2020 Summer Prime Therapeutics Report

Asthma: Current Guidelines and Treatment Options

Peanut Allergy: Advances in Treatment

Oncology Biosimilars: Landscape Update and Payer Considerations

Developing a Successful WeightManagement Program

Prime Therapeutics

Report

Sickle Cell Disease: Clinical and Management Update

IN THIS ISSUE | Summer 2020

Published By

Magellan Rx Management

15950 N. 76th St. Scottsdale, AZ 85260

Tel: 401-344-1000

Fax: 401-619-5215

magellanrx.com

Editor

Lindsay Speicher, J.D.

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

Advertising, Sales and Distribution

Carole Kallas

ckallas@magellanhealth.com 401-344-1132

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

Contributors

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

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

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

Misty Grefcz Director, Marketing

Joe Tavares SVP, Sales and Business Development, Specialty

Corrado Panno VP, Business Development, Magellan Method

Stacy Inman, Pharm.D. Senior Clinical Project Manager

Carole Kallas Project Manager

Brian Kinsella, Esq. Senior Legal Counsel

Lilly Ackley VP, External Communications

Kristen Durocher Director, External Communications

Editorial Advisory Board

Mona M. Chitre, Pharm.D., CGP

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

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

Yousaf Ali M.D., FACR Chief, Division of Rheumatology, Mount Sinai West; Associate Professor of Medicine, Icahn School of Medicine at Mount Sinai

Steven L. D’Amato, B.S.Pharm. Executive Director, New England Cancer Specialists

Joseph Mikhael M.D., M.Ed., FRCPC, FACP Chief Medical Ofcer, International Myeloma Foundation

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

Steve Marciniak, R.Ph. Director II, Medical Beneft Drug Management, BlueCross BlueShield of Michigan

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

A NOTE FROM OUR CMO

Dear Managed Care Colleagues,

Welcome to our summer 2020 issue of the Magellan Rx Report! With so much disruption and uncertainty in 2020, Magellan Rx Management is committed to serving as a consistent and stable source by bringing our clients up-to-date reporting on managed care and clinical trends. Despite turbulence in the industry brought by COVID-19, we are bringing our readers the crucial news stories and highlighting exciting clinical advances and updates.

In our cover story (page 28), we update our readers on the current state of sickle cell disease treatment, focusing on associated challenges and delving into new and emerging therapies and the implications for managed care.

Oncology biosimilars are changing the treatment and management landscape. On page 24, we explore payer considerations and strategies for e ectively navigating and managing iosimilars A peanut allergy treatment update (page 6), also focused around emerging therapies, highlights a Magellan Rx Management Clinical Connections webinar held earlier in 2020. We discuss the challenges of treating and managing peanut allergy, as well as both newly approved and pipeline treatments.

Continuing a Magellan Rx Report series on obesity management see the frst installment in our spring eport , we e plore the process re uired to e ectively develop an employer sponsored weight management program page An upcoming and fnal installment will focus on results from the implementation of such a program.

Other timely topics include asthma management (page 12) and Magellan Method’s health and economics outcomes research capabilities (page 43).

No issue of the Magellan Rx Report would be complete without our pipeline (page 51). To learn more about Magellan Rx Management and our support for payer initiatives of the future, please feel free to contact us at Magellan eport magellanhealth com As always, we value any feedback you may have. I hope you enjoy the Report!

Sincerely,

Caroline Carney, M.D., M.Sc., FAPM, CPHQ Chief Medical Ofcer Magellan Health & Magellan Rx Management

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

MANAGED CARE NEWSSTAND

Senate Passes 3-Digit Suicide Prevention Hotline

In May, the U.S. Senate passed legislation designating 9-8-8 as the new three-digit National Suicide Prevention Hotline. The House is expected to pass the bill sometime this summer. Congress initially passed legislation in 2018 to require the Federal Communications Commission (FCC) to study the creation of a hotline similar to the national 9-1-1 emergency hotline. The FCC approved a proposal in December 2019 along with various recommendations. This legislation allows states to collect fees to support operations of a national hotline and to expand existing capacity in their states. Estimated costs are $570 million for the frst year and million for the second year. The bill mandates that the Substance Abuse and Mental Health Services Administration (SAMHSA) facilitates training on addressing suicide prevention for LGBTQ youth, Native Americans, and people living in rural areas — populations of critical concern for suicide. The three-digit hotline will allow veterans to press to access a specifc hotline An estimated 45,000 people die by suicide every year in the United States, including approximately 6,000 veterans. The hotline is directed to be in place a year following passage. The current national hotline, 1-800-273-TALK, will remain in place after the three-digit hotline is operational.

Coronavirus Emergency Relief Legislation Includes Temporary Increase in the Federal Medicaid Match Rate

On March 18, Congress passed, and the president signed into law, the second emergency relief package dealing

with the coronavirus pandemic, which included a temporary increase in the Federal Medical Assistance Program (FMAP) match rate. The temporary increase of 6.2% for states began on Jan. 1 and goes until the end of the calendar quarter in which the public health emergency declared by the secretary of Health and Human Services is lifted. States are required to continue eligibility, or may expand eligibility, but they cannot restrict or remove Medicaid enefciaries in the program as of March 18. States must also cover all coronavirus-related costs, including testing and treatment, and they may not impose any premiums, deductibles, or copays. The temporary increase does not apply to populations that are included in higher Medicaid match rates, such as Medicaid expansion populations under the A orda le Care Act, but rather only populations included in the ordinary Medicaid match rate. The House passed legislation in May to increase the FMAP rate to 14% beginning July 1 and ending June 30, 2021. The increased FMAP is designed to help support states and maintain insurance coverage within the Medicaid program as they deal with increased fscal pressures resulting from the pandemic. The Senate has not acted on this bill.

Congress Passes Four Relief Packages Addressing the Pandemic and Is Expected to Pass a Fifth Package This Summer

Through March and April, Congress passed sweeping legislation totaling $3 trillion to address the healthcare and economic challenges associated with the coronavirus pandemic. Four bills were passed and signed into law over an eight-week period, between March 6 and April 24. Provisions included critical funding for hospitals and providers, funding for testing supplies, two weeks of medical and family leave for people in companies with

less than 500 employees, $1,200 stimulus checks to individuals, a $600 federal add on to wee ly unemployment enefts, increased enefts for the food stamp program, and funds to provide school lunches while children were out of school. The legislation also created a paycheck protection program, providing grants and loans to small businesses to retain their employees during the crisis, as well as a program designed to assist large business, including the airlines. The four relief packages provided substantial funding for vaccine research, among countless other provisions. Congress is again considering a ffth pac age to address the fallout from the pandemic. The House passed a $3 trillion package to extend and expand many of these programs. The bill provided for nearly $1 trillion in aid to states and localities. It also would provide for a 100% subsidy for COBRA insurance for those who lose their jobs and would provide for a Special Enrollment Period (SEP) to sign up for health insurance coverage through the health exchanges. The package would also provide signifcant funding for increased testing and contact tracing. This legislation has ignited partisan di erences, and the Senate has indicated that it would take a pause before devoting more funding to the crisis his ffth pac age has een a focus of debate during the early part of the summer.

All States Began Some Form of Reopening by Memorial Day

On April 16, the Trump administration announced a set of principles to reopen states and localities. The principles included that communities should be allowed to open through three phases. The states localities should frst show a day downward trajectory of cases. Testing and contact-tracing programs should also be robust in these areas.

• In phase one, no more than 10 people

should congregate together, and social distancing should remain in place. Only essential travel should be allowed, and vulnerable populations should continue to shelter in place.

• In phase two, groups of 50 or less would be allowed, and nonessential travel could resume. Vulnerable populations should continue to remain cautious.

• In phase three, normal activity could resume, but people should limit time in crowded environments.

In May, the Centers for Disease Control and Prevention (CDC) had initially developed a 60-page document detailing recommendations on reopening, but it was not released. Instead, more general one-page documents were released providing guidance on reopening the workplace, mass transit, childcare, schools, and restaurants and bars. Guidance for churches was initially held up. The recommendations contained general guidance, leaving it up to the states to determine processes for reopening various segments of society. All states had begun some sort of reopening by Memorial Day. Very few states had met the more stringent criteria frst announced in April guidance as the Memorial Day weekend began.

Supreme Court to Hear Repeal of Afordable Care Act in the Fall

The Supreme Court announced in March that it will again take up the issue of the A orda le Care Act s constitutionality

This will be the third time that justices have heard cases dealing with the landmark 2010 law. Arguments are expected in the fall of 2020. In 2017, Congress struck down the individual mandate tax penalty in the tax bill passed that year. In a previous case, the justices ruled that the individual mandate was constitutional

under the taxation powers. The argument now before the Court is that without a tax penalty, the individual mandate is invalid, and therefore the entire law should now be struck down given its central place in the law. The case will likely ensure that the A orda le Care Act will e highly visi le in this fall s presidential campaign, along with other major issues such as Medicare for All, drug pricing, surprise medical billing, and healthcare issues associated with the coronavirus pandemic.

Many in Congress Call for Changes in the Medical and Drug Supply Chain

The coronavirus pandemic highlighted weaknesses in the medical and drug supply chain, and Congress saw at least 10 bills introduced in the spring to try and address these issues. These bills range from creating incentives to bring manufacturing back to the United States to requiring the U.S. Food and Drug Administration (FDA) to improve drug tracking. Many called for studies to better understand vulnerabilities within the medical and drug supply chains. Drug shortages and the lack of medical equipment became critical issues early in the pandemic. It is expected that this will be a major policy issue for years to come.

Race for a Vaccine

More than 100 research teams are working to fnd a vaccine for the coronavirus quickly, according to many media reports. Many experts believe it will take 12 to 18 months to develop a vaccine, ut e orts are underway to shorten that time frame. As of Memorial Day, the U.S. Department of Health and Human Services (HHS) has awarded four contracts to the following companies in hopes of fast-tracking a vaccine: $1.2 billion to AstraZeneca for a phase three clinical

trial this summer, $483 million to Moderna, $500 million to Johnson & Johnson, and million to Sanof

Telehealth

The pandemic has moved telehealth forward in ways no one could have anticipated. Various federal and state regulatory actions, most of which are tied to emergency declarations, removed previous regulatory barriers. Many states have temporarily mandated equal payments through various administrative actions. Previously, providers had little fnancial incentive to o er telehealth visits because of the coverage and reimbursement gaps.

Supreme Court to Hear PBM Case

On Jan. 10, the U.S. Supreme Court granted review of Rutledge v. Pharmaceutical Care Management Association (PCMA), meaning they will hear the case. In 2015, Arkansas enacted a “MAC/transparency” law that imposed onerous regulations on PBMs and their relationships with pharmacies he PCMA fled suit challenging the Arkansas statute as preempted by the Employee Retirement Income Security Act of 1974 and Medicare Part D. The PCMA as ed the Court to fnd the statute unconstitutional because it establishes requirements on PBMs that the state has no authority to establish and dictates terms of PBM contracts with ERISA plans and Medicare Part D plans. Both ERISA and Medicare Part D have very broad preemption provisions that limit states ability to enact laws impacting these areas of federal policy. The Supreme Court was originally anticipated to hold oral arguments April 27 and wrap up the case y June, ut the Court s schedule was disrupted by COVID-19. Oral arguments are now expected to occur next year.

Peanut Allergy: Advances

in Treatment

Over the coming year, the peanut allergy space will likely transform from relying on strict avoidance as a long-term management option to introducing multiple available therapies. These advances will inevitably come with challenges to managing care.

Christopher Parrish, M.D., FAAAAI, FACAAI

Assistant Professor of Pediatrics and Internal Medicine

UT Southwestern Medical Center

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

An allergy is when the immune system reacts in a potentially harmful way to a normally harmless substance. In the U.S., 1 in 13 children has food allergies, and an estimated 40% of those with food allergies are allergic to more than one food.1 Peanut allergy is among the most common food allergies in the U.S., impacting 2.5% of children and 1.2% of the overall population.2, 3 Moreover, peanut allergy is the leading cause of food-allergy-related deaths in children.4 The prevalence of the allergy more than tripled from 1997 to 2008, and, according to a 2017 study, it has increased by 21% since 2010.5, 6 Thus, although the allergy resolves in an estimated 20% of children, it is conceivable that the number of adults living with the allergy will increase in the decades to come.

After the publication of a landmark study showing that early introduction of peanut may reduce the risk of developing peanut allergy in high-risk infants,7 the National Institute of Allergy and Infectious Diseases (NIAID) published an addendum to its guidelines detailing when to introduce children to peanut-containing foods. The NIAID recommended adding peanut protein to the diet of infants with severe eczema, egg allergy, or both at age 4 to 6 months; of infants with mild to moderate eczema at 6 months; and of infants with none of those conditions at any time appropriate for the family.8 In 2019, the American Academy of Pediatrics updated its guidelines to recommend introducing allergenic foods, including peanut protein, into a ies diets at as early as to months of age, in an e ort to reduce the ris of developing food allergies.9 This is contrary to prior recommendations of avoiding allergens.

Peanut is the food allergen most commonly associated with anaphylaxis, which occurs when the patient ingests the peanut protein.1 Symptoms of food allergy vary. Skin symptoms such as hives or swelling are most common. Anaphylaxis is a severe, potentially fatal, systemic (whole-body) reaction that may include skin symptoms and/or some combination of wheezing, shortness of breath, repetitive cough, throat swelling, vomiting, stomach cramps, diarrhea, dizziness, confusion, and other symptoms.

According a 2012 survey, annual costs associated with food allergies in U.S. children totaled $24.8 billion, with $4.3 billion in direct medical costs.10 The majority of these medical costs are tied to emergency

Emergency department visits for food-induced anaphylaxis by allergen, per 100,000 children

department (ED) visits and inpatient hospitalizations resulting from anaphylaxis. Food allergies account for approximately 25% of anaphylaxis-related ED visits. Peanut and tree nut allergies are the most common cause of food-related anaphylaxis. In a 20072012 study, peanut allergies were responsible for 37% of foodinduced anaphylaxis cases and 35% of hospital admissions due to anaphylaxis.11

Diagnosis

As with other food allergies, diagnosing peanut allergy can be a complicated process, considering the variance in symptoms from patient to patient and from reaction to reaction. Typically, an allergist will be able to identify the culprit food by taking a detailed history of food eaten in the minutes to hours preceding symptom onset S in and lood tests are used to confrm the diagnosis In uncertain cases, an oral food challenge — in which the patient will be fed increasing amounts of peanut protein over time while in

a controlled medical environment — may be necessary to clarify whether an individual is truly allergic or not.

Current Management and Treatment

There is no cure for peanut allergy. Current treatment options for peanut allergy include avoidance, education and label reading, recognition of a reaction, and administration of emergency epinephrine in the event of a severe reaction after accidental exposure. Due to the severe nature of many peanut allergy cases, the condition is typically managed by strict avoidance of peanuts and any product that contains peanut protein. The results of such avoidance strategies are variable.

Strict avoidance can present numerous challenges to those with peanut allergy and their families, including substantial burdens on quality of life and activities.12 Despite peanut-free schools, there are continued challenges with unintended exposure. Those with peanut allergies have reported limiting travel specifcally air travel and e periencing difculty dining out due to fear

Current treatment options for peanut allergy include avoidance, education and label reading, recognition of a reaction, and administration of emergency epinephrine in the event of a severe reaction after accidental exposure.

Figure 1. Incidence and Burden of Peanut Allergy

Figure 2. U.S. Peanut Allergy Statistics

of e posure Additionally, la el reading can often e ine ective, due to potential cross-contamination in product manufacturing and packaging. Therefore, strict avoidance not only burdens those with peanut allergy ut can also sometimes e ine ective in preventing severe allergic reactions and anaphylaxis.

Emerging Therapies

Palforzia™

On Jan. 31, the U.S. Food and Drug Administration (FDA) approved Palforzia™ (peanut (Arachis hypogaea) allergen powder-dnfp) (called AR101 prior to approval), an oral immunotherapy indicated for the mitigation of allergic reactions, including anaphylaxis, that may occur with accidental exposure to peanut in patients with peanut allergy.13 Palforzia™ is approved for initiation of treatment in peanut-allergic patients ages 4 through 17. This immunotherapy is formulated to require phased-dose escalation over a period of time followed by ongoing maintenance at a dose of 300 mg, which is approximately equivalent to the protein content of a single peanut kernel.13 he frst several doses initial dose escalation) and each subsequent dose escalation of oral Palforzia™ are conducted under supervision by a healthcare professional in a certifed healthcare setting In the pivotal PA ISAD trial, patients ages 4 to 17 with peanut allergy participated with a primary endpoint of ingesting a single dose of at least 600 mg of peanut protein (cumulative dose of 1043 mg) after six months of maintenance treatment, without dose-limiting symptoms at the exit food challenges.14

PALISADE Results:14

» 67.2% of patients receiving AR101 were able to tolerate >600 mg of peanut protein (cumulative 1043 mg), compared to 4% of those receiving placebo (primary endpoint).

» 76.6% of patients receiving AR101 tolerated a single dose of 300 mg of peanut protein (cumulative 443 mg), compared to 8.1% of those receiving placebo (p<0.0001).

» 50.3% of patients receiving AR101 tolerated 1,000 mg of peanut protein (cumulative 2043 mg) without dose-limiting e ects, compared to 2.4% of placebo patients (p<0.0001).

» At each dose level, the maximum severity of symptoms was lower for patients receiving AR101 than for those receiving placebo.

» Over 95% of patients total experienced some adverse event, mostly categorized as mild to moderate.

» During the trial, excluding the food challenges, 14% of patients on AR101 received epinephrine, compared with 6.5% of patients receiving placebo.

» 11.6% of patients receiving AR101 dropped out due to adverse events. Notably, the most common adverse events experienced were nausea, vomiting, and throat itching.

» fcacy was not shown in patients years of age

While Palforzia™ has been shown to help reduce the severity of allergic reactions that may occur with peanut exposure, patients still must maintain a strict peanut-free diet while on the treatment regimen.14

Palforzia™ is only available through a restricted Risk Evaluation and Mitigation Strategies (REMS) program; patients as well as prescribers, pharmacies, and healthcare facilities involved the treatment plan must be enrolled.

Viaskin® Peanut

Currently under FDA review, the Viaskin® Peanut patch from DBV Technologies is an epicutaneous immunotherapy targeting peanut allergy in pediatric patients.15 Viaskin® delivers very small amounts of peanut protein via a patch worn on intact skin to induce desensitization over time.

PEPITES Results:15

The trial tested 238 pediatric patients who were administered Viaskin® Peanut patch containing 250 mcg of peanut protein (equivalent to approximately 1/1000th of one peanut kernel) daily over 12 months. Patients receiving Viaskin® had a 35.3% responder rate, compared with patients receiving placebo, who had a 13.6% responder rate.16

magellanrx.com/watch

GUEST SPEAKER

DR. CHRISTOPHER PARRISH Allergist Immunologist Specialist

BARBARA CORN Vice President, MRx Navigate Secretary, Asthma & Allergy Foundation, St. Louis Chapter

he prespecifed lower ound of confdence interval threshold was not met. A total of 89.9% of patients completed the trial, and adherence rates of 98.5% were reported.

