Adalimumab Biosimilars: Launch and Payer Management

Payers should focus on assessing reimbursement agreements to ensure they are best managing this category, ensuring patients have access to appropriate therapies and both patients and payers are benefiting from cost savings.

Adalimumab (HUMIRA®) has been a highly profitable and utilized drug in the U.S. market, generating more than $20.7 billion in sales in 2021 and ranking second on a list of the top-selling drugs of all time in 2018.1 Through 2023 and 2024, an anticipated 14 or more adalimumab biosimilars may launch. At least seven adalimumab biosimilars will likely launch in 2023, which will include both the original formulation (50 mg/mL) and new high-concentration formulation (100 mg/mL) products.1 The U.S. Food & Drug Administration (FDA) has approved seven biosimilars for adalimumab so far, with several more being reviewed and investigated.

Upon launch, the adalimumab biosimilars will impact the treatment landscape across several indications, including rheumatoid arthritis (RA), Crohn’s disease (CD), ulcerative colitis (UC), plaque psoriasis, psoriatic arthritis, and more.

Martin Burruano, R.Ph. Vice President, Pharmacy Services Independent Health

Adalimumab-atto (AMJEVITA™) was the first adalimumab biosimilar to launch in the U.S. on Jan. 31, 2023; it was also the first approved in September 2016.1, 2 In early July 2023, five additional adalimumab biosimilars are set to launch: adalimumab-adbm (Cyltezo®, Boehringer Ingelheim), adalimumab-bwwd (HADLIMA®, Organon), adalimumab-fkjp (Hulio®, Mylan), adalimumab-adaz (HYRIMOZ®, Sandoz), and adalimumab-aqvh (YUSIMRY™, Coherus BioSciences).1, 3

The FDA is currently reviewing biologics license applications (BLAs) for three biosimilars and a highconcentration version of one biosimilar, which has already been approved for low-concentration formulation.

Interchangeability

The FDA designation interchangeable allows biosimilar products to be substituted for the reference product at the pharmacy level, without requiring provider permission.1 The interchangeability designation creates an ease of access to biosimilars, as the burden of pharmacists obtaining approval is removed. Cyltezo® is the only adalimumab biosimilar that is currently deemed interchangeable, although manufacturers are seeking the designation for some others currently approved or under review.1

Notably, the interchangeability designation does not indicate superiority in safety or efficacy for some biosimilars over others, just that studies assessing patients switching between the reference and biosimilar have been conducted and completed.1 While generally interchangeable biosimilars can be dispensed in place of a reference product, some states have made restrictions as providers can request dispensing of the reference drug rather than any biosimilar regardless of interchangeability.4

Different Formulations

Only the reference product and HADLIMA™ currently have highconcentration formulations approved by the FDA. The vast majority of reference adalimumab prescriptions in the U.S. market, more than 80%, are for the high-concentration solution. High-concentration formulations of adalimumab reduce the number of doses required for effective treatment, compared to low-concentration formulations.1

Citrate-free formulations may reduce injection site pain and allow for the use of a smaller needle during treatment administration. Of the biosimilar products approved or under FDA review, all have citratefree options, except for HYRIMOZ and low-concentration HADLIMA™.1

Impact on Treatment & Management Landscape

The launch of adalimumab biosimilars will create a burden and opportunity for all stakeholders. Providers will face the challenge of serving as a liaison between patients and payers, weighing payer preferences and management strategies against the needs and appropriate management of the patient. 1 Rheumatologists or other providers treating patients using adalimumab are likely already familiar with biosimilars, as biosimilars for infliximab and rituximab have been available in the treatment landscape. 5 Providers’ experience and familiarity with biosimilars will undoubtedly impact their comfortability in using biosimilars when starting new patients on adalimumab as well as switching patients from the reference to biosimilars.5 In many cases, when patients respond well to the reference drug, providers may feel more confident switching them to an interchangeable biosimilar. 4

The key to uptake in biosimilar utilization will be stakeholder education, especially for patients. Payers and providers alike can provide educational materials and updates to patients so they are more comfortable and confident in the transition to biosimilar adalimumab, where that decision is deemed appropriate.6

There are studies that show that effective patient education can mitigate the nocebo effect in biosimilar use, where an adverse event occurs that cannot be attributed to the therapy and may be psychosomatic.7 Instances of potential nocebo effects have shown to be less prevalent when patients are confident and informed about the safety and efficacy of biosimilars.7

