and food urges, as well as lack of self- monitoring.24 Studies have shown that unrecognized and untreated eating and psychiatric disorders may lead to post-surgery weight regain in some patients; cognitive behavioral treatment has shown in the design of weight-loss interventions in order to improve long- more success in treating these types of disorders than programs term success.20 An example of this type of approach may include without a behavioral or psychological component.25 physical activity, behavior therapy, and pharmacotherapy, where appropriate, with weight-loss surgery as an option where other The absence of a program structure that results in early or pre- treatment options have failed.22 Additionally, according to the NIH, ventive formal involvement with weight-management programs after six months of initial weight loss, the rate of weight loss tends results in gaps in care, despite employers’ best intentions. Current- to plateau due to the physiologic response to weight loss that ly, few existing programs intervene in a comprehensive or struc- defends the higher fat mass, thus promoting weight regain again; tured manner prior to the point where members have obesity of a thus, after targeted weight loss goals are achieved, individuals degree that warrants surgical intervention. In an effort to address must continue multifaceted therapy indefinitely for maintenance.22 these challenges, Magellan Rx began to explore the necessary steps to develop a comprehensive weight-management program A multifaceted weight-management program would likely include that includes accessible behavior modification, lifestyle modifica- a combination of medical benefits, pharmacy benefits, and em- tion, nutritional modification, physical activity, pharmacotherapy, ployer-sponsored programs; managing a program that includes and metabolic surgery. support from various sources can be challenging and would require a unique and targeted benefit design. Moving Forward Access to obesity-targeting pharmacologic agents would be implemented through pharmacy benefits, while programs such as life- In the next issue of the Magellan Rx Report, we will explore the style coaching and physical activity initiatives are typically employ- paths employers can take to develop and implement these er-sponsored; behavioral therapy, weight-loss surgery, and office weight-management programs as well as potential challenges they visits fall under medical benefits. A certain disjointedness exists may face.

48 | Magellan Rx Report | Spring 2020 References

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Ochner, Christopher N. et al. “Treating obesity seriously: when Health Annual Wellness Summit, September 2016, https://www. recommendations for lifestyle change confront biological gpbch.org/docs/gpbch_employer_weight_management_survey_ adaptations.” The Lancet: Diabetes and Endocrinology, Feb. 11, final20160914.pdf. 2015, https://www.thelancet.com/journals/landia/article/PIIS2213- 17. Nyce, Steven. “Boosting Wellness Participation Without 8587(15)00009-1/fulltext. Breaking the Bank. Willis Towers Watson, July 2010, http:// 5. “The State of Obesity 2017: Better Policies for a Healthier America.” www.towerswatson.com/en-US/Insights/Newsletters/Americas/ Trust for America’s Health, 2017, https://stateofobesity.org/ insider/2010/boosting-wellness-participation-without-breaking- healthcare-costs-obesity/. the-bank. 6. Pickering, Laurel et al. “Weight Control and the Workplace: 18. Garvey, W. Timothy et al. “American Association of Clinical Employers and Health Plans Explore Their Toughest Health Endocrinologists and American College of Endocrinology Clinical Improvement Challenge.” Northeast Business Group on Health, Practice Guidelines for Comprehensive Medical Care of Patients 2013, nebgh.org/wp-content/uploads/2016/04/NEBGH_SC_ with Obesity — Executive Summary.” Endocrine Practice, May 24, WeightControlFINAL10-31-13.pdf. 2016, https://www.ncbi.nlm.nih.gov/pubmed/27219496. 7. Trogdon, Justin G. et al. “Indirect costs of obesity: A review of the 19. Hafekost, Katherine et al. “Tackling overweight and obesity: does current literature.” Obesity Reviews, September 2008, https://www. the public health message match the science?” BMC Medicine, ncbi.nlm.nih.gov/pubmed/18331420. Feb. 18, 2013, https://bmcmedicine.biomedcentral.com/ articles/10.1186/1741-7015-11-41. 8. Gates, Donna M. et al. “Obesity and presenteeism: the impact of body mass index on workplace productivity.” Journal of 20. Acharya, Sushama D. et al. “Adherence to a behavioral weight Occupational and Environmental Medicine, January 2008, https:// loss treatment program enhances weight loss and improvements www.ncbi.nlm.nih.gov/pubmed/18188080. in biomarkers.” Patient Preference and Adherence, Nov. 3, 2009, https://www.ncbi.nlm.nih.gov/pubmed/19936157. 9. Ramasamy Abhilasha et al. “Direct and Indirect Cost of Obesity Among the Privately Insured in the United States.” Journal of 21. “The Practical Guide: Identification, Evaluation, and Treatment of Occupational and Environmental Medicine, November 2019, Overweight and Obesity in Adults.” National Institutes of Health, https://journals.lww.com/joem/Fulltext/2019/11000/Direct_and_ National Heart, Lung, and Blood Institute Obesity Education Indirect_Cost_of_Obesity_Among_the.3.aspx#pdf-link. Initiative, 2000, https://www.nhlbi.nih.gov/files/docs/guidelines/ prctgd_c.pdf. 10. “Large Employers’ 2015 Health Plan Design Survey.” National Business Group on Health, August 2014, http://www.fightthe40. 22. Karasu, Sylvia R. “Psychotherapy-lite: obesity and the role of the com/AlliancetoFightThe40/assets/File/Studies/2015_NBGH_ mental health practitioner.” American Journal of Psychotherapy, health_plan_design_survey.pdf. 2013, https://www.ncbi.nlm.nih.gov//pubmed/23682511. 11. “Designing and Managing Wellness Programs.” Society for 23. Odom, J. et al. “Behavioral predictors of weight regain after Human Resource Management, June 15, 2016, https://www. bariatric surgery.” Obesity Surgery, June 25, 2009, https://www. shrm.org/resourcesandtools/tools-and-samples/toolkits/pages/ ncbi.nlm.nih.gov/pubmed/19554382. designingandmanagingwellnessprograms.aspx. 24. Maleckas, Almantas et al. “Weight regain after gastric bypass: 12. “About the Affordable Care Act.” Department of Health and Human etiology and treatment options.” Gland Surgery, December 2016, Services, July 3, 2017, https://www.hhs.gov/healthcare/about-the- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5233838/. aca/index.html.