PEPITES Follow-Up Results:16

More recent trial results showed that after 36 months of treatment, 51.8% of patients reacted at an eliciting dose of >1000 mg of peanut protein, compared to 40.4% after 12 months. The most common treatment-emergent adverse events were mild to moderate skin reactions localized at the administration site.

Biologics and Alternative Treatments on the Horizon

Biologics indicated for allergic diseases such as asthma and severe eczema are currently being studied for peanut allergy. Roche’s Xolair® (omalizumab), an FDA-approved biologic indicated for asthma and chronic idiopathic urticaria, is currently in a phase three trial assessing its e ectiveness as a monotherapy or adjunct therapy in combination with an oral immunotherapy in both children and adults with peanut allergy.18 Regeneron Pharmaceuticals’ Dupixent® (dupilumab), an FDA-approved biologic indicated for asthma, severe eczema, and nasal polyps, is currently in a phase two trial evaluating the efcacy of dupilumab as a monotherapy in pediatric patients with peanut allergy.19 While more research must be done here, these biologics could present another treatment option for those living with peanut allergy. Alternative avenues of therapeutics are in earlier stages of research as well.

ICER Review

In May, the Institute for Clinical and Economic Review (ICER) conducted a review of AR101, Viaskin® Peanut, and oral immunotherapy (OIT).20

• Cl al efe e e The review concluded that highcertainty evidence demonstrates that OIT increases allergic and anaphylactic reactions for at least the frst year of treatment despite e ective desensitization, without evidence of long term enefts

• o er o efe e e The economic model estimated incremental cost e ectiveness ratios for A and Vias in® Peanut as follows:

◦ AR101: $88,000 (95% credible range (CR) = $52,000, per uality ad usted life year A

◦ Viaskin® Peanut: $216,000 (95% CR = $126,000-$491,000) per A

The ICER review also provided several key policy recommendations, including the following:20

• Prescription of peanut-desensitization therapies should be restricted to allergists and immunology specialists, or, where there is inadequate access to allergists, to primary care physicians in consultation with a specialist.

• Payers may consider limiting coverage for initiation of desensitization treatment to patients between ages 4 and 17 who represent the population studied to date.

• Payers should not stop coverage at age 18 for patients who have been on continuous desensitization therapy.

Management Implications

Over the coming year, the peanut allergy space has the potential to be transformed from relying on strict avoidance as the sole longterm management option to introducing multiple available therapies. Currently, patients must continue to maintain a strict peanutfree diet, including while on a treatment regimen, and carry injectable epinephrine. Advances in peanut allergy treatment may present opportunities for improved quality of life for patients and their families, but not without challenges in managing care. Still, some unknowns remain in the allergy treatment space. While immunotherapies have the potential to positively impact quality of life, data have not yet een reported to confrm this impact Additionally, sustained unresponsiveness to peanut allergens after stopping long-term use of immunotherapy has proven elusive. The nature of peanut allergy and the immunotherapies introduced require close healthcare supervision, monitoring, and care.

Continual daily dosing of immunotherapy, which can be costly, is crucial for continued desensitization he short term fnancial urden of increased healthcare resource utilization — from provider hours and prolonged visits in healthcare facilities to dose escalations possibly requiring multiple prescriptions over the course of

References

1. “Peanut Allergy.” American College of Allergy, Asthma, and Immunology, 2019, https://acaai.org/allergies/types/food-allergies/ types-food-allergy/peanut-allergy.

2. Sicherer, Scott et al. “Prevalence of peanut and tree nut allergy in the United States determined by means of a random digit dial telephone survey: A 5-year follow-up study.” The Journal of Allergy and Clinical Immunology, Dec. 1, 2003, https://doi.org/10.1016/S00916749(03)02026-8.

3. Gupta, R. et al. “OR078 The prevalence of childhood food allergy in the United States: an update.” American College of Allergy, Asthma & Immunology Annual Scientifc Meeting, Oct , , https doi org/10.1016/j.anai.2017.08.060.

4. Cannon, H. Eric. “The Economic Impact of Peanut Allergies.” American Journal of Managed Care, Oct. 19, 2018, https://www.ajmc.com/ journals/supplement/2018/managed-care-perspective-peanutallergy/the-economic-impact-of-peanut-allergies.

5. Sicherer, Scott et al. “Prevalence of peanut and tree nut allergy in the US determined by a random digit dial telephone survey.” The Journal of Allergy and Clinical Immunology, April 1999, https://doi. org/10.1016/s0091-6749(99)70224-1.

6. Sicherer, Scott et al. “US prevalence of self-reported peanut, tree nut, and sesame allergy: 11-year follow-up.” The Journal of Allergy and Clinical Immunology, May 12, 2010, https://doi.org/10.1016/j. jaci.2010.03.029.

7. Du Toit, George et al. “Randomized trial of peanut consumption in infants at risk for peanut allergy.” The New England Journal of Medicine, Feb. 26, 2015, https://www.nejm.org/doi/full/10.1056/ NEJMoa1414850.

8. Togias, Alkis et al. “Addendum Guidelines for the Prevention of Peanut Allergy in the United States: Report of the NIAID-Sponsored Expert Panel.” National Institute of Allergy and Infectious Diseases, , https www niaid nih gov sites default fles addendum peanut-allergy-prevention-guidelines.pdf.

9. Greer, Fran et al he ects of arly Nutritional Intervention on the Development of Atopic Disease in Infants and Children: The Role of Maternal Dietary Restriction, Breastfeeding, Hydrolyzed Formulas, and Timing of Introduction of Allergenic Complementary Foods.” Pediatrics, April 2019, https://doi.org/10.1542/peds.2019-0281.

10. Gupta, Ruchi et al. “The Economic Impact of Childhood Food Allergy in the United States.” JAMA Pediatrics, November 2013, https://doi. org/10.1001/jamapediatrics.2013.2376.

treatment — must be taken into consideration when developing management plans and determining the patients who will most eneft from treatment regimen Solid criteria may e e plored to ensure access is available for appropriate patients.

11. Parlaman, Joshua et al. “Emergency and Hospital Care for FoodRelated Anaphylaxis in Children.” Hospital Pediatrics, May 2016, https://doi.org/10.1542/hpeds.2015-0153.

12. Parrish, Christopher. “Management of Peanut Allergy: A Focus on Novel Immunotherapies.” American Journal of Managed Care, Oct. 19, 2018, https://www.ajmc.com/journals/supplement/2018/managedcare-perspective-peanut-allergy/management-of-peanut-allergy-afocus-on-novel-immunotherapies.

13. “Palforzia.” U.S. Food and Drug Administration, Feb. 24, 2020, https:// www.fda.gov/vaccines-blood-biologics/allergenics/palforzia.

14. he PA ISAD Group of Clinical Investigators A Oral Immunotherapy for Peanut Allergy.” The New England Journal of Medicine, Nov. 22, 2018, https://doi.org/10.1056/NEJMoa1812856.

15. “DBV Aims to Unlock the Powerful Immune Properties of the Skin.” DBV Technologies, 2020, https://www.dbv-technologies.com/viaskinplatform/.

16. Fleischer, David et al ect of picutaneous Immunotherapy vs Placebo on Reaction to Peanut Protein Ingestion Among Children With Peanut Allergy: The PEPITES Randomized Clinical Trial.” Journal of the American Medical Association, Feb. 22, 2019, https://doi. org/10.1001/jama.2019.1113.

17. Fleischer, David et al Open a el Follow Up of the P PI S Study P OP to valuate the ong erm fcacy and Safety of Epicutaneous Peanut Immunotherapy in Peanut-Allergic Children.” The Journal of Allergy and Clinical Immunology, Feb. 1, 2020, https:// doi.org/10.1016/j/jaci.2019.12.453.

18. Omalizumab as Monotherapy and as Adjunct Therapy to MultiAllergen OIT in Food Allergic Participants (OUtMATCH). U.S. National i rary of Medicine, Jan , , https clinicaltrials gov ct show NCT03881696.

19. Study to Evaluate Dupilumab Monotherapy in Pediatric Patients ith Peanut Allergy U S National i rary of Medicine, Fe , , https://clinicaltrials.gov/ct2/show/NCT03793608.

20. ice, Je rey et al he e ectiveness and value of oral immunotherapy and Viaskin Peanut for peanut allergy.” Journal of Managed Care and Specialty Pharmacy, May 2020, https://www.jmcp. org/doi/full/10.18553/jmcp.2020.26.5.620?mobileUi=0.

Asthma Update: Current Guidelines

and Treatment Options

The introduction of biologics has opened a new route of administration for treating asthma, including the possibility of self-administration.

Mona Chitre, Pharm.D., CGP Chief har ac Ofcer Clinical Analytics, Strategy and Innovation

Asthma is a chronic disease of the lungs that a ects adults and children of all ages and is characterized by repeated episodes of wheezing, breathlessness, chest tightness, and nighttime or early morning coughing. The cause is unknown, and the condition currently has no cure. Symptoms are managed by reduced exposure to triggers, acute treatment of exacerbations, and prevention of future attacks. Without proper management, asthma can result in absences from work or school, frequent emergency department (ED) visits, hospitalizations, and premature death.1

Asthma a ects million people, including million children In , million people visited an D for asthma related symptoms, resulting in , individuals eing hospitalized 2 Adult self-reported asthma prevalence varies by state, ranging from 7.3% in Texas to 13.2% in New Hampshire (Figure 1).2 Asthma and asthma related symptoms create a signifcant fnancial urden, contri uting to illion in medical costs for one year, with additional indirect costs of illion due to missed wor and school and illion due to asthma related mortality 3

Asthma management should include a controller medication, a rescue medication, and, in cases of severe asthma, an add on therapy Classifcations of asthma severity are as follows:

Frequency of nighttime awakenings

Frequency of short-acting inhaler use

Often

Controlling asthma to reduce e acer ations is the goal for all patients Control can e interpreted di erently depending on a patient s triggers and asthma symptoms. Below are the standards for what control should look like for all patients:

with

Global Initiative for Asthma: Current Guidelines and Recent Updates

The long-term goals of asthma management are to achieve symptom control; maintain normal activity levels; and minimize the risk of asthma related death, e acer ations, persistent air ow limitation, and side e ects ective management re uires a partnership between the patient — or, where appropriate, the parent or caregiver — and the healthcare professional managing their treatment plan. Communication of symptoms, triggers, and barriers to treatment must e discussed openly to ma imize eneft ective communication on the part of the provider can be invaluable in assessing the health literacy of the patient and or parent caregiver and can increase the success of the treatment plan.

Making Decisions About Asthma Treatment

Control-based management of asthma should take place in a continuous cycle of assessment, treatment, and review of the patient s response. This assessment should include both the level of symptom control and the future ris of e acer ation and side e ects Treatment decisions should also take into consideration the patient s inhaler techni ue, adherence, and cost to the patient Other considerations are discussed and tabulated in Tables 1, 2, and 3.

Table 2. Asthma Control4

Table 3. Recommendations4

If reported or o served symptoms indicate a need for changes in therapy, step therapy should e considered Step therapy and the timeline associated with implementing and assessing a successful change are summarized below:

Asthma Control

Well-Controlled

Not Well-Controlled

Very Poorly Controlled

Recommended Action for Treatment

• Maintain current step egular follow up for months

• Consider step down if well-controlled for at least 3 months

• Step up 1 step eevaluate in wee s

• Consider alternative therapies for adverse reactions

• Consider short course of oral corticosteroids

• Step up 1-2 steps

• Reevaluate in 2 weeks

• Consider alternative therapies for adverse reactions

Treatment Options

The current landscape for treating asthma includes several products within multiple classes, each of which has variations in mechanism of action and duration of therapy.

Short-Acting Beta Agonists (SABA)

Most, if not all, asthma patients are prescribed a rescue inhaler for acute symptoms, often a short-acting beta agonist (SABA). All patients should be taught to use a SABA as a rescue inhaler for exacerbations. Because of the likelihood for patients to become reliant on SABA treatment and the side e ects associated with overuse, the Glo al Initiative for Asthma GINA no longer recommends treatment with a SABA alone.

» Use: These rescue inhalers should be used during an asthma attack or before exercise, as directed.

» How they work: They relax the smooth muscle in the lungs that constricts and ma es it difcult to reathe during an asthma attack. They do not help to reduce the frequency of asthma attacks and should be used only as needed.

» Co o de efe l de fast heartbeat or palpitations, headache, and tremors

» Available products include: albuterol and levalbuterol

Inhaled Corticosteroids (ICS)

Depending on the severity of their condition, most asthma patients will also e prescri ed an inhaled corticosteroid ICS for as needed or daily use reatment with daily low dose ICS is highly e ective in reducing asthma symptoms and the ris of asthma related exacerbations, hospitalization, and death.4 Adults and adolescents with mild asthma should be treated with as-needed low dose ICS formoterol to reduce ris of severe e acer ations

» Use: These maintenance inhalers are meant to be used daily to reduce the risk of asthma attacks and improve lung function.

» How they work: hey reduce oth in ammation and the ody s immune response to allergens Unli e oral corticosteroids, these medications are inhaled directly into the lungs, thus carrying a lower ris of systemic side e ects It is important to rinse your mouth with water and spit it out after each use of the inhaler to avoid the risk of an infection called thrush. Daily adherence to these medications is very important in order for them to work best.

» Co o de efe l de headache, thrush, nausea, sore throat, runny nose, and hoarseness

» Available products include: beclomethasone, budesonide, ciclesonide, unisolide, uticasone, mometasone, and triamcinolone

If a patient s asthma remains uncontrolled despite adherence and proper inhaler technique, additional steps and medications may be prescribed. The following additional classes of medications are available to treat asthma symptoms.

Anticholinergic Agents

» Use: Short-acting agents such as ipratropium can be used to treat symptoms of shortness of breath and wheezing, while longeracting medications such as tiotropium are used to prevent asthma attacks.

» How they work: These medications also relax the smooth muscle in the lungs that constricts during an asthma attack. Many medications in this class are approved to treat Chronic Obstructive Pulmonary Disease (COPD), another lung condition, but are not approved to treat asthma.

» Co o de efe l de dry mouth, urinary retention, and worsening of narrow-angle glaucoma

» Available products include: ipratropium and tiotropium

Leukotriene-Modifying Agents

» Use: These medications are taken orally to reduce the risk of having an asthma attack.

» How they work: hey loc the activity of a specifc cell involved in the ody s immune response to allergens that can lead to airway swelling and smooth-muscle constriction.

» Co o de efe l de cough, headache, sore throat, and runny nose

» Available products include: montelu ast, zafrlu ast, and zileuton

Long-Acting Beta Agonists (LABA)

» Use: They should always be prescribed in combination with an inhaled corticosteroid when being used to treat asthma. Monotherapy with long-acting beta agonists may increase the risk of side e ects ut when used with inhaled corticosteroids can help achieve better asthma control than inhaled corticosteroids can alone.

» How they work: These medications work similarly to shortacting beta agonists in that they promote bronchodilation but provide a longer response.

» Co o de efe l de headache, nasal congestion, sore throat, runny nose, and bronchitis

» Available products include: salmeterol, formoterol, and vilanterol

Xanthine Derivatives

» How they work: These medications relax smooth muscle in the airways and reduce in ammation

» Co o de efe l de headache, insomnia, nausea, and vomiting

» Available products include: theophylline

Mast Cell Stabilizers

» How they work: These medications bind to a cell involved in the immune system response to block the release of histamine, a chemical involved in allergic reactions.

» Co o de efe l de throat irritation, bad taste, coughing, wheezing, and nausea

» Available products include: cromolyn

Oral Corticosteroids

» Use: Treatment should be reserved for severe asthma and should be used for as short a time as possible to reduce the risk of systemic side e ects

» How they work: This class of medications works similarly to inhaled corticosteroids in reducing in ammation and the ody s immune system response to allergens; however, they are taken orally and can therefore a ect the whole ody, not ust the lungs

» Co o de efe l de uid retention, alteration in glucose tolerance, high blood pressure, mood changes, increased appetite, and weight gain

» Available products include: prednisone, methylprednisolone, dexamethasone, hydrocortisone, cortisone, and prednisolone

Biologics

» Use: hese medications are in ected under the s in y a healthcare professional or by the patient and are administered generally every two, four, or eight weeks. They are used in severe asthma that is not well controlled by inhaled corticosteroids or if patients have asthma that is associated with allergies and a type of immune cell known as an eosinophil.

» How they work: hey are all anti odies that target specifc cell types in the ody s immune system to loc the in ammatory response that occurs in asthma.

» Co o de efe l de fatigue, pain, and in ection site reaction

» Available biologics include: omalizumab, reslizumab, benralizumab, mepolizumab, and dupilumab

Treatment should be customized for the patient’s symptoms, lifestyle, and ability e di ere de ice administer medicine.

Personalized Management

reatment should e customized for the patient s symptoms, lifestyle, and a ility to use di erent devices to administer medicine Patients with hand eye coordination and or de terity issues may need tools to help with administration of their therapy. Treatment plans should also include assessment of inhaler technique, adherence with the chosen therapy, and cost to the patient. Changes to therapy should be driven by symptoms patients are having while using their prescribed asthma treatment regimen or by results of spirometry testing. See Figures 2 and 3 for step therapy recommendations.

Figure 2. Personalized Management for Adults and Adolescents (12+ Years): Control Symptoms and Minimize Future Risk5

Personalized asthma management:

Access, ad ust, review response

Confrm diagnosis if necessary

Control symptoms and modifable risk factors (including lung function)

Comorbidities

Inhaler technique and adherence

Patient goals Symptoms Exacerbations Side efects Lung function Patient satisfaction

Treat modifable risk factors and comorbidities

Nonpharmacological strategies

Ad ust treatment up and down for individual patient needs

Asthma medication options: PREFERRED CONTROLLER

to prevent exacerbations and control symptoms

low-dose ICS-formoterol*

Low-dose ICS taken whenever SABA is taken†

PREFERRED RELIEVER

Daily low-dose inhaled corticosteroid (ICS) or as-needed low-dose ICS-formoterol*

Leukotriene receptor antagonist (LTRA) or low-dose ICS taken whenever SABA taken†

As-needed low-dose ICS-formoterol*

*Of-label; data only with budesonide-formoterol (bud-form)

†Of-label; separate or combination ICS and SABA inhalers

Education and skills training Asthma medications

Medium-dose ICS-LABA

ICS-LABA

Medium-dose ICS or low-dose ICS+LTRA#

High-dose ICS-LABA

Refer for phenotypic assessment± add-on therapy, e.g., tiotropium, anti-lgE, anti-IL5/5R, anti-IL4R

High-dose ICS, add-on liotropium or LTRA#

Add low-dose OCS, but consider side efects

As-needed low-dose ICS-formoterol for patients prescribed maintenance and reliever therapy‡

As-neededshort-acting β2-agonist(SABA)

‡Low-dose ICS-form is the reliever for patients prescribed bud-form or BDP-form maintenance and reliever therapy

#Consider adding HDM SLIT for sensitized patients with allergist rhinitis and FEV1>70% predicted

Personalized asthma management:

Access, ad ust, review response

Symptoms

Exacerbations

Side efects

Lung function

Child and parent satisfaction

Asthma medication options:

Ad ust treatment up and down for individual child s needs

PREFERRED CONTROLLER

RELIEVER to prevent exacerbations and control symptoms

Other controller option

STEP 1

STEP 2

Daily low-dose inhaled corticosteroid (ICS) (see table of ICS dose ranges for children)

Confrm diagnosis if necessary

Control symptoms and modifable risk factors (including lung function)

Comorbidities

Inhaler technique and adherence

Child and parent goals

Low-dose ICS taken whenever SABA taken* or daily low-dose ICS

Leukotriene receptor antagonist (LTRA) or low-dose ICS taken whenever SABA taken*

Treat modifable risk factors and comorbidities

Nonpharmacological strategies

Education and skills training

Asthma medications

STEP 3

Low-dose ICS-LABA or medium-dose ICS

STEP 5

Refer for phenotypic assessment± add-on therapy, e.g. anti-lgE

STEP 4

Medium-dose ICS-LABA

Low-dose ICS+LTRA High-dose ICS-LABA or add-on triotropium or LTRA#

As-neededshort-acting β2-agonist(SABA)

Add-on anti-IL5 or low-dose OCS, but consider side-efects

*Of-label; separate ICS and SABA inhalers; only one study in children appropriate), breathing exercises, a healthy diet including fruits and vegetables, and physical activity as tolerated.