A 2022 Pharmacy Market Outlook report from Vizient suggests that payers will structure formulary lists using one of three strategies when adalimumab biosimilars enter the U.S. market. 8 The three strategies include: preferring the reference product, preferring at least one biosimilar, or covering the biosimilars and reference product at parity. 8 While arguments have been made for different approaches, the two latter strategies — preferring one biosimilar or covering biosimilars and reference product at parity — would more effectively increase market competition and generate cost savings than preferring the reference product exclusively. A 2020 survey showed that U.S. payers preferred biosimilars on formulary in 14% of coverage decisions, and specifically, 65% and 59% of U.S. payers preferred reference infliximab (REMICADE ®) over biosimilars RENFLEXIS ® and INFLECTRA ®, respectively. 9 This may result in a loss of cost savings, according to a report from the Department of Health & Human Services Office of Inspector General, which suggests that by preferring reference products over biosimilars, Medicare Part D plans missed $84 to $143 million in savings in 2019. 10 This does not account for the potential loss in savings for commercial payers. In 2019, Health New England reported saving $1.7 million by encouraging the use of biosimilar infliximab, which reached 93% utilizing in collaboration with Magellan Rx Management. 11

Payers should evaluate potential strategies to determine which is the most appropriate for their organization, re-examining formulary tiers and savings programs. 12 Notably, some states may work toward legislation to override payer preferences, requiring coverage for biosimilars; state legislators in Minnesota have begun working on such an effort. 12, 13

According to the Magellan Rx Management Medical Pharmacy Trend Report, an increasing number of payers have been adjusting reimbursement strategies to incentivize biosimilar prescriptions, with most payers indicating biosimilar pricing as having the biggest impact on reimbursement decisions.14 The second-biggest influence in the decision process was provider willingness to switch patients from reference products to biosimilars.14 Payers may want to focus on assessing reimbursement agreements to ensure they are best managing this category, ensuring patients have access to appropriate therapies and patients and payers alike are benefiting from cost savings.

References

1. Jeremias, Skylar. “Part 1: Biosimilars to Bring a Bumper Crop of Adalimumab Options.” The American Journal of Managed Care, 6 Sept. 2022, https://www.centerforbiosimilars.com/view/part-1biosimilars-to-bring-a-bumper-crop-of-adalimumab-options.

2. Jeremias, Skylar. “US Welcomes First Adalimumab Biosimilar, Amjevita.” The American Journal of Managed Care, 31 Jan. 2023, https://www.centerforbiosimilars.com/view/us-welcomes-firstadalimumab-biosimilar-amjevita.

3. “Landscape of Adalimumab biosimilars.” AmerisourceBergen, https://www.amerisourcebergen.com/manufacturer-solutions/ biosimilars/biosimilar-landscape-overview.

4. Hagen, Tony. “Humira, the biosimilars are coming, the biosimilars are coming!” Managed Healthcare, 19 May 2022, https://www. managedhealthcareexecutive.com/view/humira-the-biosimilarsare-coming-the-biosimilars-are-coming-.

5. Hagen, Tony. “Humira Biosimilars Are Hitting the Market in 2023. Finally. But Will Prescriptions Follow?” Managed Healthcare, 7 Apr. 2022, https://www.managedhealthcareexecutive.com/view/ humira-biosimilars-are-hitting-the-market-in-2023-finally-but-willprescriptions-follow-.

6. “Part 3: How Adalimumab Biosimilars Will Impact Clinicians.” The American Journal of Managed Care, 20 Sept. 2022, https:// www.centerforbiosimilars.com/view/part-3-how-adalimumabbiosimilars-will-impact-clinicians.

7. Hagen, Tony. “Nurses Can Counter Nocebo Effect in Biosimilar Switching.” The American Journal of Managed Care, 27 Jan. 2021, https://www.centerforbiosimilars.com/view/nurses-can-counternocebo-effect-in-biosimilar-switching.

8. “Pharmacy Market Outlook.” Vizient, 2022, https://campaigns. vizientinc.com/flipbook/202207-PMO/.

9. Hagen, Tony. “Tufts Study: Most Payers Don’t Give Preference to Biosimilars.” The American Journal of Managed Care, 21 May 2020, https://www.centerforbiosimilars.com/view/tufts-study-mostpayers-dont-give-preference-to-biosimilars.