Visit us online at www.magellanrx.com | 49 PIPELINE DRUG LIST

PIPELINE DRUG LIST

Dosage Expected FDA Name Manufacturer Clinical Use Approval Status Form Approval

Genentech Inc.; Chugai HCC (unresectable, atezolizumab (Tecentriq®) IV BLA; breakthrough therapy March-April 2020 Pharmaceutical Co. Ltd. first line)

Genentech; Chugai HCC (unresectable, bevacizumab (Avastin®) Pharmaceutical Co. Ltd.; Cipla IO, IV BLA March-April 2020 first line) Limited; PDL BioPharma Inc.

Glaucoma/ocular bimatoprost sustained release Allergan PLC IO Submitted March-April 2020 hypertension

Mundipharma International celecoxib and tramadol (E-58425) Moderate to severe pain PO Submitted March-April 2020 Ltd.; Esteve SA

CRC (mutant, metastatic, Pfizer Inc.; Ono Pharmaceutical encorafenib (Braftovi®) in combination with PO Breakthrough therapy April 2020 Co. Ltd. cetuximab)

Acceleron Pharma Inc.; Bristol- luspatercept-aamt (Rebloyzl®) MDS SQ Fast track; orphan drug 04/03/2020 Myers Squibb Company

Acacia Pharma Group PLC; Cosmo Pharmaceuticals N.V.; Hana Pharma Co. Ltd.; remimazolam (ByFavo™) Anesthesia/sedation IV Submitted 04/03/2020 Mundipharma International Ltd.; PAION AG; Pharmascience Inc.

Bladder cancer (low Breakthrough therapy; fast mitomycin (MitoGel™) UroGen Pharma Ltd. Intravesical 04/17/2020 grade, upper tract) track; orphan drug

Meningococcal meningococcal conjugate vaccine vaccines and other Sanofi IM BLA 04/24/2020 (Men Quad TT) meningococcal-specific agents (antibacterial)

Neurocrine Biosciences Inc.; Bial Pharmaceuticals; Parkinson’s disease (off opicapone (Ongentys®) Ono Pharmaceutical Co. PO Submitted 04/24/2020 episodes) Ltd.; Shanghai Fosun Pharmaceutical Co. Ltd.