Other treatment modalities can be leveraged for patients not responding to standard-of-care therapies mentioned above. These can include allergen immunotherapy, subcutaneous immunotherapy, sublingual immunotherapy, and bronchial thermoplasty. Additional add-on considerations for people with asthma include vitamin D supplementation and the in uenza vaccine, as asthmatic patients have an increased ris of contracting the u Nonpharmacologic interventions to consider include limiting exposure to secondhand smoke, smoking cessation for known smokers, avoiding occupational exposure to sensitizing agents, weight reduction (if

Cost of Treatment

Cost and coverage are important considerations for both the payer and the patient when changing or adding to a patient s asthma regimen. The cost of asthma treatment varies based on route of administration and therapeutic class. Table 4 shows the current costs for asthma medications.

Figure 3. Personalized Management for Children (6-11 Years): Control Symptoms and Minimize Future Risk5

Table 4. Current Asthma Treatments and Associated Whole Acquisition Cost (WAC) per Month6

Brand Control Generic Name Brand Company

Route

ADVAI DIS US uticasone propionate; salmeterol xinafoate Gla oSmith lineInhaled

ADVAI HFA uticasone propionate; salmeterol xinafoate Gla oSmith lineInhaled

Wholesale Acquisition Cost (WAC) per Month

Corticosteroid; long-acting beta-2 adrenoreceptor agonist (LABA)

Corticosteroid; LABA

AirDuo RespiClick® uticasone propionate; salmeterol Teva Inhaled Corticosteroid; LABA

B O IP A uticasone furoate vilanterol trifenatate Gla oSmith line Innoviva Inhaled Corticosteroid; LABA

Powder inhalation (0.1 mg INH, mg INH mg INH, mg INH mg INH, mg INH

Aerosol, metered inhalation mg INH, mg INH mg INH, mg INH mg INH, mg INH

Powder inhalation mg INH, mg INH mg INH, mg INH mg INH, mg INH

Powder inhalation (0.1 mg INH, mg INH mg INH, mg INH

Cinqair® reslizumab Teva Intravenous Interleu in I antagonist Single use vial mg mL)

DULERA® formoterol fumarate; mometasone furoate Merck & Co. Inhaled

Dupixent® dupilumab egeneron Sanof Genzyme

Fasenra®* benralizumab

Fasenra Pen™*benralizumab

Subcutaneous

MedImmune AstraZeneca; yowa Ha o irin

MedImmune

AstraZeneca; yowa Ha o irin

Nucala mepolizumab Gla oSmith line

Subcutaneous

Corticosteroid; LABA

Interleu in receptor I 4R) antagonist; interleukin 13 receptor I antagonist

Aerosol, metered inhalation mg INH, mg INH mg INH, mg INH

Su cutaneous in ection every other week after loading dose ,

Interleu in receptor I antagonist mg m solution in a single dose preflled syringe ,

Subcutaneous I antagonist

Subcutaneous I antagonist

Orapred ODT prednisolone sodium phosphate Concordia Oral Corticosteroid

Self-administered in ection ,

100 mg of lyophilized powder in a single-dose vial for reconstitution ,

Tablet, orally disintegrating (10 mg; mg mg mg mg , mg ,

Brand Control

QVAR RediHaler® beclomethasone dipropionate HFA Teva; Norton (Waterford) Inhaled Corticosteroid

Rayos (1 mg) prednisone Horizon Therapeutics Oral

Aerosol, metered inhalation mg IH, mg INH mg INH mg INH

Corticosteroid Tablet, delayed-release oral mg mg mg ,

Serevent® Diskus® salmeterol xinafoate Gla oSmith lineInhaled LABA

Singulair (chewable tablets) montelukast sodiumMerck & Co.Oral

Singulair (oral granules) montelukast sodiumMerck & Co.Oral

Singulair (tablets)montelukast sodiumMerck & Co.Oral

SPI IVA® SPIMA ® tiotropium bromide monohydrate Boehringer Ingelheim Inhaled

Powder inhalation mg INH

Leukotriene receptor antagonist Tablet, chewable oral mg mg

Leukotriene receptor antagonist Granule oral mg pac et

Leukotriene receptor antagonist Tablet oral (10 mg)

Long-acting muscarinic antagonist (LAMA) Spray, metered inhalation mg INH, mg INH

S MBICO ® budesonide; formoterol fumarate dihydrate AstraZeneca Inhaled Corticosteroid; LABA

S MBICO ® budesonide; formoterol fumarate dihydrate AstraZeneca Inhaled Corticosteroid; LABA

Aerosol, metered inhalation mg INH, mg INH

Aerosol, metered inhalation mg INH, mg INH

Xolair®** omalizumab Roche; Novartis; Genentech Subcutaneous Anti Ig anti ody Su cutaneous mg vial mg m PFS

*The recommended dose of Fasenra® is 30 mg administered once every four weeks for the frst three doses and then once every eight weeks thereafter.7 **Cost listed is by unit; multiple vials are needed to achieve dosing of 75 to 375 mg every two or four weeks.8

What’s on the Horizon: Pipeline for Asthma

he pipeline for asthma includes the possi ility of additional com inations of inhaled products, oral agents, and in ecta le iologics a le shows emerging asthma therapies e pected in the near future

Table 5. Current Asthma Treatment Pipeline9

Andolast andolast Rottapharm | Madaus Inhaled

APC of VA beclomethasone dipropionate Adamis Inhaled

Fostair beclometasone dipropionate; formoterol fumarate dihydrate

Chiesi Inhaled

Masitinib masitinib AB Science Oral

Calcium-activated potassium channel activator Phase III

Corticosteroid Phase III

Corticosteroid; LABA Phase III

Receptor tyrosine kinase inhibitor Phase III

PT001 glycopyrrolate AstraZeneca Inhaled LAMA Phase III

PT027 albuterol sulfate; budesonide Avillion; AstraZeneca; Pearl Therapeutics Inhaled

PT010 budesonide; glycopyrrolate; formoterol fumarate AstraZeneca Inhaled

MF indacaterol maleate; mometasone furoate Novartis

VM indacaterol maleate; mometasone furoate; glycopyrronium bromide Novartis

Corticosteroid; SABA Phase III

Corticosteroid; LABA; LAMA Phase III

Corticosteroid; LABA Phase III

Corticosteroid; LABA; LAMA Phase III

Tezepelumab tezepelumab AstraZeneca; AmgenSubcutaneous Monoclonal antibody Phase III

Trelegy Ellipta uticasone furoate umeclidinium bromide; vilanterol trifenatate

Payer Considerations

Gla oSmith line Innoviva Inhaled

he addition of iologic anti I receptor antagonists to the list of potential treatment options for asthma has introduced a new route of administration to the landscape. The cost of these medica-

Corticosteroid; LABA; LAMA Pending

tions varies depending on how often they are dosed and whether a loading dose needs to be given when initiating therapy. Four of the fve iologics are administered su cutaneously two, dupiluma

and benralizumab, can be self-administered once the patient is trained by a healthcare professional. The option of self-administration can eliminate site-of-service coverage for this class. Patients will still need to step through inhaled and oral therapies before the addition of a iologic as they are approved as ad unct therapy he addition of a iologic agent to a patient s therapy should e loo ed at by payers through their policy to ensure proper prescribing. here are fve iologic therapies that can e used as ad unct therapy to treat severe asthma not adequately controlled with inhaled corticosteroids:

• Dupixent® (dupilumab), for patients >12 years of age with severe asthma or OCS-dependent asthma.10

• Cinqair® reslizuma , for use in patients years of age 11

• Fasenra® (benralizumab), for use in patients >12 years of age.7

• Nucala (mepolizumab), for use in patients >12 years of age with an eosinophilic phenotype.12

• Xolair® omalizuma , for use in patients years of age with a positive skin test or in vitro reactivity to a perennial aeroallergen.

Not all biologics have the same mechanism of action or are approved for the same types of asthma-related symptoms. There is most li ely overlap within the class, allowing for a frst line therapy to e defned within a formulary possi ly y step therapy , prior authorization, and tiering of enefts Case management for this class of medications can be helpful to patients when adding another type of medication to what seems like an already complicated treatment plan.

There may be an opportunity for dose optimization within the biological class, specifcally with omalizuma , ased on the dose range of to mg every two to four wee s valuation of indication and response to current therapy would need to be considered and could be implemented as part of a prior authorization process. Dose optimization carries the potential for cost savings and better patient outcomes if it reduces the potential for side e ects

Asthma a ects patients in many di erent ways he ey to avoiding potential complications is to approach each patient individually and help them identify the best treatment course to manage their symptoms, preserve activities of daily living, and improve uality of life It is imperative that patients understand proper techniques for administering their medications and how to identify their triggers in order to avoid them. A strong patient-provider relationship will help in the overall management of asthma symptoms and help to ensure patient compliance and adherence with their treatment plan.

References

1. “Most Recent National Asthma Data.” Centers for Disease Control and Prevention, May , https www cdc gov asthma most recent national asthma data htm

2. “Asthma Surveillance Data.” Centers for Disease Control and Prevention, April , , https www cdc gov asthma national surveillance data default htm

3. Nurmagambetov, T. et al. “The Economic Burden of Asthma in the United States, Annual American horacic Society, March , https www nc i nlm nih gov pu med

4. “Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma.” National Heart, Lung, and Blood Institute, National Asthma ducation and Prevention Program, U S Department of Health and Human Services, National Institutes of Health, Aug , , https www nc i nlm nih gov oo s NB

“Global Strategy for Asthma Management and Prevention.” Global Initiative for Asthma, , https ginasthma org wp content uploads GINA main report June wms pdf

Red Book® System https www micromede solutions com

7. Highlights of Prescri ing Information for FAS N A U S Food and Drug Administration, https www accessdata fda gov drugsatfda docs la el s l l pdf

Highlights of Prescri ing Information for O AI U S Food and Drug Administration, , https www accessdata fda gov drugsatfda docs la el s l l pdf

IPD Analytics ® https secure ipdanalytics com User Pharma Home Insights

10. Highlights of Prescri ing Information for DUPI N U S Food and Drug Administration, , https www accessdata fda gov drugsatfda docs la el l l pdf

11. Highlights of Prescri ing Information for CIN AI U S Food and Drug Administration, , https www accessdata fda gov drugsatfda docs la el l l pdf

12. Highlights of Prescri ing Information for NUCA A U S Food and Drug Administration, , https www accessdata fda gov drugsatfda docs la el Orig s l pdf

How

A Route to Adopting Biosimilars

Based on the experience at a major health care institution. The adoption process and roles may vary by institution.

Deciding to adopt a biosimilar

• Obtaining endorsements from department chairs Go to www.biosimilarslearn.com to

Electing to adopt a biosimilar should begin by building knowledge about the product, followed by gaining a general agreement among stakeholders in the organization.

• Evaluating the clinical and financial implications of pursuing a biosimilar switch, including obtaining input from physicians, the supply chain, and other stakeholders

• Investigating the clinical evidence

- Examining the available information/data

- Reviewing the Prescribing Information

• Assessing the possibility of long-term savings to the organization, specifically for pharmacy directors, procurement and supply chain specialists, and finance directors

Assessing the payer landscape

• Getting an initial understanding of the payer landscape

• Presenting recommendations to the pharmacy and therapeutics committee for their buy-in

Implementing a biosimilar

Pharmacy Director or Change Leader

Department Chairs Updating systems

Addressing payer landscape and reimbursement Patients Educating and communicating key information

Pharmacy Director or Change Leader Finance Director

Once the organization has decided to pursue the adoption of a biosimilar, certain steps should be followed to begin the transition to implementation. Communicating with stakeholders and educating patients about switching to a biosimilar can be instrumental to overall success.

• Optimizing the electronic health record (EHR) system

• Streamlining order sets and protocols

• Identifying appropriate patients

• Reviewing billing requirements

• Assessing the payer formulary

• Evaluating payer utilization management criteria

• Researching patient support programs

• Determining the implementation date

• Outlining possible changes to the EHR system

• Addressing insurance information

Additional considerations

• Inventory control

- Stocking of new product

- Handling of mixed inventory

• Prescribing

- Approved Indications

• Dosing and frequency

• Route of administration

• Reimbursement team and payer communications

• Possible reassignment of staff to identify patients and convert existing orders

- What can be done for naïve patients?

- Who will convert orders for non-naïve patients?

• Proactive patient communication

• Communicating to patients that they are being switched to a biosimilar that has shown no clinically meaningful differences in terms of safety, purity, and potency

• Supporting patients through patient access programs

• Providing physicians, nurses, pharmacists, and patients with a resource that includes consistent contact information for questions

Monitoring biosimilar use and experience

Once a biosimilar has been implemented, a system should be established to measure the quality of the health care professional and patient experience, the utilization of the biosimilar, and the impact of biosimilar adoption on the organization as a whole.

• Regularly reporting (eg, quarterly) to department chairs, the hospital administration, and the organization’s pharmacy and therapeutics committee

Possible reporting data

• Access and reimbursement issues

• Drug use evaluations

- Adverse drug reactions

- Efficacy and patient outcomes

• Overall patient experience

• Conversion rate

• Inventory control

• Stocking of new product

• Handling of mixed inventory

As the health care landscape continues to change, consider whether adopting biosimilars presents an opportunity for your organization.

Merck does not guarantee that your use of this information will help you achieve your biosimilars goals. This educational resource was prepared in consultation with and with the permission of a health care administrator at a major health care institution who had successfully implemented a biosimilars switch within their organization.

Oncology Biosimilars:

Update and Payer Considerations

As biosimilars enter the market across specialty categories, payers must assess the potential impacts and prepare to promote adoption.

Michael Ochowski, R.Ph. Pharmacy Informatics and EMR Support

Group Health Cooperative of South Central Wisconsin

While the relationship between generic drugs and their brand-name equivalents has been well-established, the relationship between biologic drugs and their biosimilars is not as clear.

When a biologic drug patent expires, the U.S. Food and Drug Administration (FDA) approves biosimilars through a di erent process than it does traditional generic drugs 1 The abbreviated 351(k) biosimilar pathway re uires manufacturers to demonstrate that there are no clinically meaningful di erences in safety or efcacy etween the iosimilars and their reference products raditional generic drugs are capable of achieving exact chemical likeness to the brand-name versions, but this is not the case with biosimilars due to complexities in their biosynthesis. Variability exists batch to batch in both reference and biosimilar products. Because of this, the FDA reviews a variety of data and evidence including, but not limited to, structural and functional characterization of the molecule, immunogenicity, pharmacokinetics, and at least one comparative clinical trial that establishes biosimilarity.

While biosimilars have been used in Europe for more than 10 years, they have not gained traction as quickly in the U.S. Biosimilars were approved and came to market for autoimmune conditions, but nine years passed between the creation of the FDA 351(k) biosimilar approval pathway and the launch of the U S s frst therapeutic oncology iosimilar agent In the same time frame, spending on oncology drugs in general has continued to rise across all lines of usiness In , oncology drugs were the primary drivers of cost for commercial payers.2

Available Biosimilars

he frst oncology iosimilars too the form of supportive care 3 Biosimilars for Neupogen®, Neulasta®, Epogen®, and Procrit® were approved and came to market in early 2018,4 giving the oncology community an opportunity to adjust to the idea of using biosimilars prior to the arrival of therapeutic oncology biosimilars.

able A a lable olo o lar a d Rela e Co 8, 9, 10, 11, 12, 13, 14, 15, 16, 17

Cost (Based on Q1 2020 Wholesale Acquisition Cost)

be a ab

Avastin® (Genentech) m vial

Mvasi evacizuma aww Amgen)

Zirabev® evacizuma vzr Pfzer

ra ab

$677.40 (4 mL vial)

$613.40 (4 mL vial)

Herceptin® (Genentech)$1,558.42 (150 mg vial)

Herzuma® trastuzuma p r Teva) , mg vial an inti trastuzuma anns Amgen) , mg vial

Ogivri trastuzuma d st Mylan) , mg vial

razimera trastuzuma yyp Pfzer , mg vial only r ab

Rituxan® (Genentech) m vial

Truxima® ritu ima a s Teva)

Ruxience® ritu ima pvvr Pfzer

$845.55 (10 mL vial)

$716.80 (10 mL vial)

In July , iosimilars evacizuma aww Mvasi and trastuzuma anns an inti launched, uic ly followed y rituimab-abbs (Truxima®) in November.5, 6, 7 Currently, there are multiple biosimilars commercially available for each of three reference products: bevacizumab (Avastin®), trastuzumab (Herceptin®), and rituximab (Rituxan®).

fere e fro e er

Like traditional generic drugs, biosimilars are believed to present cost-savings opportunities for patients, providers, and payers. However, whereas it is common practice to substitute generics during dispensing, biosimilars are currently not considered interchangeable for their reference products in the U.S. — which is unique in holding this view. Based on the lack of incentives in the U.S., it seems unlikely that many manufacturers will perform the extra clinical trials necessary to achieve the FDA interchangeability designation.

Additionally, whereas generic drugs typically carry the same indications as the brand-name product, biosimilars are often subject to so-called “skinny labels,” which imply that the biosimilar may only be approved for some but not all of its reference product’s indications. For example, due to patent protection, biosimilars for bevacizumab currently do not carry Avastin®’s indication for ovarian cancer.

a er Co dera o

Now that biosimilars are available, payers face the question of how they should manage, or even encourage, uptake in their use. he most apparent enefts relate to reductions in costs of care From 2011 to 2016, average annual expenditures in the U.S. for Avastin®, Herceptin®, and Rituxan® totaled $8.6 billion.18 By 2018, as the frst iosimilars were approaching launch, these three drugs were among the top fve highest spend oncology drugs for nine consecutive years. Given the continued increase in specialty drug approvals and the emergence of costly gene therapies in a number of categories, more a orda le iosimilars seem to e arriving at an opportune moment.