10. Murrin, Suzanne. “Medicare Part D and Beneficiaries Could Realize Significant Spending Reductions with Increased Biosimilar Use.” U.S. Department of Health and Human Services Office of Inspector General, Mar. 2022, https://oig.hhs.gov/oei/reports/OEI-05-2000480.pdf.

11. The Center for Biosimilars Staff. “Nonprofit Payer Says it Saved $1.7 Million Through Use of Infliximab Biosimilars.” The American Journal of Managed Care, 22 Jan. 2020, https://www.centerforbiosimilars. com/view/nonprofit-payer-says-it-saved-17-million-through-useof-infliximab-biosimilars-.

12. Jeremias, Skylar. “Part 4: How Payers Can Prepare for Adalimumab Biosimilars.” The American Journal of Managed Care, 27 Sept. 2022, https://www.centerforbiosimilars.com/view/part-4-how-payers-canprepare-for-adalimumab-biosimilars.

13. “RELEASE: Rep. Schultz, Sen. Nelson introduce bill to expand access to lower-priced alternatives to brand name prescription drugs.” Minnesota House of Representatives, 24 Feb. 2021, https://www. house.leg.state.mn.us/members/Profile/News/15446/31321.

14. Magellan Rx Management Medical Pharmacy Trend Report 2022 Twelfth Edition, https://issuu.com/magellanrx/docs/medical_ pharmacy_trend_report_2022.

Hemophilia A & B: Innovative Therapies and Payer Management

With the recent approval of etranacogene dezaparvovec for hemophilia B and more potential gene therapies in the pipeline for blood disorders, hemophilia will be a high-priority management category for payers.

Hemophilia is a bleeding disorder in which the blood does not clot properly, leading to spontaneous bleeding or bleeding following injuries or surgery.1 It is often inherited and is caused by a mutation or change in one of the genes that provides instructions for creating the clotting factor proteins needed to clot blood.1 Hemophilia is an X-linked recessive disorder, predominantly affects males, and is very rare in females due to the genes being located on the X chromosome. Females are typically asymptomatic carriers of hemophilia. Fewer than 200,000 individuals in the U.S. are living with hemophilia.1

The most common type of hemophilia is hemophilia A, which occurs in one in 5,000 male births and is caused by a lack of or decrease in clotting factor VIII (FVIII).1, 2 Hemophilia B occurs in one in 25,000 male births and is caused by lack of or decrease in clotting factor IX (FIX).1, 2

Gary Tereso, Pharm.D. Director of Pharmacy Health New England

Common symptoms associated with both types of hemophilia include bleeding into the joints or skin, bleeding of the mouth and gums, bleeding after surgery or after receiving shots or injections, bleeding in urine or stool, and frequent, hard-to-stop nosebleeds. Individuals with hemophilia can be at risk for more severe bleeds, like gastrointestinal bleeds or intracranial hemorrhages.

Treatment

Hemophilia A is mainly treated via concentrated FVIII product; the two types of clotting factors are: plasma-derived, made from human plasma, and recombinant, lab-developed via DNA technology.3

Recombinant FVIII products are used about 75% of the time.1,3 For patients with severe hemophilia A, prophylactic FVIII treatment is typically used to prevent bleeds. The patient will receive treatment on a regular schedule, which can vary from every day to twice weekly, depending on the product and how the specific patient responds to treatment.3 The National Hemophilia Foundation’s Medical and Scientific Advisory Council (MASAC) recommends prophylaxis as optimal management for all individuals with severe hemophilia A.3 In February, the FDA approved ALTUVIIIO™ ([antihemophilic factor (recombinant) Fc-VWF-XTEN Fusion Protein-ehtl], Sanofi), a first-in-class FVIII replacement therapy indicated for routine propylaxis and on-demand treatment to control bleeding episodes, as well as perioperative management for adults and children with hemophilia A.4

The main treatment for hemophilia B is FIX replacement therapy, using either recombinant FIX or plasma-derived FIX concentrates.5 Replacement therapy can be used as needed in patients with mild to moderate hemophilia B. However, regular infusions may be used to prevent bleeding in individuals with severe hemophilia B.5 In individuals with severe hemophilia B, prophylactic therapy has been shown to reduce complications associated with recurrent bleeding.5 FIX replacement therapy may be administered at home, which is key for individuals with severe disease as well as mild to moderate, as infusion is most effective at limiting bleeding when administered within an hour of onset.5