United Therapeutics treprostinil patch pump Corporation; Cipher PAH; PH SQ Orphan drug 04/27/2020 (Trevyent®) Pharmaceuticals Inc.

Roche Holding AG; Chugai Breakthrough therapy; satralizumab Devic’s disease (NMO) SQ April-May 2020 Pharmaceutical Co. Ltd. orphan drug

AstraZeneca PLC; Cancer Breakthrough therapy; selumetinib Research UK; Merck & Co. Inc.; NF PO April-May 2020 orphan drug Pfizer Inc.

50 | Magellan Rx Report | Spring 2020 PIPELINE DRUG LIST

PIPELINE DRUG LIST CONT.

Dosage Expected FDA Name Manufacturer Clinical Use Approval Status Form Approval

Sumitomo Dainippon Pharma dasotraline Binge-eating disorder PO Submitted 05/14/2020 Co. Ltd.

Clovis Oncology, Inc.; Pfizer rucaparib (Rubraca®) Prostate cancer IV; PO Breakthrough therapy 05/15/2020 Inc.

Sumitomo Dainippon Parkinson’s disease (off apomorphine (APL-130277) Pharma Co. Ltd.; Aquestive SL Fast track 05/21/2020 episodes) Therapeutics Inc.

Roche Holding AG; Chugai Breakthrough therapy; fast risdiplam Pharmaceutical Co. Ltd.; PTC SMA PO 05/22/2020 track; orphan drug Therapeutics Inc.

La Jolla Pharmaceutical Breakthrough therapy; artesunate (LJPC-0118) Malaria (severe) 05/25/2020 Company orphan drug

Bladder cancer nadofaragene firadenovec FKD Therapies Oy; Ferring (high-grade, BCG- BLA; breakthrough therapy; 05/11/2020- Intravesical (Instiladrin®) Pharmaceuticals unresponsive, fast track 06/11/2020 nonmuscle-invasive)

AstraZeneca PLC; Cancer olaparib (Lynparza®) Prostate cancer PO Breakthrough therapy May-June 2020 Research UK; Merck & Co. Inc.

Novartis AG; Genmab A/S; ofatumumab (Arzerra®) MS (relapsing) IV; SQ BLA June 2020 GlaxoSmithKline PLC

biosimilar pegfilgrastim Pfizer Inc. Neutropenia/leukopenia SQ BLA June 2020

minocycyline (FMX103) Foamix Pharmaceuticals Ltd. Rosacea Topical Submitted 06/02/2020

Immunomedics, Inc.; Everest Breast cancer (triple BLA; breakthrough therapy; sacituzumab govitecan Medicines Limited; Royalty negative, metastatic, >2 IV 06/02/2020 fast track Pharma AG prior therapies)

viltolarsen Nippon Shinyaku Co. Ltd. DMD IV Fast track; orphan drug 06/02/2020

imipenem/cilastatin/relebactam Fast track; qualified Merck & Co. Inc. HAP IV 06/04/2020 (Recarbrio™) infectious disease drug

AbbVie Inc.; Neurocrine elagolix (Orlissa®) Uterine fibroids PO Submitted 06/05/2020 Biosciences Inc.

Bausch Health Companies Inc.; ketotifen (EM-100) Allergic conjunctivitis Ophthalmic Submitted 06/11/2020 Eton Pharmaceuticals Inc.

Follicular lymphoma Royalty Pharma AG; Eisai Co. tazemetostat (Tazverik™) (relapsed/refractor, 2+ PO Fast track; orphan drug 06/18/2020 Ltd.; Epizyme Inc. prior therapies)

Urinary tract infections Fast track; qualified fosfomycin (Contepo™) Nabriva Therapeutics PLC IV 06/19/2020 (complicated) infectious disease drugs

Visit us online at www.magellanrx.com | 51 PIPELINE DRUG LIST

PIPELINE DRUG LIST CONT.