Savings from biosimilars may not be realized immediately, specifically for the Medicare population. Due to the circumstances and verbiage related to biosimilars within the Centers for Medicare and Medicaid Services (CMS) 340B drug pricing program, biosimilars are not reimbursed based on average sales price plus 6% (ASP+6) markup — as is the norm for name-brand and generic drugs — but rather based on the same ASP+6 as their reference products. CMS has attempted to safeguard against these discrepancies via pass-through status, which would allow for some drugs and biologics to be reimbursed at ASP minus 22.5% rather than ASP+6, ut di erent iosimilars for the same reference products could have di erent statuses Because of this lac of standardization

Now that biosimilars are available, payers face the question of how they should manage, or even encourage, uptake in their use.

among biosimilars, and because this price determines Medicare patients’ copays (provided the copay is based on a percentage of the drug price), the choice of biosimilar may mean that Medicare patients end up with a higher copay compared to commercially insured patients.

Beyond cost savings, decisions on how to manage emerging biosimilars in the oncology space should consider payers, providers, and patients ali e In order to truly encourage the use of iosimilars and in uence prescri ing ha its, payers will need to address concerns, uncertainty, and hesitancy from some providers. Surveys into U.S.-based oncologists’ perceptions of biosimilars have identifed educational gaps around perceived arriers to provider acceptance, interchangeability, and whether biosimilars will retain all their reference products’ indications.21 Payers can address these areas of concern through upfront communication and information sharing — including cost-savings projections for all stakeholders based on historical utilization, consensus opinions from renowned thought leaders, and provider education related to both the category in general and specifc factors impacting their mar et Consensus among providers suggests that if managed care organizations are clear and proactive in communicating both product

information and anticipated goals and enefts of potential management strategies, then other concerns will likely be addressed in time as more and more providers become familiar with these new biosimilars.

Payers can leverage several management strategies to drive patients and providers toward biosimilars. Managed care organizations may have an opportunity to encourage use of biosimilars currently on the mar et through policy shaping e orts, such as placing step-therapy requirements when a biosimilar is approved for the same indication as the reference biologic.

Magellan Rx created an oncology biosimilar action team during the latter part of 2018 to evaluate such a strategy on behalf of payer clients.23 After researching and examining various clinical and business aspects related to iosimilars, Magellan identifed ey areas of focus to equip clients with a proactive management strategy. From there, health plan clients could either choose to implement step therapy for all patients who had not previously received the reference product (“new starts”) or manage oncology biosimilars at parity with the reference products. From the time clients began implementing step therapy Sept , through the end of

January , the percentage of re uests for oncology iosimilars was among clients who chose step therapy and of requests for clients who chose a parity strategy.

Limiting step-therapy requirements to treatment-naïve members can ease concerns around interchangeability and drive utilization toward less expensive treatments, all while shielding patients and providers from forced switches during ongoing treatment.

Long-term follow-up will be needed to fully assess biosimilars’ clinical and fnancial impacts on the mar et In the interim, e pect to see additional biosimilars entering the market. Managed care organizations can prepare by putting strategies in place to proactively manage the balance of biosimilars and reference products. Payers equipped with proactive utilization-management strategies for oncology biosimilars can capitalize on early utilization shifts, thereby helping to minimize disruption and allowing for easier adoption of less-expensive biosimilar products.

1. Lyman, Gary H. et al. “Rationale, Opportunities, and Reality of Biosimilar Medications New ngland Journal of Medicine, May , , https pu med nc i nlm nih gov

2. Magellan Medical Pharmacy rend eport , Magellan Management, https://www1.magellanrx.com/documents/2020/03/ mr medical pharmacy trend report pdf

3. Cornes, Paul and Matti Aapro he Impact of Biosimilars in Supportive Care in Cancer.” European Oncology & Haematology, Feb. , , https doi org OH

4. Retacrit® pac age insert a e Forest, I Hospira May

5. Mvasi pac age insert housand Oa s, CA Amgen Septem er 2017.

6. an inti pac age insert housand Oa s, CA Amgen June

7. Truxima® pac age insert eonsu gu, Incheon, orea Celltrion November 2018.

8. Avastin® pac age insert South San Francisco, CA Genentech May 2020.

Zirabev® pac age insert New or , N Pfzer June

10. Herceptin® pac age insert South San Francisco, CA Genentech Septem er

11. Herzuma® pac age insert North ales, PA eva Pharmaceuticals December 2018.

12. “FDA approves Herzuma as a biosimilar to Herceptin.” U.S. Food and Drug Administration, Dec. 18, 2018, https://www.fda.gov/Drugs/ InformationOnDrugs ApprovedDrugs ucm htm

13. Ogivri pac age insert urich, Switzerland Mylan Decem er

14. razimera pac age insert New or , N Pfzer March Refere e

15. Davio, Kelly. “FDA Approves Celltrion’s Rituximab Biosimilar, Truxima.” he Center for Biosimilars American Journal of Managed Care, Nov 28, 2018, https://www.centerforbiosimilars.com/news/fda-approvescelltrions-rituximab-biosimilar-truxima.

16. Rituxan® pac age insert South San Francisco, CA Genentech October 2018.

17. Ruxience® pac age insert New or , N Pfzer July

18. IBM Micromede D BOO IBM, https www i m com products micromedex-red-book.

Hong, S J et al Spending on Antineoplastic Agents in the United States, to Journal of Oncology Practice, Sept , , https www nc i nlm nih gov pu med

20. Magellan Rx Medical Pharmacy Trend Report 2018, Magellan Rx Management, https www magellanr com documents medical-pharmacy-trend-report_2018.pdf.

21. “The Mysteries of Pass-Through Status: Why Medicare and Seniors Are Now Paying More for Lower-Cost Biosimilars at Hospitals.” https://www.drugchannels.net/2018/04/the-mysteries-of-passthrough-status.html.

22. Nabhan, Chadi et al. “Community Oncologists’ Perception and Acceptance of Biosimilars in Oncology Journal of Clinical Pathways, March 2018, https://www.journalofclinicalpathways.com/article/ community-oncologists-perception-and-acceptance-biosimilarsoncology.

23. Borgert, Rebecca et al. “The Long-awaited Launch of Oncology Biosimilars valuating the Impact of Payer and Provider Strategies on Early Adoption.” AMCP 2020. Magellan Rx Management, April 2020, https://www1.magellanrx.com/documents/2020/04/the-longawaited-launch-of-oncology-biosimilars-evaluating-the-impact-ofpayer-and-provider-strategies-on-early-adoption.pdf/.

FASENRA is indicated as an add-on maintenance treatment of patients 12 years and older with severe eosinophilic asthma.

POWER TO PREVENT EXACERBATIONS

The primary endpoint for SIROCCO (Trial 1) and CALIMA (Trial 2) was the rate of asthma exacerbations in patients with baseline blood eosinophil counts of ≥300 cells/μL who were taking high-dose ICS and LABA1

• In SIROCCO: 51% reduction in AER* (0.74; n=267) in patients who received FASENRA + SOC compared to placebo + SOC (1.52; n=267) (48 weeks, P<0.0001)1,2

• In CALIMA: 28% reduction in AER (0.73; n=239) in patients who received FASENRA + SOC compared to placebo + SOC (1.01; n=248) (56 weeks, P=0.019)1,3

ASTHMA EXACERBATION PREVENTION DATA

OVER 2 YEARS4,5

In patients who continued on FASENRA Q8W from SIROCCO and CALIMA into BORA

EXACERBATION DATA FROM BASELINE IN YEARS 1 AND 2†‡5

Asthma exacerbation rate (AER) data in Year 1 maintained in Year 2†‡5

YEAR 1

(Weeks 0-56)

AER*

Baseline 2.7 §

Pre-Study Baseline AER*

SIROCCO and CALIMA (pooled)

YEAR 2

(Weeks 56-112)

BORA (Phase 3 Safety Extension Trial)

FASENRA + SOC (n=318)

Year 2 AER: 0.48

FASENRA + SOC (n=318)

†The analyses of these endpoints were not multiplicity protected. Results are descriptive only.

IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS

Known hypersensitivity to benralizumab or excipients.

WARNINGS AND PRECAUTIONS

Hypersensitivity Reactions

Hypersensitivity reactions (eg, anaphylaxis, angioedema, urticaria, rash) have occurred after administration of FASENRA. These reactions generally occur within hours of administration, but in some instances have a delayed onset (ie, days). Discontinue in the event of a hypersensitivity reaction.

Acute Asthma Symptoms or Deteriorating Disease

FASENRA should not be used to treat acute asthma symptoms, acute exacerbations, or acute bronchospasm.

FASENRA is not indicated for treatment of other eosinophilic conditions or for the relief of acute bronchospasm or status asthmaticus.

EXACERBATION PREVENTION DATA: BORA

OF PATIENTS WHO CONTINUED ON Q8W DOSING FROM SIROCCO OR CALIMA INTO BORA ( 56 WEEKS ) HAD

0 EXACERBATIONS II4

The analyses of these endpoints were not multiplicity protected. Results are descriptive only.

In SIROCCO and CALIMA, FASENRA and placebo were administered plus standard of care (SOC), which is de ned as high-dose ICS/LABA (inhaled corticosteroids/long-acting ß2-agonist) with or without other controllers, including systemic steroids. In SIROCCO and CALIMA, the primary endpoint was the rate of asthma exacerbations in patients with baseline blood eosinophil counts ≥300 cells/μL who were taking high-dose ICS and LABA.1

In BORA, patients from SIROCCO and CALIMA were to be maintained on their same dose of ICS/LABA.4

The most common adverse reactions (incidence greater than or equal to 3%) associated with the use of FASENRA (and placebo) included headache 8% (6%); pharyngitis 5% (3%); pyrexia 3% (2%); and hypersensitivity reactions 3% (3%).1

*Annual exacerbation rate (AER) was de ned as the total number of exacerbations multiplied by 365.25, divided by the total duration of follow-up (days) within the treatment group.

‡Patients who had baseline blood eosinophil counts ≥300 cells/μL, receiving high-dose ICS/LABA, and who received FASENRA 30 mg Q8W during SIROCCO, CALIMA, and BORA.5

§Exacerbation rate over the year before pivotal study entry.5

IIIn patients with baseline blood eosinophil counts ≥300 cells/μL in SIROCCO and CALIMA who continued on FASENRA every 8 weeks (n=339).4

IMPORTANT SAFETY INFORMATION (cont’d)

WARNINGS AND PRECAUTIONS (cont’d)

Reduction of Corticosteroid Dosage

Do not discontinue systemic or inhaled corticosteroids abruptly upon initiation of therapy with FASENRA. Reductions in corticosteroid dose, if appropriate, Please see additional Important Safety Information on next page and Brief Summary of Prescribing Information on adjacent pages.

FASENRA is indicated as an add-on maintenance treatment of patients 12 years and older with severe eosinophilic asthma.

FASENRA is not indicated for treatment of other eosinophilic conditions or for the relief of acute bronchospasm or status asthmaticus.

STUDY DESIGNS

SIROCCO and CALIMA (Trials 1 and 2)

SIROCCO (48-week) and CALIMA (56-week) were 2 randomized, double-blind, parallel-group, placebo-controlled, multicenter studies comparing FASENRA 30 mg SC Q4W for the rst 3 doses, then Q8W thereafter; benralizumab 30 mg SC Q4W, and placebo SC. A total of 1204 (SIROCCO) and 1306 (CALIMA) patients aged 12-75 years old with severe asthma uncontrolled on high-dose ICS (SIROCCO) and medium- to high-dose ICS (CALIMA) plus LABA with or without additional controllers were included. Patients had a history of ≥2 exacerbations requiring systemic corticosteroids or temporary increase in usual dosing in the previous year. Patients were strati ed by geography, age, and blood eosinophil counts (≥300 cells/μL and <300 cells/μL). The primary endpoint was annual exacerbation rate ratio vs placebo in patients with blood eosinophil counts of ≥300 cells/μL on high-dose ICS and LABA. Exacerbations were de ned as a worsening of asthma that led to use of systemic corticosteroids for ≥3 days, temporary increase in a stable OCS background dose for ≥3 days, emergency/urgent care visit because of asthma that needed systemic corticosteroids, or inpatient hospital stay of ≥24 hours because of asthma. Key secondary endpoints were pre-bronchodilator FEV1 and total asthma symptom score at Week 48 (SIROCCO) and Week 56 (CALIMA) in the same population.2,3

BORA (Phase 3 Safety Extension Trial)

A randomized, double-blind, parallel-group, phase 3 extension study that enrolled patients who completed SIROCCO or CALIMA (n=1576). Patients enrolled in the previous studies were aged 12-75 years and had physician-diagnosed asthma requiring treatment with medium-dosage or high-dosage ICS plus LABA for at least 12 months with or without additional controllers prior to enrollment. Patients originally randomized to FASENRA continued FASENRA 30 mg SC Q8W or benralizumab SC Q4W. Patients previously receiving placebo were re-randomized 1:1 to FASENRA 30 mg SC Q4W for the rst 3 doses, then Q8W thereafter or benralizumab 30 mg SC Q4W except for adolescent patients in the EU who were randomized to FASENRA 30 mg SC Q8W. Patients were to be maintained on their same dose of ICS/LABA. End of treatment was at Week 56 for adults and Week 108 for adolescents. The primary objective was assessment of safety and tolerability. Secondary objectives included assessments of asthma exacerbations, pre-bronchodilator forced expiratory volume in 1 second (FEV1), and impact of treatment on blood eosinophil levels. Results are at Weeks 68 (adult follow-up) and 56 (adolescents), unless otherwise noted.4

References: 1. FASENRA [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; October 2019. 2. Bleecker ER, FitzGerald JM, Chanez P, et al. E cacy and safety of benralizumab for patients with severe asthma uncontrolled with high-dosage inhaled corticosteroids and long-acting β2-agonists (SIROCCO): a randomised, multicentre, placebocontrolled phase 3 trial. Lancet. 2016;388:2115-2127. 3. FitzGerald JM, Bleecker ER, Nair P, et al. Benralizumab, an anti-interleukin-5 receptor α monoclonal antibody, as add-on treatment for patients with severe, uncontrolled, eosinophilic asthma (CALIMA): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2016;388:2128-2141. 4. Busse WW, Bleecker ER, FitzGerald JM, et al. Long-term safety and e cacy of benralizumab in patients with severe, uncontrolled asthma: 1-year results from the BORA phase 3 extension trial. Lancet Respir Med. 2019;7:46-59. 5. FitzGerald JM, Bleecker ER, Bourdin A, et al. Two-year integrated e cacy and safety analysis of benralizumab SIROCCO, CALIMA, ZONDA, and BORA trials in severe asthma. Presented at: the American Thoracic Society (ATS) International Conference; May 17-22, 2019; Dallas, TX.

IMPORTANT SAFETY INFORMATION (cont’d)

WARNINGS AND PRECAUTIONS (cont’d)

Reduction of Corticosteroid Dosage (cont’d) should be gradual and performed under the direct supervision of a physician. Reduction in corticosteroid dose may be associated with systemic withdrawal symptoms and/or unmask conditions previously suppressed by systemic corticosteroid therapy.

Parasitic (Helminth) Infection

It is unknown if FASENRA will in uence a patient’s response against helminth infections. Treat patients with pre-existing helminth infections before initiating therapy with FASENRA. If patients become infected while receiving FASENRA and do not respond to antihelminth treatment, discontinue FASENRA until infection resolves.

ADVERSE REACTIONS

The most common adverse reactions (incidence % 5%) include headache and pharyngitis.

Injection site reactions (eg, pain, erythema, pruritus, papule) occurred at a rate of 2.2% in patients treated with FASENRA compared with 1.9% in patients treated with placebo.

USE IN SPECIFIC POPULATIONS

A pregnancy exposure registry monitors pregnancy outcomes in women exposed to FASENRA during pregnancy. To enroll call 1-877-311-8972 or visit www.mothertobaby.org/fasenra.

The data on pregnancy exposure from the clinical trials are insu cient to inform on drug-associated risk. Monoclonal antibodies such as benralizumab are transported across the placenta during the third trimester of pregnancy; therefore, potential e ects on a fetus are likely to be greater during the third trimester of pregnancy.

INDICATION

FASENRA is indicated for the add-on maintenance treatment of patients with severe asthma aged 12 years and older, and with an eosinophilic phenotype.

• FASENRA is not indicated for treatment of other eosinophilic conditions

• FASENRA is not indicated for the relief of acute bronchospasm or status asthmaticus

Please see Brief Summary of Prescribing Information on adjacent pages.

You are encouraged to report negative side e ects of prescription drugs to the FDA. Visit www.FDA.gov/medwatch or call 1-800-FDA-1088

companies.

FASENRA® (benralizumab) injection, for subcutaneous use

Initial U.S. Approval: 2017

Brief Summary of Prescribing Information. For complete prescribing information consult official package insert.

INDICATIONS AND USAGE

FASENRA is indicated for the add-on maintenance treatment of patients with severe asthma aged 12 years and older, and with an eosinophilic phenotype [see Clinical Studies (14) in the full Prescribing Information]

Limitations of use:

• FASENRA is not indicated for treatment of other eosinophilic conditions.

• FASENRA is not indicated for the relief of acute bronchospasm or status asthmaticus.

DOSAGE AND ADMINISTRATION

Recommended Dose

FASENRA is for subcutaneous use only.

The recommended dose of FASENRA is 30 mg administered once every 4 weeks for the first 3 doses, and then once every 8 weeks thereafter by subcutaneous injection into the upper arm, thigh, or abdomen.

General Administration Instructions

FASENRA is intended for use under the guidance of a healthcare provider. In line with clinical practice, monitoring of patients after administration of biologic agents is recommended [see Warnings and Precautions (5.1) in the full Prescribing Information]

Administer FASENRA into the thigh or abdomen. The upper arm can also be used if a healthcare provider or caregiver administers the injection. Prior to administration, warm FASENRA by leaving carton at room temperature for about 30 minutes. Visually inspect FASENRA for particulate matter and discoloration prior to administration. FASENRA is clear to opalescent, colorless to slightly yellow, and may contain a few translucent or white to off-white particles. Do not use FASENRA if the liquid is cloudy, discolored, or if it contains large particles or foreign particulate matter.

Prefilled Syringe

The prefilled syringe is for administration by a healthcare provider.

Autoinjector (FASENRA PEN™)

FASENRA PEN is intended for administration by patients/caregivers. Patients/caregivers may inject after proper training in subcutaneous injection technique, and after the healthcare provider determines it is appropriate.

Instructions for Administration of FASENRA Prefilled Syringe (Healthcare Providers)

Refer to Figure 1 to identify the prefilled syringe components for use in the administration steps.