Other nonfactor replacement therapies for hemophilia A help prevent bleeding or assist in better clotting using different methods. Emicizumab (HEMLIBRA®) is a FVIII mimetic, which imitates the way FVIII works — bringing together IX and X and allowing the blood to clot.3 Emicizumab was approved by the U.S. Food & Drug Administration (FDA) in 2017 for people with hemophilia A with inhibitors and in 2018 for people with hemophilia A without inhibitors.3 MASAC concluded that individuals with hemophilia A with inhibitors experiencing spontaneous or traumatic bleeding episodes would derive significant benefit from emicizumab prophylaxis; it was given a recommendation for first-line therapy.6 MASAC noted that individuals on prophylactic bypassing agent with few bleeding episodes could consider switching to emicizumab based on cost-effectiveness, reduced administration burden, and superior hemostatic efficacy.6

Desmopressin can be used for joint and muscle bleeds, nose and mouth bleeds, and before and after surgery in patients with mild hemophilia A.3 Aminocaproic acid is used to prevent the breakdown of blood clots, often before dental procedures and to treat nose and mouth bleeds in patients with hemophilia A and B.3 MASAC recommends that a dose of clotting factor should be taken first to form a clot, then aminocaproic acid can be used to preserve the clot and keep it from being broken down prematurely.3

Gene Therapies

Etranacogene dezaparvovec (HEMGENIX®)

In November 2022, the FDA approved etranacogene dezaparvovec (HEMGENIX®, CSL Behring) as the first gene therapy to treat adults with hemophilia B.7 Etranacogene dezaparvovec is an adeno-associated virus vector-based gene therapy for adults with hemophilia B who currently use FIX prophylaxis therapy, or have current or historical life-threatening hemorrhage, or have repeated, serious spontaneous bleeding episodes.7 The treatment is a one-time single-dose gene therapy given by IV infusion. In one study with 54 participants, adult men ages 18 to 75 with severe or moderately severe hemophilia B, the subjects had increases in FIX activity levels, a decreased need for routine FIX replacement prophylaxis, and a 54% reduction in annualized bleeding rate (ABR) compared to baseline.7-9 Adverse reactions associated with etranacogene dezaparvovec included liver enzyme elevations, headache, mild infusion-related reactions, and flu-like symptoms.7, 9 Patients receiving the gene therapy should be monitored for adverse infusion reactions and transaminitis in their blood.7, 9

The Institute for Clinical and Economic Review (ICER) published an evidence report concluding that there is moderate certainty of a small or substantial health benefit with high certainty of at least a small net health benefit (B+) for etranacogene dezaparvovec compared with FIX prophylaxis.10 The ICER health benefit price benchmark (HBPB) for etranacogene dezaparvovec is $2.93 million to $2.96 million.10 ICER noted that the drug will become more cost-effective the more durable it is.10 Etranacogene dezaparvovec will have a list price of $3.5 million.

Valoctocogene roxaparvovec (ROCTAVIAN™)

In October 2022, BioMarin announced that the FDA accepted the Biologic License Application (BLA) resubmission for valoctocogene roxaparvovec gene therapy for adults with severe hemophilia A.11 Valoctocogene roxaparvovec is an adeno-associated virus-based gene therapy vector containing a coagulation FVIII complementary DNA driven by a liver-selective promoter.12 The BLA included data from the GENEr8-1 phase 3 study. Results from the study showed stable and durable bleed control, including a reduction

Abbreviations: in the mean ABR and mean annualized FVIII infusion rate.11 The mean annualized rate of FVIII concentrate use and treated bleeding after four weeks had decreased after infusion by 98.6% and 83.8%, respectively. All participants reported at least one adverse event; the most common adverse events were headache, nausea, and elevations in aspartate aminotransferase levels.11, 12 A decision from the FDA is expected on March 31, 2023.11

ICER noted in a November 2022 evidence report that there is moderate certainty of a comparable, small, or substantial health benefit with high certainty of at least a comparable net health benefit for valoctocogene roxaparvovec compared to FVIII prophylaxis.10 ICER’s HBPB for valoctocogene roxaparvovec ranges from $1.958 million to $1.963 million.10

Payer Impact: Gene Therapy Strategies

With the recent approval of etranacogene dezaparvovec for hemophilia B and more potential gene therapies in the pipeline for blood disorders, hemophilia will be a high-priority management category for payers.13 This new gene therapy has set a new record for the most expensive single-use gene therapy in the U.S. However, current treatment costs, specifically prophylactic treatment costs, are significant; for patients with severe hemophilia B, the cost of regular infusions over a lifetime could cost up to $20 million per patient.13 Thus, despite the high list price of the gene therapy, the cost burden may not be as significant considering the offset cost of the regular prophylactic infusions.13 However, the durability of etranacogene dezaparvovec is not yet known. Payers also must consider the rate at which members switch payers, limiting the long-term cost benefit.