Dosage Expected FDA Name Manufacturer Clinical Use Approval Status Form Approval

Evoke Pharma Inc.; metoclopramide (Gimoti™) Diabetic gastroparesis IN Submitted 06/19/2020 Mallinckrodt PLC

Diffuse large B-cell Karyopharm Therapeutics; lymphoma (relased/ Antengene Corporation; refractory, post >2 selinexor (Xpovio®) HealthCare Royalty Partners; PO Fast track; orphan drug 06/23/2020 multi-drug therapies, Ono Pharmaceutical Co. Ltd.; bone marrow transplant- Promedico Ltd. ineligible)

obeticholic acid (Ocaliva®) Intercept Pharmaceuticals Inc. NASH PO Breakthrough therapy 06/26/2020

octreotide acetate (Mycapssa®) Chiasma Inc. Acromegaly PO Orphan drug 06/26/2020

Cutaneous squamous cell carcinoma Merck & Co. Inc.; DRI Capital pembrolizumab (Keytruda®) (recurrent, metastatic; IV BLA 06/29/200 Inc. not curable with surgery/radiation)

Viela Bio Inc.; Hansoh Pharmaceutical Group Co. Ltd.; BLA; breakthrough therapy; 06/13/2020- inebilizumab Devic’s disease (NMO) IV Mitsubishi Tanabe Pharma orphan drug 07/13/2020 Corporation

Allergan PLC; Molecular abicipar pegol Wet AMD IO BLA June-July 2020 Partners AG

Migraine and other celecoxib (DFN-15) Dr. Reddy’s Laboratories PO Submitted June-July 2020 headaches

nintedanib (Ofev®) Boehringer Ingelheim GmbH Pulmonary fibrosis PO Breakthrough therapy July 2020

Endo International PLC; collagenase clostridium BioSpecifics Technologies Cellulite SQ BLA 07/06/2020 histolyticum Corp.

dantrolene sodium (Ryanodex®) Eagle Pharmaceuticals Inc. Heat stroke (exertional) IV Fast track; orphan drug 07/09/2020

Janssen Pharmaceutica; daratumumab/rHuPH20 Genmab A/S; Halozyme MM SQ BLA 07/10/2020 Therapeutics, Inc.

cantharidin (Ycanth™) Verrica Pharmaceticals Inc. Molluscum contagiosum Topical Submitted 07/13/2020

Janssen Pharmaceutica; guselkumab (Tremfya®) MorphoSys AG; Otsuka PA IV; SQ BLA 07/16/2020 Holdings Co. Ltd.

oxymetazoline hydrochloride Osmotica Pharmaceuticals PLC Acquired blepharoptosis Topical Submitted 07/16/2020 (RVL-1201)

Grünenthal GmbH; Acorda capsaicin (Qutenza®) Therapeutics Inc.; NeurogesX DPN Topical Submitted 07/17/2020 Inc.

52 | Magellan Rx Report | Spring 2020 PIPELINE DRUG LIST

PIPELINE DRUG LIST CONT.

Dosage Expected FDA Name Manufacturer Clinical Use Approval Status Form Approval

calcipotriene/betamethasone MC2 Therapeutics A/S Psoriasis Topical Submitted 07/20/2020 dipropionate (Wynzora™ Cream)

lower-sodium oxybate (JZP-258) Jazz Pharmaceuticals PLC Narcolepsy PO Orphan drug 07/21/2020

donepezil (Adlarity) Corium International Inc. Alzheimer’s disease TD Submitted 07/30/2020

GlaxoSmithKline PLC; Innoviva fluticasone furoate/umeclidinium/ Inc.; Theravance Biopharma, Asthma Inhaled Submitted 07/31/2020 vilanterol (Trelegy Ellipta) Inc.

Ultragenyx Pharmaceutical Inc.; Baylor Scott & White Fatty acid oxidation triheptanoin PO Fast track; orphan drug 07/31/2020 Research Institute; UniQuest disorders Pty Limited

NSCLC (RET-altered); Eli Lilly and Company; Pfizer Breakthrough therapy; 07/15/2020- selpercatinib thyroid cancer (RET- PO Inc. orphan drug 08/14/2020 altered)

AstraZeneca PLC; The Atherosclerosis (in ticagrelor (Brilinta®) PO Submitted May-August 2020 Medicines Company patients with T2DM)

Genentech Inc.; DRI Capital May-September omalizumab (Xolair®) Inc.; Novartis AG; PDL Nasal polyposis SQ BLA 2020 BioPharma Inc.