Figure 1 Needle guard activation clips Syringe body Label with expiration date Needle cover

4

Inject all of the medication by pushing in the plunger all the way until the plunger head is completely between the needle guard activation clips. This is necessary to activate the needle guard. 5

After injection, maintain pressure on the plunger head and remove the needle from the skin. Release pressure on the plunger head to allow the needle guard to cover the needle. Do not re-cap the prefilled syringe.

6 Discard the used syringe into a sharps container.

Instructions for Administration of FASENRA PEN

Refer to the FASENRA PEN ‘Instructions for Use’ for more detailed instructions on the preparation and administration of FASENRA PEN [See Instructions for Use in the full Prescribing Information]. A patient may self-inject or the patient caregiver may administer FASENRA PEN subcutaneously after the healthcare provider determines it is appropriate.

CONTRAINDICATIONS

FASENRA is contraindicated in patients who have known hypersensitivity to benralizumab or any of its excipients [see Warnings and Precautions (5.1) in the full Prescribing Information]

WARNINGS AND PRECAUTIONS

Hypersensitivity Reactions

Hypersensitivity reactions (e.g., anaphylaxis, angioedema, urticaria, rash) have occurred following administration of FASENRA. These reactions generally occur within hours of administration, but in some instances have a delayed onset (i.e., days). In the event of a hypersensitivity reaction, FASENRA should be discontinued [see Contraindications (4) in the full Prescribing Information]

Acute Asthma Symptoms or Deteriorating Disease

FASENRA should not be used to treat acute asthma symptoms or acute exacerbations. Do not use FASENRA to treat acute bronchospasm or status asthmaticus. Patients should seek medical advice if their asthma remains uncontrolled or worsens after initiation of treatment with FASENRA.

Reduction of Corticosteroid Dosage

Do not discontinue systemic or inhaled corticosteroids abruptly upon initiation of therapy with FASENRA. Reductions in corticosteroid dose, if appropriate, should be gradual and performed under the direct supervision of a physician. Reduction in corticosteroid dose may be associated with systemic withdrawal symptoms and/or unmask conditions previously suppressed by systemic corticosteroid therapy.

Parasitic (Helminth) Infection

Do not touch the needle guard activation clips to prevent premature activation of the needle safety guard.

1 Grasp the syringe body, not the plunger, to remove prefilled syringe from the tray. Check the expiration date on the syringe. The syringe may contain small air bubbles; this is normal. Do not expel the air bubbles prior to administration.

2 Do not remove needle cover until ready to inject. Hold the syringe body and remove the needle cover by pulling straight off. Do not hold the plunger or plunger head while removing the needle cover or the plunger may move. If the prefilled syringe is damaged or contaminated (for example, dropped without needle cover in place), discard and use a new prefilled syringe.

3 Gently pinch the skin and insert the needle at the recommended injection site (i.e., upper arm, thigh, or abdomen).

Eosinophils may be involved in the immunological response to some helminth infections. Patients with known helminth infections were excluded from participation in clinical trials. It is unknown if FASENRA will influence a patient’s response against helminth infections.

Treat patients with pre-existing helminth infections before initiating therapy with FASENRA. If patients become infected while receiving treatment with FASENRA and do not respond to anti-helminth treatment, discontinue treatment with FASENRA until infection resolves.

ADVERSE REACTIONS

The following adverse reactions are described in greater detail in other sections: • Hypersensitivity Reactions [see Warnings and Precautions (5.1) in the full Prescribing Information]

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Across Trials 1, 2, and 3, 1,808 patients received at least 1 dose of FASENRA [see Clinical Studies (14) in the full Prescribing Information]. The data described below reflect exposure to FASENRA in 1,663 patients, including 1,556 exposed for at least 24 weeks and 1,387 exposed for at least 48 weeks. The safety exposure for FASENRA is derived from two Phase 3 placebo-controlled studies (Trials 1 and 2) from 48 weeks duration [FASENRA every 4 weeks (n=841), FASENRA every 4 weeks for 3 doses, then every 8 weeks (n=822), and placebo (n=847)]. While a dosing regimen of FASENRA every 4 weeks was included in clinical trials, FASENRA administered every 4 weeks for 3 doses, then every 8 weeks thereafter is the recommended dose [see Dosage and Administration (2.1) in the full Prescribing Information]. The population studied was 12 to 75 years of age, of which 64% were female and 79% were white. Adverse reactions that occurred at greater than or equal to 3% incidence are shown in Table 1 Table 1. Adverse Reactions with FASENRA with Greater than or Equal to 3% Incidence in Patients with Asthma (Trials 1 and 2)

Adverse Reactions FASENRA (N=822) % Placebo (N=847) %

* Pharyngitis was defined by the following terms: ‘Pharyngitis’, ‘Pharyngitis bacterial’, ‘Viral pharyngitis’, ‘Pharyngitis streptococcal’.

† Hypersensitivity Reactions were defined by the following terms: ‘Urticaria’, ‘Urticaria papular’, and ‘Rash’ [see Warnings and Precautions (5.1) in the full Prescribing Information].

FASENRA® (benralizumab) injection, for subcutaneous use

28-Week Trial

Adverse reactions from Trial 3 with 28 weeks of treatment with FASENRA (n=73) or placebo (n=75) in which the incidence was more common in FASENRA than placebo include headache (8.2% compared to 5.3%, respectively) and pyrexia (2.7% compared to 1.3%, respectively) [see Clinical Studies (14) in the full Prescribing Information]. The frequencies for the remaining adverse reactions with FASENRA were similar to placebo.

Injection site reactions

In Trials 1 and 2, injection site reactions (e.g., pain, erythema, pruritus, papule) occurred at a rate of 2.2% in patients treated with FASENRA compared with 1.9% in patients treated with placebo.

Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to benralizumab in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.

Overall, treatment-emergent anti-drug antibody response developed in 13% of patients treated with FASENRA at the recommended dosing regimen during the 48 to 56 week treatment period. A total of 12% of patients treated with FASENRA developed neutralizing antibodies. Anti-benralizumab antibodies were associated with increased clearance of benralizumab and increased blood eosinophil levels in patients with high anti-drug antibody titers compared to antibody negative patients. No evidence of an association of anti-drug antibodies with efficacy or safety was observed.

The data reflect the percentage of patients whose test results were positive for antibodies to benralizumab in specific assays.

Postmarketing Experience

In addition to adverse reactions reported from clinical trials, the following adverse reactions have been identified during post approval use of FASENRA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These events have been chosen for inclusion due to either their seriousness, frequency of reporting, or causal connection to FASENRA or a combination of these factors.

Immune System Disorders: Hypersensitivity reactions, including anaphylaxis.

DRUG INTERACTIONS

No formal drug interaction studies have been conducted.

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to FASENRA during pregnancy. Healthcare providers can enroll patients or encourage patients to enroll themselves by calling 1-877-311-8972 or visiting mothertobaby.org/Fasenra.

Risk Summary

The data on pregnancy exposure from the clinical trials are insufficient to inform on drugassociated risk. Monoclonal antibodies such as benralizumab are transported across the placenta during the third trimester of pregnancy; therefore, potential effects on a fetus are likely to be greater during the third trimester of pregnancy. In a prenatal and postnatal development study conducted in cynomolgus monkeys, there was no evidence of fetal harm with IV administration of benralizumab throughout pregnancy at doses that produced exposures up to approximately 310 times the exposure at the maximum recommended human dose (MRHD) of 30 mg SC [see Data].

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

Disease-associated maternal and/or embryo/fetal risk:

In women with poorly or moderately controlled asthma, evidence demonstrates that there is an increased risk of preeclampsia in the mother and prematurity, low birth weight, and small for gestational age in the neonate. The level of asthma control should be closely monitored in pregnant women and treatment adjusted as necessary to maintain optimal control.

Data

Animal Data

In a prenatal and postnatal development study, pregnant cynomolgus monkeys received benralizumab from beginning on GD20 to GD22 (dependent on pregnancy determination), on GD35, once every 14 days thereafter throughout the gestation period and 1-month postpartum (maximum 14 doses) at doses that produced exposures up to approximately 310 times that achieved with the MRHD (on an AUC basis with maternal IV doses up to 30 mg/kg once every 2 weeks). Benralizumab did not elicit adverse effects on fetal or neonatal growth (including immune function) up to 6.5 months after birth. There was no evidence of treatment-related external, visceral, or skeletal malformations. Benralizumab was not teratogenic in cynomolgus monkeys. Benralizumab crossed the placenta in cynomolgus monkeys. Benralizumab concentrations were approximately equal in mothers and infants on postpartum day 7, but were lower in infants at later time points. Eosinophil counts were suppressed in infant monkeys with gradual recovery by 6 months postpartum; however, recovery of eosinophil counts was not observed for one infant monkey during this period.

Lactation

Risk Summary

There is no information regarding the presence of benralizumab in human or animal milk, and the effects of benralizumab on the breast fed infant and on milk production are not known. However, benralizumab is a humanized monoclonal antibody (IgG1/κ-class), and immunoglobulin G (IgG) is present in human milk in small amounts. If benralizumab is transferred into human milk, the effects of local exposure in the gastrointestinal tract and potential limited systemic exposure in the infant to benralizumab are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for benralizumab and any potential adverse effects on the breast-fed child from benralizumab or from the underlying maternal condition.

Pediatric Use

There were 108 adolescents aged 12 to 17 with asthma enrolled in the Phase 3 exacerbation trials (Trial 1: n=53, Trial 2: n=55). Of these, 46 received placebo, 40 received FASENRA every 4 weeks for 3 doses, followed by every 8 weeks thereafter, and 22 received FASENRA every 4 weeks. Patients were required to have a history of 2 or more asthma exacerbations requiring oral or systemic corticosteroid treatment in the past 12 months and reduced lung function at baseline (pre-bronchodilator FEV1<90%) despite regular treatment with medium or high dose ICS and LABA with or without OCS or other controller therapy. The pharmacokinetics of benralizumab in adolescents 12 to 17 years of age were consistent with adults based on population pharmacokinetic analysis and the reduction in blood eosinophil counts was similar to that observed in adults following the same FASENRA treatment. The adverse event profile in adolescents was generally similar to the overall population in the Phase 3 studies [see Adverse Reactions (6.1) in the full Prescribing Information]. The safety and efficacy in patients younger than 12 years of age has not been established.

Geriatric Use

Of the total number of patients in clinical trials of benralizumab, 13% (n=320) were 65 and over, while 0.4% (n=9) were 75 and over. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

OVERDOSAGE

Doses up to 200 mg were administered subcutaneously in clinical trials to patients with eosinophilic disease without evidence of dose-related toxicities.

There is no specific treatment for an overdose with benralizumab. If overdose occurs, the patient should be treated supportively with appropriate monitoring as necessary.

PATIENT COUNSELING INFORMATION

Advise the patients and/or caregivers to read the FDA-approved patient labeling (Patient Information and Instructions for Use for FASENRA PEN) before the patient starts using FASENRA and each time the prescription is renewed as there may be new information they need to know.

Provide proper training to patients and/or caregivers on proper subcutaneous injection technique using the FASENRA PEN, including aseptic technique, and the preparation and administration of FASENRA PEN prior to use. Advise patients to follow sharps disposal recommendations [see Instructions for Use in the full Prescribing Information].

Hypersensitivity Reactions

Inform patients that hypersensitivity reactions (e.g., anaphylaxis, angioedema, urticaria, rash) have occurred after administration of FASENRA. These reactions generally occurred within hours of FASENRA administration, but in some instances had a delayed onset (i.e., days). Instruct patients to contact their healthcare provider if they experience symptoms of an allergic reaction [see Warnings and Precautions (5.1) in the full Prescribing Information]

Not for Acute Symptoms or Deteriorating Disease

Inform patients that FASENRA does not treat acute asthma symptoms or acute exacerbations. Inform patients to seek medical advice if their asthma remains uncontrolled or worsens after initiation of treatment with FASENRA [see Warnings and Precautions (5.2) in the full Prescribing Information]

Reduction of Corticosteroid Dosage

Inform patients to not discontinue systemic or inhaled corticosteroids except under the direct supervision of a physician. Inform patients that reduction in corticosteroid dose may be associated with systemic withdrawal symptoms and/or unmask conditions previously suppressed by systemic corticosteroid therapy [see Warnings and Precautions (5.3) in the full Prescribing Information]

Pregnancy Exposure Registry

Inform women there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to FASENRA during pregnancy and that they can enroll in the Pregnancy Exposure Registry by calling 1-877-311-8972 or by visiting mothertobaby.org/Fasenra [see Use in Specific Populations (8.1) in the full Prescribing Information]

Manufactured by AstraZeneca AB

Södertälje, Sweden SE-15185

US License No. 2059

Distributed by AstraZeneca Pharmaceuticals LP, Wilmington, DE 19850

FASENRA is a trademark of the AstraZeneca group of companies.

©AstraZeneca 2019

Rev. 10/19 US-30659 10/19

Sickle Cell Disease:

Clinical and Management Update

Most SCD patients today are not eing treated appropriately due to underutilization of current therapies, ut emerging therapies present an opportunity to provide more e ective management of SCD.

Samir Mistry, Pharm.D. Vice President, Pharmacy PreferredOne

Sickle cell disease (SCD) causes red blood cells to cluster together, which leads to vascular occlusion and impairs oxygen supply to tissues, causing cell destruction and a shortage of healthy blood cells. These blockages can cause vaso-occlusive crises (VOCs), a painful condition that can lead to hospitalizations. Symptoms of SCD include infection, pain, anemia, swelling of the hands and feet, and fatigue. The condition can advance to organ damage.1

SCD primarily a ects people from, or descended from, African, Mediterranean, and Spanish spea ing countries An estimated , Americans have SCD, and the condition occurs in an estimated in African American irths Appro imately in African American a ies are orn with sic le cell trait (SCT).1

SCD a ects millions around the world and has very high associated medical costs over illion annually in the U S For adults, the total cost per patient per month pea s at around , For patients who reach the age of , annual costs are estimated at million Medicaid paid for a out of hospital stays for SCD in , and less than of doctors in the U S accepted new Medicaid patients A study showed that a out of hospital stays for patients with a SCD diagnosis were paid for y Medicaid, and, according to data, only of doctors in the U S accepted new Medicaid patients;3, 4 thus, this su set of patients has limited access to care, which a ects health outcomes ,

Course and Pathogenesis

SCD is autosomal recessive and caused by a mutation in the ß-globin chain of the hemoglobin molecule (HBB) in infancy.5 People who inherit one sickle cell gene and one normal gene have SCT, and though they do not have SCD symptoms, they can pass on the trait.1 The mutation causes the sixth amino acid in the ß-globin chain to be switched from glutamic acid to valine.5 The mutated hemoglobin molecule is prone to sticking to other hemoglobin molecules under certain conditions.

SICKLE CELL DISEASE

Hematologists, pediatric hematologists, ophthalmologists,

and pulmonologists are typically tasked with SCD management.

hile normal red lood cells last to days and can freely ow through the ody, H S molecules ecome viscous and cannot travel as freely. VOCs can prevent oxygen from reaching tissues, causing tissues to become ischemic. VOCs usually occur in the lower back, legs, hips, abdomen, and chest and can last days or even weeks. If VOC-associated pain reaches the chest, it can cause an infection of the lungs acute chest syndrome a leading cause of death for SCD patients.5

There are three major types of SCD.

» HbSS, or sickle cell anemia, is the most severe form and occurs when a person inherits two sickle cell genes from each parent.

» HbSC occurs when a person inherits one sickle cell gene from one parent and one gene for abnormal hemoglobin C from the other.

» HbS ß-thalassemia occurs when a person inherits one sickle cell gene from one parent and one gene for a type of anemia called ß-thalassemia.1

Complications

Splenic sequestration, which usually occurs in younger children and can be severe and life-threatening, is a sudden phenomenon wherein large amounts of sickle cells get trapped in the spleen. The hemoglobin can drop rapidly, causing anemia quickly and leading to hypovolemic shock. Treatment is needed quickly, with focus on expanding blood volume through blood transfusions.6 Other SCD complications include infections, hand-foot syndrome, eye disease, acute chest syndrome, and stroke.

Treatment Challenges

Hematologists, pediatric hematologists, ophthalmologists, and pulmonologists are typically tasked with SCD management.

Patients often present to the emergency department (ED) when they are undergoing a VOC.6

Opioids are often prescribed to manage the excruciating pain that accompanies VOCs; however, studies show that not all patients eneft from pain relievers, possi ly due to opioid tolerance or inappropriately low doses of prescri ed opioids which is especially common from ED doctors who lack full understanding of the patient’s medical history. Curbing opioid use due to the potential for a use or misuse is another challenge Alternatives to opioids for SCD-associated pain management are being researched.5

Diagnosis

Newborns in the U.S. receive a routine blood test that checks for defective forms of hemoglo in to detect SCD Adults can also undergo this blood test to determine if they are a carrier for SCTs. Patients with SCD will be diagnosed with one of the three main types: HbSS, HbSC, or HbS. Symptoms usually do not present until around 5-6 months of age, as patients are initially protected by their fetal hemoglobin.6

Current Treatment Options

Infection Prevention and Treatment: Antibiotics and Vaccinations

Immunization and prophylactic treatment with antibiotics can reduce the risk of infection and further complications. Children who have SCD at birth should take penicillin twice daily until 5 years of age to prevent pneumococcal sepsis. Infections are a major cause of death in patients with SCD; therefore, it is essential that they get certain vaccinations to prevent infections. Pediatric patients should receive Haemophilus in uenzae type Hi , Meningococcal conjugate, and Pneumococcal conjugate (PCV13, or Prevnar 13).6

VOC Prevention and Treatment: Hydroxyurea and L-glutamine

Hydroxyurea and L-glutamine are used to prevent or reduce the frequency of acute and chronic complications.

Hydroxyurea stimulates the production of HbF, or fetal hemoglobin, and, when used long-term, can reduce the frequency of acute pain crises and the need for blood transfusions. It is only indicated for adults with three or more moderate-to-severe VOCs a year. It is proven to reduce the fre uency of painful VOC episodes y

and raise hemoglobin, and it is associated with increased survival rates in patients with SCD. However, it can also cause myelosuppression, or bone marrow suppression; therefore, hematology labs must be monitored regularly. When taking this hazardous agent, contraception is required for both males and females, and patients should avoid live vaccines.

L-glutamine oral powder, or Endari®, is approved for adults and children older than 5 years with SCD who have failed hydroxyurea or for concurrent use. Glutamine can reduce acute complications related to SCD such as pain crises. Each 5g dose is mixed with ounces of cold or room temperature li uid or ounces of food. Glutamine , mg is also availa le as an over the counter product, but this is generally not recommended since it has not een approved y the U S Food and Drug Administration FDA

Pain Management: Opioids and Other Pain Relievers

VOCs usually require IV opioids or patient-controlled analgesia to tolerate the severe pain.6 Acute moderate pain is usually managed with a less potent opioid, such as codeine or hydrocodone, in com ination with an NSAID, such as i uprofen or acetaminophen. For acute severe pain, stronger opioids, such as intravenous morphine or fentanyl may be used.