Value-based pricing arrangements, such as milestone-based reimbursement strategies, will likely be implemented, which have been used in the management of other high-cost gene and innovative therapies. These arrangements help mitigate the impact of the high upfront costs per dose.

References

1. “What is Hemophilia?” Centers for Disease Control and Prevention, 1 Aug. 2022, https://www.cdc.gov/ncbddd/hemophilia/facts.html.

2. “Hemophilia A, B, & C: The Three Different Clotting Factor Deficiencies.” Indiana Hemophilia & Thrombosis Center, https:// www.ihtc.org/types-of-hemophilia.

3. “Current Treatments.” National Hemophilia Foundation, https:// www.hemophilia.org/bleeding-disorders-a-z/treatment/currenttreatments.

4. “Press Release: FDA approves once-weekly ALTUVIIIO™, a new class of factor VIII therapy for hemophilia A that offers significant bleed protection.” Sanofi, 23 Feb. 2023, https://www.sanofi.com/en/media-room/press-releas es/2023/2023-02-23-21-00-00-2614759.

5. “Hemophilia B.” National Organization for Rare Disorders, 2018, https://rarediseases.org/rare-diseases/hemophilia-b/.

6. “MASAC Document 268 - Recommendation on the Use and Management of Emicizumab-kxwh (Hemlibra®) for Hemophilia A with and without Inhibitors.” National Hemophilia Foundation, 27 Apr. 2022, https://www.hemophilia.org/healthcare-professionals/ guidelines-on-care/masac-documents/masac-document-268recommendation-on-the-use-and-management-of-emicizumabkxwh-hemlibrar-for-hemophilia-a-with-and-without-inhibitors.

7. “FDA Approves First Gene Therapy to Treat Adults with Hemophilia B.” U.S. Food & Drug Administration, 22 Nov. 2022, https://www.fda. gov/news-events/press-announcements/fda-approves-first-genetherapy-treat-adults-hemophilia-b.

8. Von Drygalski, Annette, et al. “Etranacogene dezaparvovec (AMT061 phase 2b): normal/near normal FIX activity and bleed cessation in hemophilia B.” Blood Advances, 12 Nov. 2019, https://www.ncbi. nlm.nih.gov/pmc/articles/PMC6855101/.

9. “Final Analysis of Pivotal HOPE-B Study Demonstrates Durable and Sustained Therapeutic Effect of Etranacogene Dezaparvovec Gene Therapy in Hemophilia B - Data Presented at EAHAD 2022.” CSL Behring, 4 Feb. 2022, https://newsroom.csl.com/2022-02-04Final-Analysis-of-Pivotal-HOPE-B-Study-Demonstrates-Durableand-Sustained-Therapeutic-Effect-of-Etranacogene-DezaparvovecGene-Therapy-in-Hemophilia-B-Data-Presented-at-EAHAD-2022.

10. “ICER Publishes Evidence Report on Gene Therapies for Hemophilia A and B.” Institute for Clinical and Economic Review, 2 Nov. 2022, https://icer.org/news-insights/press-releases/icer-publishesevidence-report-on-gene-therapies-for-hemophilia-a-and-b/.

11. “FDA Accepts BioMarin’s Biologics License Application (BLA) for Valoctocogene Roxaparvovec AAV Gene Therapy for Adults with Severe Hemophilia A.” BioMarin, 12 Oct. 2022, https://investors. biomarin.com/2022-10-12-FDA-Accepts-BioMarins-BiologicsLicense-Application-BLA-for-Valoctocogene-Roxaparvovec-AAVGene-Therapy-for-Adults-with-Severe-Hemophilia-A.

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

13. Cohen, Joshua. “Despite Eye-Popping $3.5 Million Price Tag For Gene Therapy Hemgenix, Budget Impact For Most Payers Will Be Relatively Small.” Forbes, 2 Dec. 2022, https://www.forbes.com/ sites/joshuacohen/2022/12/02/despite-eye-popping-35-millionprice-tag-for-gene-therapy-hemgenix-budget-impact-for-mostpayers-will-be-relatively-small.