Merck & Co. Ltd.; 3SBio Inc.; NSCLC; CRC; biosimilar bevacizumab Mundipharma International glioblastoma; ovarian IV BLA July-August 2020 Ltd.; Samsung Bioepis Co. Ltd. cancer; RCC

cedazuridine and decitabine Otsuka Holdings Co., Ltd. MDS; CMML PO Orphan drug July-August 2020 (ASTX727)

Catheter complications (prevention of Fast track; qualified July-December taurolidine (Neutrolin®) CorMedix Inc. catheter-related IV infectious disease drug 2020 bloodstream infection in hemodialysis patients)

insulin lispro, ultra-rapid July-October Eli Lilly and Company T1DM; T2DM SQ Submitted (LY900014) 2020

Eli Lilly and Company; Alzheimer’s disease — July-September flortaucipir F 18 IV Submitted Siemens AG imaging 2020

Abbreviations: AMD=age-related macular degeneration; BCG=Bacillus Calmette-Guerin; BLA=biologics license application; CMML=chronic myelomonocytic leukemia; CRC=colorectal cancer; DMD=Duchenne muscular dystrophy; DPN=diabetic peripheral neuropathy; HAP=hospital-acquired pneumonia; HCC=hepatocellular carcinoma; IM=intramuscular; IN=intranasal; IO=intraocular; IV=intravenous; MDS=myelodysplastic syndrome; MM=multiple myeloma; MS=multiple sclerosis; NASH=nonalcoholic steatohepatitis; NF=neurofibromatosis; NMO=neuromyelitis optica; NSCLC=non- small cell lung cancer; PA=psoriatic arthritis; PAH=pulmonary arterial hypertension; PH=pulmonary hypertension; PO=oral; RCC=renal cell carcinoma; SL=sublingual; SMA=spinal muscular atrophy; SQ=subcutaneous; T1DM=type 1 diabetes mellitus; T2DM=type 2 diabetes mellitus

Visit us online at www.magellanrx.com | 53

A Missed Opportunity to Recognize Narcolepsy Symptoms Can Have a Significant Impact on Pediatric Patients

$ Personality and Behavior Academic Economic Anxiety, depression, introversion, About 3.5 times higher likelihood 5 times higher medical feelings of inferiority, and of repeating a grade vs pediatric costs vs pediatric patients sorrowfulness1-3 patients without narcolepsy4* without narcolepsy5†

Visit NarcolepsyLink.com/Pediatric to learn more about pediatric narcolepsy.

* Based on a health-related quality of life (HRQL) study assessed through a questionnaire completed by children and adolescents with narcolepsy (N=117) and control subjects (N=69). Academic performance was evaluated in the study.4 † Based on a retrospective, cross-sectional, case-control, claims-based analysis of health care utilization and costs, that included narcolepsy patients ≤18 years of age (N=1427) and control subjects (N=4281).5

References: 1. Nevsimalova S. Narcolepsy in childhood. Sleep Med Rev. 2009;13(2):169-180. 2. Marcus C. Daytime sleepiness in children: when a quiet child is not necessarily a good thing. Paediatr Respir Rev. 2018;25:1-2. 3. Blackwell JE, Alammar HA, Weighall AR, Kellar I, Nash HM. A systematic review of cognitive function and psychosocial well-being in school-age children with narcolepsy. Sleep Med Rev. 2017;34:82-93. 4. Inocente CO, Gustin MP, Lavault S, et al. Quality of life in children with narcolepsy. CNS Neurosci Ther. 2014;20(8):763-771. 5. Reiss Reddy S, Broder MS, Tieu R, et al. Disease burden in pediatric narcolepsy: a claims-based analysis of health care utilization and costs and medical comorbidity. Poster presented at: SLEEP 2018, the 32nd Annual Meeting of the APSS; June 2-6, 2018; Baltimore, MD.