Chelation Therapy

SCD patients receive regular blood transfusions, and within each unit of pac ed red lood cells is a out mg of iron After of these transfusions, the body accumulates excess iron due to saturation of transferrin. Iron overload can cause organ damage. Chelation therapy is used to manage the iron load that patients receive from blood transfusions. Oral chelation therapy has recently become available: deferasirox (Exjade®, Jadenu®) and deferiprone (Ferriprox®).11

Transplantation

Bone marrow or stem cell transplantation is currently the only real cure for SCD. Unfortunately, it is not utilized widely due to the high costs and risks that accompany such an invasive treatment. There is signifcant to icity as well as serious side e ects and even death associated with this procedure Additionally, for these transplants to wor e ectively, the one marrow must e a close match 1

New Pharmacotherapies

he FDA recently approved two new drugs crizanlizuma tmca Ada veo® and vo elotor O ryta Ada veo® is an intravenous infusion-administered monoclonal antibody developed by

SICKLE CELL DISEASE

The FDA recently approved two new drugs: crizanlizumabtmca (Adakveo®) and voxelotor (Oxbryta™).

Novartis. It is used to reduce the frequency of VOCs in adults 16 years and older with SCD. Oxbryta™ is an oral medication developed by Global Blood Therapeutics and approved for people with SCD aged years and older and with a pretreatment hemogloin level of g d or less It wor s y eeping red lood cells in an oxygenated state and preventing the hemoglobin from sticking together.13

Crizanlizumab

he SUS AIN study evaluated crizanlizuma in a randomized, double-blind, phase two, placebo-controlled clinical trial. The post-hoc analysis loo ed at patients with SCD and randomized them to di erent doses of crizanlizuma mg g, mg g, or place o, administered via IV times over wee s Patients were randomized using a loc design and then stratifed according to the num er of VOCs in the prior year two to four or fve to and whether concomitantly using hydroxyurea. The primary endpoint analyzed was the yearly VOC with crizanlizumab versus with placebo. Secondary endpoints were further analyzed and showed that crizanlizuma signifcantly increased time to frst VOC versus place o 14

SUSTAIN Results:

» 25.8% of patients receiving crizanlizumab did not experience a VOC, compared with 16.9% of those receiving placebo. This pattern was also shown in each subgroup, especially for patients who had experienced many VOCs in the year prior.

» 28% of patients receiving mg g crizanlizuma were VOC free, compared to 4.2% of patients receiving placebo.

» 33.3% of patients using hydroxyurea concomitantly were VOC-free, compared to 17.5% of patients who were not using hydroxyurea.

» 31.9% of patients with the HbSS genotype were VOC-free, compared with 17% of patients without it.

» ime to frst VOC for patients receiving crizanlizuma was 4.07 months, compared with 1.12 months for patients receiving placebo.

Overall, this study was successful, as it showed that patients had a decreased chance of a VOC occurring and a delay in the time to the frst VOC while ta ing crizanlizuma 14

Voxelotor (Oxbryta™)

Voxelotor (Oxbryta™) was studied in a phase three, multicenter, double-blind, randomized, placebo-controlled trial. Two doses of vo elotor were analyzed to compare safety and efcacy participants were randomized in a 1:1:1 ratio to receive once-daily voxelotor , mg, once daily vo elotor mg, or place o Most participants had SCD, and about two-thirds were already on hydroxyurea treatment. The primary endpoint was the percentage of patients with a hemoglo in response, shown as an increase of g d from aseline at wee

Results:

» 51% of patients receiving vo elotor , mg and 33% of patients receiving mg had a hemoglo in response, compared to 7% in the place o group, which is a signifcant di erence

» Vo elotor improved anemia etween aseline and wee compared to placebo.

» Most adverse e ects reported y patients were not related to the drug or placebo.

his study was considered a success, as vo elotor signifcantly increased hemoglobin levels and reduced hemolysis markers, although it did not show a statistical eneft in VOC reduction 15

ICER Review

A March Institute for Clinical and conomic eview IC eport issued ey clinical fndings on SCD therapies 16

» Crizanlizumab, the report concluded, will provide a positive net health eneft however, considering the difculties in estimating the amount of long term organ system enefts and the uncertainty a out long term safety, IC could only ma e the conclusion with moderate certainty and gave the therapy a B+ rating.

» Voxelotor got a “promising but inconclusive” rating in the report, due to difculties in ascertaining the clinical eneft of the drug with data availa le at its launch however, IC found that the clinical enefts are li ely to e somewhat greater than those eperienced with usual care.16

» L-Glutamine was rated as “promising but inconclusive” due to fndings on clinical eneft eing too uncertain to allow for a clear determination of their magnitude however, IC found Glutamine most li ely provides some clinical eneft 16

IC reported that at the treatments current list prices, of patients could be treated in a given year with crizanlizumab, and could e treated with vo elotor efore crossing IC s potential udget impact threshold of million per year 16

Pipeline Treatments

Pharmaceutical companies such as Vertex Pharmaceuticals, lue ird io, Sangamo herapeutics, and C ISP herapeutics are investigating the use of gene therapies to treat SCD. Gene therapy involves genetically altering a patient’s own hematopoietic stem cells using C ISP clustered regularly interspaced short palindromic repeats) and a viral vector to boost the production of fetal hemoglobin. This research provides more options for patients with SCD and may even act as a functional cure.

SICKLE CELL DISEASE

Managed Care Implications

SCD presents a signifcant urden on the U S healthcare system he ma ority of the SCD patient population is of African descent and on Medicaid or Medicare he fnancial disparity in this demographic population can often ma e access to treatment difcult, which ultimately leads to poor health outcomes, disease complications, and increased costs.

Most SCD patients today are not eing treated appropriately due to the underutilization of current therapies. Emerging therapies present an opportunity to provide more e ective management of SCD, reducing VOCs and, ultimately, ED visits and healthcare resource utilization. However, although there are four medications

approved for SCD, chronic medical complications remain a burden. Ensuring appropriate use of therapies, including optimizing care before moving to these new medications, is important because of the high associated costs Additionally, ecause Adaveo® is an intravenous infusion that requires administration by a healthcare professional, access may e difcult for many patients

SCD is a lifelong disease; while bone marrow transplant is a comple treatment and fnding a match is difcult, it remains the only potential cure for SCD. Gene therapies on the horizon show promising curative potential for SCD, which will undoubtedly impact patients and the healthcare system as they become a reality.

References

1. “Sickle Cell Disease (SCD).” Centers for Disease Control and Prevention, Oct , , https www cdc gov nc ddd sic lecell data.html.

Azevedo, Margarida eport Highlights Challenges of Sic le Cell Disease in reatment, Access to Care Sic le Cell Disease News, Nov , , https sic lecellanemianews com report-highlights-challenges-sickle-cell-disease-treatment-accesscare

3. Fingar, Kathryn et al. “Characteristics of inpatient hospital stays involving sic le cell disease, Healthcare Cost and Utilization Pro ect, Sept , https hcup us ahr gov reports stat riefs s Sic le Cell Disease Stays sp

4. “National Center for Health Statistics Web Tables.” Centers for Disease Control and Prevention, Apr , , https www cdc gov nchs ahcd ahcd products htm

5. Field, Joshua J. “Five lessons learned about long-term pain management in adults with sic le cell disease American Society of Hematology ducation Program Hematology, Dec , , https doi org asheducation

6. “Sickle Cell Disease (SCD): Complications and Treatments of Sickle Cell Disease Centers for Disease Control and Prevention, Oct , , https www cdc gov nc ddd sic lecell treatments html Agrawal, ohit umar et al Hydro yurea in Sic le Cell Disease Drug eview Indian Journal of Hematology and Blood ransfusion, May , , https doi org s

McGann, Patric and ussell are Hydro yurea therapy for sic le cell anemia pert Opinion on Drug Safety, pp , Sept , , https doi org

Al Salem, Ahmed Hydro yurea reatment for Sic le Cell Anemia Medical and Surgical Complications of Sic le Cell Anemia, pp , Dec , , https doi org

ndari pac age insert orrance CA mmaus Medical Inc

11. Ballas, Samir et al he e ect of iron chelation therapy on overall survival in sickle cell disease and β thalassemia A systematic review American Journal of Hematology, April , , https doi org a h

Ada veo® [package insert]. East Hanover, NJ: Novartis Pharmaceuticals

13. O ryta pac age insert San Francisco, CA Glo al Blood herapeutics

14. utlar, A dullah ect of crizanlizuma on pain crises in su groups of patients with sic le cell disease A SUS AIN study analysis American Journal of Hematology, Oct , , https doi org a h

15. Vichins y, lliott et al A Phase andomized rial of Vo elotor in Sic le Cell Disease he New ngland Journal of Medicine, Aug , , https doi org ne moa

16. “Crizanlizumab, Voxelotor, and L-Glutamine for Sickle Cell Disease: ectiveness and Value Institute for Clinical and conomic eview, March , , https icer review org wp content uploads IC SCD vidence eport pdf

“NIH researchers create new viral vector for improved gene therapy in sic le cell disease National Institutes of Health, Oct , , https www nhl i nih gov news nih researchers create new viral-vector-improved-gene-therapy-sickle-cell-disease. Gene herapy Sic le Cell Disease News, https sic lecellanemianews com gene therapy

ee, a asha et al educing health care disparities in sic le cell disease A review Pu lic Health eports, Nov Dec , https doi org

Method Capa ility Spotlight

Health Economics and Outcomes Research

Considering the high rate of D visits among adults with dia etes, the Magellan Method team evaluated the potential need for more e ective management of D use in this population

In spring 2020, Magellan Method virtually presented research with the Academy of Managed Care Pharmacy (AMCP) highlighting health economics and outcomes research (HEOR) around the classifcation of ype dia etes DM patients

he Magellan Method H O team focused on the New or University mergency Department Algorithm DA , which is a tool that can e used to classify emergency department D visits he DA is used to determine the emergent nature of D visits ased on full chart review and assesses information on patient complaints, symptoms, vital signs, diagnoses, procedures, and D resource use 1 Considering the high rate of D visits among adults over years with dia etes who account for an estimated million visits a year the Method team aimed to evaluate the potential need for more e ective management of D use in this population In this study, Magellan Method sought to assess the association of emergent classifcation of an D visit ased on the modifed DA with hospital admissions in DM patients

Methods

In order to achieve this o ective, the team conducted a retrospective analysis of two commercial claims made y adult DM patients within the study period he modifed DA categorized D visits into three levels emergent, intermediate, and nonemergent he study focused on specifc outcomes, including healthcare resource utilization and proportion of patients with D visits or hospitalizations within months efore or after the study period

Findings

Of the , patients who met the inclusion criteria, , , and of the patients had emergent, intermediate, and nonemergent D visits, respectively, in the pre inde period, compared to , , and , respectively, in the post inde period he results were nota le he DA measure of emergent D visits was signifcantly associated with hospitalizations in the period efore diagnosis odds ratio O , confdence interval CI , and in the period after diagnosis O , CI, compared to those with nonemergent visits As a tool, the DA can e used to assess trends in D utilization and can e used y health plans for intervention assessment See a les and Figure for an illustration of the methodology and results he full AMCP poster presentation can e found at https://www1.magellanrx.com/read-watch-listen/read/ clinical-research/

HEOR Capabilities

Utilizing real world health plan medical and pharmacy claims data, Method H O is a le to uantify the clinical and economic needs for proposed partnership interventions such as assessing D trends and interventions for patients with various disease states, with the goal of reducing D use for nonemergent conditions while improving outcomes In addition to the analysis completed in this study, Method H O has a range of capa ilities providing innovative solutions to pharmaceutical partners needs Many past Method H O pro ects have een award winning presentations at industry

HEOR SPOTLIGHT |

Table 2. Patient Demographics and Clinical Characteristics

conferences such as the AMCP esearch and reporting capa ilities o ered y Method H O include predictive and udget impact modeling product utilization reviews, cost assessment evaluation, and trend prescription clinical and fnancial impact of programs or policies; reduction in negative health outcomes; adherence and persistence and related e ects patient reported outcomes and pu lication planning and a stract or poster su missions

Table 1. Patient Attrition

Table 3. Emergency Department Use and Hospitalizations

Table 4. Regression: Predictors of Hospitalization

his

References

Gandhi, Sa ina Ohri and indsay Sa i mergency department visit classifcation using the N U algorithm American Journal of Managed Care, April , , https www nc i nlm nih gov pu med

Ballard, Dustin et al Validation of an Algorithm for Categorizing the Severity of Hospital mergency Department Visits Medical Care , https doi org M e d ad https www nc i nlm nih gov pu med

Figure 1. NYU Algorithm for Classifying Diagnoses2

actual patients.

Indications and Usage

Saxenda® (liraglutide) injection 3 mg is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adult patients with an initial body mass index (BMI) of 30 kg/m2 or greater (obesity) or 27 kg/m2 or greater (overweight) in the presence of at least one weight-related comorbid condition (eg, hypertension, type 2 diabetes mellitus, or dyslipidemia)

Limitations of Use

• Saxenda® is not indicated for the treatment of type 2 diabetes

• Saxenda® and Victoza® both contain the same active ingredient, liraglutide, and therefore should not be used together. Saxenda® should not be used in combination with any other GLP-1 receptor agonist

• Saxenda® has not been studied in patients taking insulin. Saxenda® and insulin should not be used together

• The safety and efficacy of Saxenda® in combination with other products for weight loss, including prescription drugs, over-the-counter drugs, and herbal preparations, have not been established

Important Safety Information

WARNING: RISK OF THYROID C-CELL TUMORS

Liraglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors at clinically relevant exposures in both genders of rats and mice. It is unknown whether Saxenda® causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as the human relevance of 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® 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®

Contraindications

Saxenda® is contraindicated in:

• Patients with a personal or family history of MTC or MEN 2

• Patients with a prior serious hypersensitivity reaction to liraglutide or to any of the product components

• Pregnancy

Warnings and Precautions

• 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 noted on physical examination or neck imaging should also be further evaluated

• Acute Pancreatitis: Acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, has been observed in patients treated with liraglutide 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

• Acute Gallbladder Disease: Substantial or rapid weight loss can increase the risk of cholelithiasis; however, the incidence of acute gallbladder disease was greater in patients treated with Saxenda® than with placebo even after accounting for the degree of weight loss. If cholelithiasis is suspected, gallbladder studies and appropriate clinical follow-up are indicated

Not

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 ability to lose weight and keep it off.2

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

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

People living with obesity want you to ask them about their weight-loss attempts.

Tell them how adding Saxenda® can help them lose weight and keep it off.

bA 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

cMajor Adverse Cardiovascular Event (MACE) defined as: cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke. Results from a randomized 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, 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 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. 96.8% of the patients completed the trial.1

Important Safety Information (cont’d)

• Risk of Hypoglycemia with Concomitant Use of Anti-Diabetic Therapy: When Saxenda® is used with an insulin secretagogue (eg, a sulfonylurea) serious hypoglycemia can occur. Consider lowering the dose of the insulin secretagogue to reduce the risk of hypoglycemia. Monitor blood glucose parameters prior to starting Saxenda® and during treatment and adjust anti-diabetic drugs as needed

• 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 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

• Renal Impairment: Acute renal failure and worsening of chronic renal failure, which may sometimes require hemodialysis, have been reported, usually in 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 hypersensitivity reaction occurs, patients should stop taking Saxenda® and promptly seek medical advice

• 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 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. Avoid Saxenda® in patients with a history of suicidal attempts or active suicidal ideation

Adverse Events

• The most common adverse reactions, reported in ≥5% are: nausea, hypoglycemia, diarrhea, constipation, vomiting, headache, decreased appetite, dyspepsia, fatigue, dizziness, abdominal pain, and increased lipase

Drug Interactions

• Saxenda® causes a delay of gastric emptying, and has the potential to impact the absorption of concomitantly administered oral medications. Monitor for potential consequences of delayed absorption of oral medications concomitantly administered with Saxenda®

Use in Specific Populations

• There are no data on the presence of liraglutide in human breast milk; liraglutide was present in the milk of lactating rats

• Saxenda® has not been studied in patients below 18 years of age and is not recommended for use in pediatric patients

• Saxenda® slows gastric emptying. Saxenda® has not been studied in patients with preexisting gastroparesis

Please see Brief Summary of Information about Saxenda® on the following pages.

References

1. Saxenda® [package insert]. Plainsboro, NJ: Novo Nordisk Inc; 2018.

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

Saxenda ® (liraglutide) injection

Rx Only

BRIEF SUMMARY. Please consult package insert for full prescribing information.

WARNING: RISK OF THYROID C-CELL TUMORS: Liraglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors at clinically relevant exposures in both genders of rats and mice. It is unknown whether Saxenda ® causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as the human relevance of liraglutide-induced rodent thyroid C-cell tumors has not been determined [see Warnings and Precautions]. 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 ® and inform them of symptoms of thyroid tumors (e.g., 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 ® [see Contraindications, Warnings and Precautions]

INDICATIONS AND USAGE: Saxenda ® is indicated as an adjunct to a reducedcalorie diet and increased physical activity for chronic weight management in adult patients with an initial body mass index (BMI) of 30 kg/m 2 or greater (obese), or 27 kg/m 2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia).

Limitations of Use: Saxenda ® is not indicated for the treatment of type 2 diabetes mellitus. Saxenda ® and Victoza ® both contain the same active ingredient, liraglutide, and therefore should not be used together. Saxenda ® should not be used in combination with any other GLP-1 receptor agonist. Saxenda ® has not been studied in patients taking insulin. Saxenda ® and insulin should not be used together [see Warnings and Precautions]. The safety and effectiveness of Saxenda ® in combination with other products intended for weight loss, including prescription drugs, over-thecounter drugs, and herbal preparations, have not been established.

CONTRAINDICATIONS: Saxenda ® is contraindicated in: Patients with a personal or family history of medullary thyroid carcinoma (MTC) or patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) [see Warnings and Precautions]; Patients with a prior serious hypersensitivity reaction to liraglutide or to any of the product components [see Warnings and Precautions]; Pregnancy [see Use in Specific Populations].

WARNINGS AND PRECAUTIONS: Risk of Thyroid C-cell Tumors: Liraglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors (adenomas and/or carcinomas) at clinically relevant exposures in both genders of rats and mice. Malignant thyroid C-cell carcinomas were detected in rats and mice. It is unknown whether Saxenda ® will cause thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as the human relevance of liraglutide-induced rodent thyroid C-cell tumors has not been determined. Cases of MTC in patients treated with liraglutide have been reported in the postmarketing period; the data in these reports are insufficient to establish or exclude a causal relationship between MTC and liraglutide use in humans. Saxenda ® is contraindicated in patients with a personal or family history of MTC or in patients with MEN 2. Counsel patients regarding the potential risk for MTC with the use of Saxenda ® and inform them of symptoms of thyroid tumors (e.g., 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 ®. Such monitoring may increase the risk of unnecessary procedures, due to low test specificity for serum calcitonin and a high background incidence of thyroid disease. Significantly elevated serum calcitonin may indicate MTC, and patients with MTC usually have calcitonin values greater than 50 ng/L. If serum calcitonin is measured and found to be elevated, the patient should be further evaluated. Patients with thyroid nodules noted on physical examination or neck imaging should also be further evaluated. Acute Pancreatitis: Based on spontaneous postmarketing reports, acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, has been observed in patients treated with liraglutide. After initiation of Saxenda ®, observe patients carefully for signs and symptoms of pancreatitis (including persistent severe abdominal pain, sometimes radiating to the back and which may or may not be accompanied by vomiting). If pancreatitis is suspected, Saxenda ® should promptly be discontinued and appropriate management should be initiated. If pancreatitis is confirmed, Saxenda ® should not be restarted. In Saxenda ® clinical trials, acute pancreatitis was confirmed by adjudication in 9 (0.3%) of 3291 Saxenda-treated patients and 2 (0.1%) of 1843 placebo-treated patients. In addition, there were 2 cases of acute pancreatitis in Saxenda-treated patients who prematurely withdrew from these clinical trials, occurring 74 and 124 days after the last dose. There were 2 additional cases in Saxenda-treated patients, 1 during an off-treatment follow-up period within 2 weeks of discontinuing Saxenda ®, and 1 that occurred in a patient who completed treatment and was off-treatment for 106 days. Liraglutide has been studied in a limited number of patients with a history of pancreatitis. It is unknown if patients with a history of pancreatitis are at higher risk for development of pancreatitis on Saxenda ® Acute Gallbladder Disease: In Saxenda ® clinical

trials, 2.2% of Saxenda-treated patients reported adverse events of cholelithiasis versus 0.8% of placebo-treated patients. The incidence of cholecystitis was 0.8% in Saxenda-treated patients versus 0.4% in placebo-treated patients. The majority of Saxenda-treated patients with adverse events of cholelithiasis and cholecystitis required cholecystectomy. Substantial or rapid weight loss can increase the risk of cholelithiasis; however, the incidence of acute gallbladder disease was greater in Saxenda-treated patients than in placebo-treated patients even after accounting for the degree of weight loss. If cholelithiasis is suspected, gallbladder studies and appropriate clinical follow-up are indicated. Risk for Hypoglycemia with Concomitant Use of Anti-Diabetic Therapy: The risk for serious hypoglycemia is increased when Saxenda ® is used in combination with insulin secretagogues (for example, sulfonylureas) in patients with type 2 diabetes mellitus. Therefore, patients may require a lower dose of sulfonylurea (or other concomitantly administered insulin secretagogues) in this setting [see Adverse Reactions]. Saxenda ® should not be used in patients taking insulin. Saxenda ® can lower blood glucose. Monitor blood glucose parameters prior to starting Saxenda ® and during Saxenda ® treatment in patients with type 2 diabetes. If needed, adjust co-administered anti-diabetic drugs based on glucose monitoring results and risk of hypoglycemia. Heart Rate Increase: Mean increases in resting heart rate of 2 to 3 beats per minute (bpm) were observed with routine clinical monitoring in Saxenda-treated patients compared to placebo in clinical trials. More patients treated with Saxenda ®, compared with placebo, had changes from baseline at two consecutive visits of more than 10 bpm (34% versus 19%, respectively) and 20 bpm (5% versus 2%, respectively). At least one resting heart rate exceeding 100 bpm was recorded for 6% of Saxenda-treated patients compared with 4% of placebo-treated patients, with this occurring at two consecutive study visits for 0.9% and 0.3%, respectively. Tachycardia was reported as an adverse reaction in 0.6% of Saxenda-treated patients and in 0.1% of placebo-treated patients. In a clinical pharmacology trial that monitored heart rate continuously for 24 hours, Saxenda ® treatment was associated with a heart rate that was 4 to 9 bpm higher than that observed with placebo. Heart rate should be monitored at regular intervals consistent with usual clinical practice. Patients should inform health care providers of palpitations or feelings of a racing heartbeat while at rest during Saxenda ® treatment. For patients who experience a sustained increase in resting heart rate while taking Saxenda ®, Saxenda ® should be discontinued. Renal Impairment: In patients treated with GLP-1 receptor agonists, including Saxenda ®, there have been reports of acute renal failure and worsening of chronic renal failure, sometimes requiring hemodialysis [see Adverse Reactions]. Some of these events were reported in patients without known underlying renal disease. A majority of the reported events occurred in patients who had experienced nausea, vomiting, or diarrhea leading to volume depletion. Some of the reported events occurred in patients receiving one or more medications known to affect renal function or volume status. Altered renal function has been reversed in many of the reported cases with supportive treatment and discontinuation of potentially causative agents, including liraglutide. Use caution when initiating or escalating doses of Saxenda ® in patients with renal impairment [see Use in Specific Populations] Hypersensitivity Reactions: There have been reports of serious hypersensitivity reactions (e.g., anaphylactic reactions and angioedema) in patients treated with liraglutide [see Contraindications and Adverse Reactions]. If a hypersensitivity reaction occurs, the patient should discontinue Saxenda ® and other suspect medications and promptly seek medical advice. Anaphylaxis and angioedema have been reported with other GLP-1 receptor agonists. Use caution in a patient with a history of anaphylaxis or angioedema with another GLP-1 receptor agonist because it is unknown whether such patients will be predisposed to these reactions with Saxenda ® Suicidal Behavior and Ideation: In Saxenda ® clinical trials, 9 (0.3%) of 3384 Saxenda-treated patients and 2 (0.1%) of the 1941 placebo-treated patients reported suicidal ideation; one of these Saxenda-treated patients attempted suicide. Patients treated with Saxenda ® should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Discontinue Saxenda ® in patients who experience suicidal thoughts or behaviors. Avoid Saxenda ® in patients with a history of suicidal attempts or active suicidal ideation.

ADVERSE REACTIONS: The following serious adverse reactions are described below or elsewhere in the prescribing information: Risk of Thyroid C-Cell Tumors [see Warnings and Precautions]; Acute Pancreatitis [see Warnings and Precautions]; Acute Gallbladder Disease [see Warnings and Precautions]; Risk for Hypoglycemia with Concomitant Use of Anti-Diabetic Therapy [see Warnings and Precautions]; Heart Rate Increase [see Warnings and Precautions]; Renal Impairment [see Warnings and Precautions]; Hypersensitivity Reactions [see Warnings and Precautions]; Suicidal Behavior and Ideation [see Warnings and Precautions] Clinical Trials

Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. Saxenda ® was evaluated for safety in 5 double-blind, placebo controlled trials that included 3384 overweight or obese patients treated with Saxenda ® for a treatment period up to 56 weeks (3 trials), 52 weeks (1 trial), and 32 weeks (1 trial). All patients received study drug in addition to diet and exercise counseling. In these trials, patients received Saxenda ® for a mean treatment duration of 46 weeks (median, 56 weeks). Baseline characteristics included a mean age of 47 years, 71% women, 85% white, 39% with hypertension, 15% with type 2 diabetes, 34% with dyslipidemia, 29% with a BMI greater than 40 kg/m 2, and 9% with cardiovascular disease. In one of the 56-week trials, a subset of patients (with abnormal glucose measurements at randomization) were enrolled for a placebo-

controlled 160-week period instead, followed by a 12-week off-treatment follow-up. For those participating in this 160-week period, patients received Saxenda ® for a mean treatment duration of 110 weeks (median, 159 weeks). For all trials, dosing was initiated and increased weekly to reach the 3 mg dose. In clinical trials, 9.8% of patients treated with Saxenda ® and 4.3% of patients treated with placebo prematurely discontinued treatment as a result of adverse reactions. The most common adverse reactions leading to discontinuation were nausea (2.9% versus 0.2% for Saxenda ® and placebo, respectively), vomiting (1.7% versus less than 0.1%), and diarrhea (1.4% versus 0%). Adverse reactions reported in greater than or equal to 2% of Saxenda-treated patients and more frequently than in placebo-treated patients are shown in Table 3.

Table 3. Adverse Reactions Reported in Greater Than or Equal to 2% of Saxenda-treated Patients and More Frequently than with Placebo*

Disorders

1 Documented symptomatic (defined as documented symptoms of hypoglycemia in combination with a plasma glucose less than or equal to 70 mg/dL) in patients with type 2 diabetes (Study 2). See text below for further information regarding hypoglycemia in patients with and without type 2 diabetes. T2DM = type 2 diabetes mellitus

* Adverse reactions for trials with treatment period up to 56 weeks

Hypoglycemia: Saxenda ® can lower blood glucose. In a clinical trial involving patients with type 2 diabetes mellitus and overweight or obesity, severe hypoglycemia (defined as requiring the assistance of another person) occurred in 3 (0.7%) of 422 Saxenda-treated patients and in none of the 212 placebo-treated patients. Each of these 3 Saxenda-treated patients was also taking a sulfonylurea. In the same trial, among patients taking a sulfonylurea, documented symptomatic hypoglycemia (defined as documented symptoms of hypoglycemia in combination with a plasma glucose less than or equal to 70 mg/dL) occurred in 48 (43.6%) of 110 Saxendatreated patients and 15 (27.3%) of 55 placebo-treated patients. The doses of sulfonylureas were reduced by 50% at the beginning of the trial per protocol. The frequency of hypoglycemia may be higher if the dose of sulfonylurea is not reduced. Among patients not taking a sulfonylurea, documented symptomatic hypoglycemia occurred in 49 (15.7%) of 312 Saxenda-treated patients and 12 (7.6%) of 157 placebo-treated patients. In Saxenda ® clinical trials involving patients without type 2 diabetes mellitus, there was no systematic capturing or reporting of hypoglycemia, as patients were not provided with blood glucose meters or hypoglycemia diaries. Spontaneously reported symptomatic episodes of unconfirmed hypoglycemia were reported by 46 (1.6%) of 2962 Saxenda-treated patients and 19 (1.1%) of 1729 placebo-treated patients. Fasting plasma glucose values obtained at routine clinic visits less than or equal to 70 mg/dL, irrespective of hypoglycemic symptoms, were

reported as “hypoglycemia” in 92 (3.1%) Saxenda-treated patients and 13 (0.8%) placebo-treated patients. Gastrointestinal Adverse Reactions: In the clinical trials, approximately 68% of Saxenda-treated patients and 39% of placebo-treated patients reported gastrointestinal disorders; the most frequently reported was nausea (39% and 14% of patients treated with Saxenda ® and placebo, respectively). The percentage of patients reporting nausea declined as treatment continued. Other common adverse reactions that occurred at a higher incidence among Saxendatreated patients included diarrhea, constipation, vomiting, dyspepsia, abdominal pain, dry mouth, gastritis, gastroesophageal reflux disease, flatulence, eructation and abdominal distension. Most episodes of gastrointestinal events were mild or moderate and did not lead to discontinuation of therapy (6.2% with Saxenda® versus 0.8% with placebo discontinued treatment as a result of gastrointestinal adverse reactions). There have been reports of gastrointestinal adverse reactions, such as nausea, vomiting, and diarrhea, associated with volume depletion and renal impairment [see Warnings and Precautions] Asthenia, Fatigue, Malaise, Dysgeusia and Dizziness: Events of asthenia, fatigue, malaise, dysgeusia and dizziness were mainly reported within the first 12 weeks of treatment with Saxenda ® and were often co-reported with gastrointestinal events such as nausea, vomiting, and diarrhea. Immunogenicity: Patients treated with Saxenda ® may develop anti-liraglutide antibodies. Anti-liraglutide antibodies were detected in 42 (2.8%) of 1505 Saxendatreated patients with a post-baseline assessment. Antibodies that had a neutralizing effect on liraglutide in an in vitro assay occurred in 18 (1.2%) of 1505 Saxendatreated patients. Presence of antibodies may be associated with a higher incidence of injection site reactions and reports of low blood glucose. In clinical trials, these events were usually classified as mild and resolved while patients continued on treatment. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, the incidence of antibodies to Saxenda ® cannot be directly compared with the incidence of antibodies of other products. Allergic Reactions: Urticaria was reported in 0.7% of Saxenda-treated patients and 0.5% of placebo-treated patients. Anaphylactic reactions, asthma, bronchial hyperreactivity, bronchospasm, oropharyngeal swelling, facial swelling, angioedema, pharyngeal edema, type IV hypersensitivity reactions have been reported in patients treated with liraglutide in clinical trials. Cases of anaphylactic reactions with additional symptoms such as hypotension, palpitations, dyspnea, and edema have been reported with marketed use of liraglutide. Anaphylactic reactions may potentially be life-threatening. Injection Site Reactions: Injection site reactions were reported in approximately 13.9% of Saxenda-treated patients and 10.5% of placebo-treated patients. The most common reactions, each reported by 1% to 2.5% of Saxenda-treated patients and more commonly than by placebo-treated patients, included erythema, pruritus, and rash at the injection site. 0.6% of Saxenda-treated patients and 0.5% of placebo-treated patients discontinued treatment due to injection site reactions. Breast Cancer: In Saxenda ® clinical trials, breast cancer confirmed by adjudication was reported in 17 (0.7%) of 2379 Saxendatreated women compared with 3 (0.2%) of 1300 placebo-treated women, including invasive cancer (13 Saxenda- and 2 placebo-treated women) and ductal carcinoma in situ (4 Saxenda- and 1 placebo-treated woman). The majority of cancers were estrogen- and progesterone-receptor positive. There were too few cases to determine whether these cases were related to Saxenda ®. In addition, there are insufficient data to determine whether Saxenda ® has an effect on pre-existing breast neoplasia. Papillary Thyroid Cancer: In Saxenda ® clinical trials, papillary thyroid carcinoma confirmed by adjudication was reported in 8 (0.2%) of 3291 Saxenda-treated patients compared with no cases among 1843 placebo-treated patients. Four of these papillary thyroid carcinomas were less than 1 cm in greatest diameter and 4 were diagnosed in surgical pathology specimens after thyroidectomy prompted by findings identified prior to treatment. Colorectal Neoplasms: In Saxenda ® clinical trials, benign colorectal neoplasms (mostly colon adenomas) confirmed by adjudication were reported in 20 (0.6%) of 3291 Saxenda-treated patients compared with 7 (0.4%) of 1843 placebo-treated patients. Six positively adjudicated cases of malignant colorectal neoplasms were reported in 5 Saxenda-treated patients (0.2%, mostly adenocarcinomas) and 1 in a placebo-treated patient (0.1%, neuroendocrine tumor of the rectum). Cardiac Conduction Disorders: In Saxenda ® clinical trials, 11 (0.3%) of 3384 Saxenda-treated patients compared with none of the 1941 placebotreated patients had a cardiac conduction disorder, reported as first degree atrioventricular block, right bundle branch block, or left bundle branch block. Hypotension: Adverse reactions related to hypotension (that is, reports of hypotension, orthostatic hypotension, circulatory collapse, and decreased blood pressure) were reported more frequently with Saxenda ® (1.1%) compared with placebo (0.5%) in Saxenda ® clinical trials. Systolic blood pressure decreases to less than 80 mmHg were observed in 4 (0.1%) Saxenda-treated patients compared with no placebo-treated patients. One of the Saxenda-treated patients had hypotension associated with gastrointestinal adverse reactions and renal failure [see Warnings and Precautions] Laboratory Abnormalities: Liver Enzymes: Increases in alanine aminotransferase (ALT) greater than or equal to 10 times the upper limit of normal were observed in 5 (0.15%) Saxenda-treated patients (two of whom had ALT greater than 20 and 40 times the upper limit of normal) compared with 1 (0.05%) placebotreated patient during the Saxenda ® clinical trials. Because clinical evaluation to exclude alternative causes of ALT and aspartate aminotransferase (AST) increases was not done in most cases, the relationship to Saxenda ® is uncertain. Some

increases in ALT and AST were associated with other confounding factors (such as gallstones). Serum Calcitonin: Calcitonin, a biological marker of MTC, was measured throughout the clinical development program [see Warnings and Precautions]. More patients treated with Saxenda ® in the clinical trials were observed to have high calcitonin values during treatment, compared with placebo. The proportion of patients with calcitonin greater than or equal to 2 times the upper limit of normal at the end of the trial was 1.2% in Saxenda-treated patients and 0.6% in placebo-treated patients. Calcitonin values greater than 20 ng/L at the end of the trial occurred in 0.5% of Saxenda-treated patients and 0.2% of placebo-treated patients; among patients with pre-treatment serum calcitonin less than 20 ng/L, none had calcitonin elevations to greater than 50 ng/L at the end of the trial. Serum Lipase and Amylase: Serum lipase and amylase were routinely measured in the Saxenda ® clinical trials. Among Saxenda-treated patients, 2.1% had a lipase value at anytime during treatment of greater than or equal to 3 times the upper limit of normal compared with 1.0% of placebo-treated patients. 0.1% of Saxenda-treated patients had an amylase value at anytime in the trial of greater than or equal to 3 times the upper limit of normal versus 0.1% of placebo-treated patients. The clinical significance of elevations in lipase or amylase with Saxenda ® is unknown in the absence of other signs and symptoms of pancreatitis [see Warnings and Precautions] Post-Marketing Experience: The following adverse reactions have been reported during post-approval use of liraglutide, the active ingredient of Saxenda ®. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Neoplasms: Medullary thyroid carcinoma [see Warnings and Precautions]; Gastrointestinal Disorders: Acute pancreatitis, hemorrhagic and necrotizing pancreatitis, sometimes resulting in death [see Warnings and Precautions]; Metabolism and Nutrition Disorders: Dehydration resulting from nausea, vomiting and diarrhea [see Adverse Reactions]; Renal and Urinary Disorders: Increased serum creatinine, acute renal failure or worsening of chronic renal failure, sometimes requiring hemodialysis [see Warnings and Precautions]; General Disorders and Administration Site Conditions: Allergic reactions: rash and pruritus [see Adverse Reactions]; Immune System Disorders: Angioedema and anaphylactic reactions [see Warnings and Precautions]; Hepatobiliary Disorders: Elevations of liver enzymes, hyperbilirubinemia, cholestasis and hepatitis [see Adverse Reactions]

DRUG INTERACTIONS: Oral Medications: Saxenda ® causes a delay of gastric emptying, and thereby has the potential to impact the absorption of concomitantly administered oral medications. In clinical pharmacology trials, liraglutide did not affect the absorption of the tested orally administered medications to any clinically relevant degree. Nonetheless, monitor for potential consequences of delayed absorption of oral medications concomitantly administered with Saxenda ®

USE IN SPECIFIC POPULATIONS: Pregnancy: Risk Summary: Saxenda ® is contraindicated during pregnancy because weight loss offers no potential benefit to a pregnant woman and may result in fetal harm [see Clinical Considerations]. There are no available data with liraglutide in pregnant women to inform a drug associated risk for major birth defects and miscarriage. Saxenda ® should not be used during pregnancy. If a patient wishes to become pregnant, or pregnancy occurs, treatment with Saxenda ® should be discontinued. Animal reproduction studies identified increased adverse embryofetal developmental outcomes from exposure during pregnancy. Liraglutide exposure was associated with early embryonic deaths and an imbalance in some fetal abnormalities in pregnant rats administered liraglutide 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 has been shown to cause reduced growth and increased total major abnormalities 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, 0.25 and 1 mg/kg/day liraglutide beginning 2 weeks before mating through gestation day 17 had estimated systemic exposures 0.8-, 3-, and 11-times the exposure in obese humans at the MRHD based on plasma AUC comparison. The number of early embryonic deaths in the 1 mg/kg/day group increased slightly. Fetal abnormalities and variations in kidneys and blood vessels, irregular ossification of the skull, and a more complete state of ossification occurred at all doses. Mottled liver and minimally kinked ribs occurred at the highest dose. The incidence of fetal malformations in 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

humans at the MRHD of 3 mg/day at all doses, based on plasma AUC comparison. Liraglutide decreased fetal weight and dose-dependently increased the incidence of total major fetal abnormalities at all doses. The incidence of malformations exceeded concurrent and historical controls at 0.01 mg/kg/day (kidneys, scapula), greater than or equal to 0.01 mg/kg/day (eyes, forelimb), 0.025 mg/kg/day (brain, tail and sacral vertebrae, major blood vessels and heart, umbilicus), greater than or equal to 0.025 mg/kg/day (sternum) and at 0.05 mg/kg/day (parietal bones, major blood vessels). Irregular ossification and/or skeletal abnormalities occurred in the skull and jaw, vertebrae and ribs, sternum, pelvis, tail, and scapula; and dose-dependent minor skeletal variations were observed. Visceral abnormalities occurred in blood vessels, lung, liver, and esophagus. Bilobed or bifurcated gallbladder was seen in all treatment groups, but not in the control group. In pregnant female rats given subcutaneous doses of 0.1, 0.25 and 1 mg/kg/day liraglutide from gestation day 6 through weaning or termination of nursing on lactation day 24, estimated systemic exposures were 0.8-, 3-, and 11-times exposure in obese humans at the MRHD of 3 mg/day, based on plasma AUC comparison. A slight delay in parturition was observed in the majority of treated rats. Group mean body weight of neonatal rats from liraglutide-treated dams was lower than neonatal rats from control group dams. Bloody scabs and agitated behavior occurred in male rats descended from dams treated with 1 mg/ kg/day liraglutide. Group mean body weight from birth to postpartum day 14 trended lower in F2 generation rats descended from liraglutide-treated rats compared to F 2 generation rats descended from controls, but differences did not reach statistical significance for any group. Lactation: Risk Summary: There are no data on the presence of liraglutide in human milk, the effects on the breastfed infant, or effects on milk production. Liraglutide was present in the milk of lactating rats (see Data ). The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Saxenda ® and any potential adverse effects on the breastfed infant from Saxenda ® or from the underlying maternal condition. Data: In lactating rats, liraglutide was present unchanged in milk at concentrations approximately 50% of maternal plasma concentrations. Pediatric Use: Safety and effectiveness of Saxenda ® have not been established in pediatric patients. Saxenda ® is not recommended for use in pediatric patients. Geriatric Use: In the Saxenda ® clinical trials, 232 (6.9%) of the Saxenda-treated patients were 65 years of age and 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 and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Renal Impairment: There is limited experience with Saxenda ® in patients with mild, moderate, and severe renal impairment, including end-stage renal disease. However, there have been postmarketing reports of acute renal failure and worsening of chronic renal failure with liraglutide, which may sometimes require hemodialysis [see Warnings and Precautions and Adverse Reactions]. Saxenda ® should be used with caution in this patient population. Hepatic Impairment: There is limited experience in patients with mild, moderate, or severe hepatic impairment. Therefore, Saxenda ® should be used with caution in this patient population. Gastroparesis: Saxenda ® slows gastric emptying. Saxenda ® has not been studied in patients with pre-existing gastroparesis.

OVERDOSAGE: Overdoses have been reported in clinical trials and post-marketing use of liraglutide. Effects have included severe nausea and severe vomiting. In the event of overdosage, appropriate supportive treatment should be initiated according to the patient’s clinical signs and symptoms.

More detailed information is available upon request.

Version: 5

Saxenda ® and Victoza ® are registered trademarks of Novo Nordisk A/S. PATENT Information: http://novonordisk-us.com/patients/products/productpatents.html

Manufactured by: Novo Nordisk A/S, DK-2880 Bagsvaerd, Denmark

For information about Saxenda ® contact: Novo Nordisk Inc., 800 Scudders Mill Road, Plainsboro, NJ 08536 1-844-363-4448

© 2014-2018 Novo Nordisk US20SX00007 2/2020

Managing Obesity:

Developing a Successful eight Management Program

A comprehensive weight-management program providing access to varying treatment strategies can improve health outcomes for employees and economic outcomes for employers.

Lindsay C. Speicher, J.D. Project Manager Magellan Method

In the spring 2020 Magellan Rx Report, we discussed gaps in employer weight-management program strategies Here, we will e plore the process of developing and implementing an e ective employer sponsored program.

Identifying Key Decision-Makers

It is crucial to identify eneft design decision ma ers at the outset of program development, since they will have ey insights into aspects of the employer organization s culture and fnancial and logistical considerations that will in uence the o ectives, structure, evolution, and scope of the weight management program. The decision to implement a weight-management program should include input from individuals within multiple areas of the employer organization specifcally those in human resources H and any others who determine eneft design

Some employers have eneft management teams with e pertise in employer sponsored programs and eneft design to research employee eneft options In many other organizations, the employees charged with recommending eneft design have a road range of responsi ilities hen e ploring various eneft programs including weight management initiatives these individuals often reach out to eneft consultants and vendors with wellness program o erings to facilitate their understanding of their options hether they rely on e ternal support or investigate coverage options independently, these employees will ultimately ma e recommendations for eneft coverage, which may include supplemental programs or services such as weight management and other riders enefts offered in addition to basic health insurance coverage, typically at an additional cost) for employees and their dependents.

eight management program developers can ma e insight sharing into program design and implementation gaps more e ective y ma ing it relevant to the decision ma ers organization

MANAGING OBESITY

Organization specifc employee population health information can provide conte t and support informed decision ma ing regarding the clinical and economic value of o ering a comprehensive, proven weight-management program.

r a a o al r re a d e e e

An e ective weight management program will present an intersection of medical enefts, pharmacy enefts, and employer sponsored programs. In order to better understand how this type of program will wor in a specifc employer organization, weight management program developers must conduct research and evaluate the organization s structure he e ploration of the eneft design with regard to weight management programs will require a detailed understanding of the current program, the coordination of the medical eneft and pharmacy eneft, and its corresponding ft within a roader employer sponsored initiative Decision ma ers within the employer organization may have limited e perience with e ective weight management programs and how such an initiative would align with the overall eneft structure, which may in uence how weight management programs are presented, reviewed, and considered. Limited information and time for in uiry, competing fnancial priorities, and still emergent nowledge of weight-management challenges and obesity as a medical condition may lead organizations to choose only asic weight management programs (such as those discussed in part one of this series) that primarily rely on surgical intervention.

An expert panel discussion conducted by Magellan Rx Management in March 2017 and another in 2007 determined that successful wellness programs must be embedded in existing infrastructure, including eneft design 1, 2 According to a 2015 International Foundation of mployee Beneft Plans wor place wellness survey, a out half of employers coordinated wellness incentives and penalties with employer-provided insurance plans, and employers most often tied incentives to eneft design through changes to premiums, copays, coinsurance, deductibles, or contributions to health savings accounts.2 arger scale incentives such as employee enefts can positively impact participation companies that lin wellness and weight-management programs with outcomes-based incentives report a 30% higher participation rate than those that do not.2 Historically, employer-sponsored wellness initiatives were considered a separate entity from employer-provided health plans, including medical and pharmacy enefts, ut it is ecoming more common for employers to combine them. This trend only became more prevalent with the A orda le Care Act, which, along with mandating employer coverage of preventive services, increased the limit on rewards that can e o ered through a group health plan for completing wellness programs.2, 3

Access to weight management services may e challenged y fnancial constraints and competing organizational priorities In the event there is employer interest and commitment to providing access to e ective, multifaceted weight management programs, decision ma ers must ta e signifcant, proactive steps to e plore the nature, scope, and potential strategies for integrating these services into the medical and pharmacy enefts Decision ma ers will wor closely with their health plan to determine criteria, eligibility, and conditions around weight-management coverage. This step will li ely e the most complicated in the process

Strategic planning and implementation are essential to ensuring the program s success Surveying employees regarding their specifc health interests and concerns, comparing plan options with employee needs in mind, and analyzing organizational fnancial capacity are important frst steps 2 Successful implementation will rely heavily on employee education, since without comprehensive nowledge of the enefts availa le to them, employees cannot ta e full advantage of wellness initiatives 2

al e a ed e e e

Value ased eneft design VBBD , a relatively new approach to health insurance, allows for lower copayments and costs for high-value clinical services.1 mployees may eneft from educational e orts, as many large employers are implementing this approach in order to control healthcare spending. As of September , a out a third of large employers o ered fnancial incentives to employees who opted to participate in wellness programs, including obesity-management or weight-loss programs.4

Under VBBD, health plans or employers must develop a enefts pac age that incentivizes mem ers or employees to see providers who have proven success in patient weight control.5 Employers have the a ility to manage employees treatment strategies y reducing copayments on proven e ective therapies and increasing cost on therapies of lower value.6 The most favorable VBBD outcomes occur when both patients and providers are committed to the weight management process and employers e ectively engage with health plans to develop performance-based provider networ s and negotiate performance ased rates 5 In terms of weight management, VBBD s true value is long term, as this eneft structure drives employees toward treatments and therapies that are proven to e e ective and that will produce the long term outcomes employees strive to achieve when participating in a weight-loss program.5 hile VBBD may not e the ideal eneft structure for all employers, it is an innovative solution that may prove enefcial in terms of long term health outcomes as well as decreased spending.

Drug Indication

Phentermine

Orlistat

Lorcaserin

Phentermine topiramate

Naltrexone-bupropion

Liraglutide

Sympathomimetic amine that functions as a centrally acting appetite suppressant through pro opiomelanocortin POMC neuronal activation

Inhibits absorption of dietary fat, both by inactivating lipase enzymes and inhi iting triglyceride hydrolysis in the gut

Serotonin C receptor agonist that acts to suppress appetite via activation of hypothalamic POMC neurons, which play a ey role in appetite regulation and energy expenditure

Phentermine is an appetite suppressant and stimulant topiramate is an anticonvulsant used as an antiepileptic with a weight loss side e ect

Naltrexone is an opioid antagonist; bupropion is an antidepressant of the amino etone class that inhi its neuronal reupta e of dopamine and norepinephrine

G P receptor agonist that acts on the G P receptor in the hypothalamus to reduce hunger and increase satiety

Multifaceted Approach

In order to achieve long-term success, weight-loss programs should ma e various treatments and management strategies such as weight maintenance, behavioral therapy, pharmacotherapy options, physical ftness initiatives, and surgical options availa le when clinically appropriate.7, 8 imiting the availa ility of any proven e ective weight loss strategies would reduce the li elihood of success An OptumHealth survey of 505 public and private employers reported that employees are willing to pay higher premiums for wor place wellness programs, creating potential for employers to o set costs 9 mployers that o er employees ro ust wellness programs often report positive return on investment, re ected in healthier employees, less absenteeism, increased productivity, lower premiums per employee, and decreased overall healthcare costs.9 he ey to an e ective weight management program is to e pand resources and initiatives beyond bariatric surgery and address the varying factors contributing to overweight and obesity. Additionally, programs must encourage employee engagement with ey interventions

Behavioral Health Component

Managing overweight and obesity requires a targeted intervention strategy, often including a psychological component; researchers

Short term ad unct in a weight loss regimen ased on e ercise, ehavioral modifcation, and caloric restriction in the management of exogenous obesity for patients with an initial BMI g m2 or g m2 in the presence of other ris factors

Ad unct to reduced calorie diet in o esity management, including weight loss and weight maintenance in patients with initial BMI g m2 or g m2

Ad unct to reduced calorie diet and increased physical activity for chronic weight management in adults with initial BMI g m2 or g m2 in the presence of at least one weightrelated comorbidity

Ad unct to a reduced calorie diet and increased physical activity for chronic weight management in adults with an initial BMI of g m2 or g m2 in the presence of at least one weight-related comorbidity

Ad unct to a reduced calorie diet and increased physical activity for chronic weight management in adults with an initial BMI of g m2 or g m2 in the presence of at least one weight-related comorbidity

Ad unct to reduced calorie diet and increased physical activity for chronic weight management in adults with an initial BMI of g m2 or g m2 in the presence of at least one weightrelated comorbidity

note that long-term and constant behavioral vigilance will lead to the most successful weight-loss maintenance.10 ithin a successful weight-loss program, behavioral therapy can help participants develop long term s ills, such as healthy eating and physical activity habits, to lose weight and maintain weight loss.11 It can ta e a variety of forms, including in-person counseling, group sessions, or interactive technology-based interventions. Smartphones are a convenient modality for behavioral weight-loss therapy, as they provide access to resources at the users fngertips 11 In a clinical trial of a smartphone technology enhancing self-monitoring and feed ac within a weight loss program, results showed remar a le achieved weight loss and adherence, as well as retention, when compared to behavioral therapy provided in group and individual in-person sessions.5 Smartphone-based behavioral interventions provide a sense of privacy and remove the vulnerability that could prevent many potential candidates from participating in this aspect of a weight-loss program.

Studies show that weight-loss programs with a focus on behavioral health can provide signifcant outcomes and potential cost savings with reasonable implementation costs.12 Additionally, some evidence suggests that the cost e ectiveness of ehavioral weight loss therapy increases over the long term, over a period of 10 years.13

Pharmacotherapy Component

The U.S. Food and Drug Administration (FDA) has approved several weight-loss drugs as part of a comprehensive program targeting obesity that includes diet and exercise (see Table 1). Antiobesity medications may be an appropriate solution for obesity management, especially for patients with obesity-related complications such as cardiovascular disease and diabetes; in these cases, pairing behavioral health therapy with a targeted weight-loss drug could e e ective 5 Studies show that when combined with lifestyle intervention, FDA-approved medications for long-term obesity treatment can lead to greater weight loss than lifestyle intervention alone.14 Given the proven e ectiveness of pharmacotherapies in a comprehensive treatment strategy, an e ective weight management program would li ely include access for qualifying patients to appropriate weight-loss drugs.

Moving Forward

A comprehensive weight-management program providing access to varying treatment strategies can improve health outcomes for employees and economic outcomes for employers. A thoughtful approach requires employers to apply learnings regarding advances in o esity management, wor within their organization, and partner with medical eneft insurers hrough these collective e orts, employers will e e uipped to structure an appropriate eneft design with their health plan coordinating medical enefts, pharmacy enefts, and employer sponsored initiatives and ensure that employees are a le to utilize e ective therapies that will help them achieve weight-loss goals and maintain long-term success.

References

1. From vidence to Practice or place ellness that or s Institute for Health and Productivity Studies, Johns Hop ins Bloom erg School of Pu lic Health ransamerica Center for Health Studies, Septem er , https www transamericacenterforhealthstudies org docs default source wellness page from evidence to practice wor place wellness that wor s pdf sfvrsn

2. Pic ering, aurel et al eight Control and the or place mployers and Health Plans plore heir oughest Health Improvement Challenge Northeast Business Group on Health Oct , , http ne gh org wp content uploads N BGH SC eightControlFINA pdf

3. Pollitz, aren and Matthew ae or place ellness Programs Characteristics and e uirements aiser Family Foundation, May , , http www org private insurance issue rief wor place wellness programs characteristics and re uirements

4. Value Based Insurance Design National Conference of State egislatures, Dec , , http www ncsl org research health value-based-insurance-design.aspx.

5. No el, Jeremy et al eight Control and mployees One Size Doesn t Fit All Practical Guidance for Implementing eight Control Programs in the or place Solutions Center Northeast Business Group on Health, Octo er , http ne gh org wp content uploads eight Control FINA pdf

6. Miller, Stephen Value Based Insurance Design Spar s Increased Interest.” Society for Human Resource Management, Feb. 11, 2009, https www shrm org resourcesandtools hr topics enefts pages value asedinsurancedesignspar sincreasedinterest asp

7. Acharya, Sushama D. et al. “Adherence to a behavioral weight loss treatment program enhances weight loss and improvements in iomar ers Patient Preference and Adherence, June , , https doi org ppa s

8. arasu, Sylvia Psychotherapy ite O esity and the ole of the Mental Health Practitioner he American Journal of Psychotherapy, April , , https doi org appi psychotherapy.2013.67.1.3.

9. rogdon, J G et al Indirect costs of o esity A review of the current literature O esity eviews, Aug , , https doi org

10. Odom, Jac ueline et al Behavioral Predictors of eight egain after Bariatric Surgery O esity Surgery, June , , https doi org s

11. homas, J Graham and ena ing Health Call, a Smartphone Assisted Behavioral O esity reatment Pilot Study JMI mHealth and uHealth, April , , https doi org mhealth

12. Stum o, Scott P et al Costs of implementing a ehavioral weight loss and lifestyle-change program for individuals with serious mental illnesses in community settings.” Translational Behavioral Medicine, May , , https doi org s 0322-3.

13. sai, A G et al Cost e ectiveness of a primary care intervention to treat o esity International Journal of O esity, Aug , , https doi org i o

14. anovs i, Susan and Jac A ong term Drug reatment for O esity A Systematic and Clinical eview he American Journal of Medicine, Jan , , https doi org ama

15. Daneschvar, H.L. et al. “FDA-Approved Anti-Obesity Drugs in the United States he American Journal of Medicine, March , , https doi org am med

(SPRAVATO™) Janssen

Viaskin™ Peanut DBV Technologies

ipilimumab (Yervoy®) Bristol-Myers Squibb

nivolumab (Opdivo®) Bristol-Myers Squibb

(with suicidal ideation with intent)

allergy (in ages 4 to 11 years)

C frst line, metastatic or recurrent, GF and A negative, in combination with nivolumab)

C frst line, metastatic or recurrent, GF and A negative, in combination with ipilimumab and chemotherapy)

(Stelara®) Janssen

(QINLOCK™) Deciphera Pharmaceuticals

(in ages 6 to 11 years)

(prior treatment with imatini , sunitini , and regorafenib)

(Devic’s

reviations

lymphoma DMD = Duchenne muscular dystrophy; GIST = gastrointestinal stromal tumor; GvHD = graft-versus-host-disease; HRS = hepatorenal syndrome; IBS = irritable bowel syndrome; IM = intramuscular; IN = intranasal; IV = intravenous; MDD = major depressive disorder; NDA = new drug application; NMO = neuromyelitis optica; NSCLC = non-small cell lung cancer; OTDD = oral transmucosal drug delivery; PO = oral; PSO = psoriasis; RA = rheumatoid arthritis; RTOR = real-time oncology review; sBLA = supplemental biologics license application; SC = subcutaneous; SCLC = small cell lung cancer; SLL = small lymphocytic lymphoma; SMA = spinal muscular atrophy; sNDA = supplemental new drug application; TD = transdermal

Infacort®)