2023 Notable FDA Approvals Include Several Cell and Gene Therapies, First-Time Biosimilars

Reprinted with AIS Health permission from the January 2024 issue of Radar on Specialty Pharmacy

This past year, the FDA continued to rebound from a drop in approvals, marking the highest number in years. The agency's Center for Drug Evaluation and Research (CDER) approved 55 novel drugs last year, and its Center for Biologics Evaluation and Research (CBER) approved 17 agents. That's up from 37 CDER-approved therapies in 2022 and 51 in 2011. In 2022, CBER OK'd 13 agents, up from 10 in 2021. Specialty agents, such as cell and gene therapies, continued to make up a large portion of those new approvals, while the FDA approved several biosimilars, including a handful that were the first versions of their reference drugs. AIS Health, a division of MMIT, spoke with industry experts about what they view as the most notable FDA approvals of 2023.

Haita Makanji, Pharm.D., vice president of clinical strategy and programs supporting the specialty division of Magellan Rx Management: Notable FDA approvals in 2023 must include gene therapies and some highly anticipated biosimilars. Specifically, Roctavian [(valoctocogene roxaparvovec-rvox) from BioMarin Pharmaceuticals Inc.] was the first gene therapy approved for hemophilia A. Most recently, two separate gene therapies were approved in December for sickle cell disease, Casgevy [(exagamglogene autotemcel; exa-cel) from Vertex Pharmaceuticals Inc. and CRISPR Therapeutics] and Lyfgenia [(lovotibeglogene autotemcel; lovo-cel) from bluebird bio, Inc.]. These approvals are important because the products not only present potential curative treatment options for patients but, depending on the durability of each product's effect, could at least present a long-term cost benefit by reducing the need for current standard-of-care treatment options, which are also costly.

The approval of Elevidys [(delandistrogene moxeparvovec-rokl) from Sarepta Therapeutics, Inc.] for a rare condition such as Duchenne muscular dystrophy was controversial due to concerns over its benefits vs. risks and $3.2 million price tag. Elevidys was the first gene therapy approved based on a surrogate biomarker, dystrophin protein, which was believed to predict likelihood of clinical benefit.

Leqembi [(lecanemab-irmb) from Eisai Co., Ltd. and Biogen Inc.] for Alzheimer's disease created controversy due to its modest slowing of the progression of cognitive and functional decline in people with Alzheimer's disease and amyloid-related imaging abnormalities (ARIA), such as brain swelling and/or bleeding. There are about 6.7 million Americans diagnosed with Alzheimer's, and this approval had the potential to reach a significant amount of people.

In terms of biosimilars, most of the interest was in biosimilars for Humira [(adalimumab) from AbbVie Inc.]. There have been multiple approvals [and launches] for Humira biosimilars in 2023. In addition, there were biosimilars for other biologics approved, including [Bio-Thera and Biogen's] Tofidence (tocilizumab-bavi), a biosimilar to Actemra [(tocilizumab) from Genentech USA, Inc., a member of the Roche Group]; [Celltrion USA's] Zymfentra (infliximab-dyyb) a subcutaneous version of Inflectra, which is a biosimilar to [the Janssen Pharmaceutical Companies of Johnson & Johnson's] Remicade (infliximab), and has the potential to shift patients from long infusions to self-administered subcutaneous injections; [Polypharma Biologics and Sandoz Inc.'s] Tyruko (natalizumab-sztn), a biosimilar to [Biogen's] Tysabri (natalizumab); and [Amgen Inc.'s] Wezlana ((ustekinumab-auub), an interchangeable biosimilar to [the Janssen Pharmaceutical Companies of Johnson & Johnson's] Stelara (ustekinumab). Biologics that treat autoimmune inflammatory conditions are among the most frequently prescribed specialty drugs, so the presence of biosimilars in the market brings the potential for improved affordability and accessibility to critical treatments.

In addition, on Dec. 22, 2023, the FDA approved [Coherus BioSciences, Inc.'s] Udenyca Onbody (pegfilgrastim-cbqv), which is the first biosimilar of the Neulasta Onpro (pegfilgrastim) on-body injector [from Amgen]. Approval may increase the slow biosimilar utilization and adoption seen with long-acting colony stimulating factors.

In April, the FDA approved [Astellas Pharma Inc. and Seagen Inc.'s] Padcev (enfortumab vedotin-ejfv) in combination with [Merck & Co., Inc.'s] Keytruda (pembrolizumab) as first line for the treatment of patients with locally advanced or metastatic bladder cancer not eligible for cisplatin-containing chemotherapy. Almost 50% of patients with metastatic bladder cancer are cisplatin-ineligible. Then in December, the FDA approved the same combination as first line for patients with locally advanced or metastatic urothelial cancer. For the first time, a nonplatinum-based combination therapy received approval as a first-line therapy. Due to the high price of these two agents, the cost of therapy increases significantly, as does the projected budget impact.

The FDA approved three new combination therapies for metastatic castration-resistant prostate cancer.

Six new FDA indication expansions for Keytruda and use earlier in lines of therapy grow pembrolizumab's market share as one of the most highly utilized drugs in cancer therapy.

Andy Szczotka, Pharm.D, chief pharmacy officer at AscellaHealth: [Last year's] approvals across the various drug classes represent new therapeutic options for clinicians to use in treatment of the related medical conditions.

Some notable approvals include Leqembi, which is the first of a new class of medications to be converted from an accelerated FDA approval to a traditional approval for the treatment of early-stage Alzheimer's disease. AD causes cognitive, functional and behavioral impairments and accounts for 60%-80% of all dementia cases. The disease is thought to be caused by the accumulation of amyloid beta plaques in the brain. Leqembi works by removing these plaques. It has been shown to modestly slow the progression of the disease but has not been definitively shown to demonstrate a clinical benefit. Leqembi comes with a warning of the potential for small amounts of bleeding in the brain. The condition is usually asymptomatic, but serious brain hemorrhaging has occurred in patients treated with this class of medications. While Leqembi is not a cure for AD, it does provide hope for patients and their caregivers. The knowledge gained from real-world experience with Leqembi should contribute to the success of future medications that could prevent or reverse the memory problems and dementia associated with the disease.

Roctavian is the first approved single-dose gene therapy for the treatment of severe hemophilia A, a lifelong bleeding disorder. The disease is caused by a single genetic defect that reduces the production of a protein called clotting factor VIII. Patients living with hemophilia A typically require regular prophylactic treatment with clotting factor treatment to prevent bleeding episodes. Prophylactic intravenous infusions can cost over $500,000 annually. Roctavian uses a nonharmful virus to deliver a functional gene to liver cells that will enable the body to produce factor VIII on its own. As a result, patients treated with Roctavian need very little, if any, prophylactic therapy. In fact, in the most recent study at the end of year three, 92% of patients remained off prophylactic therapy. To date, a single dose of Roctavian has been well tolerated with no delayed-onset treatment-related adverse events. Roctavian has the potential to dramatically change the way severe hemophilia A patients are treated and improve their quality of life.

Altuviiio [(antihemophilic factor [recombinant], Fc-VWF-XTEN fusion protein-ehtl) from Sanofi and Sobi] is a new class of factor VIII therapy for hemophilia A. It is the first treatment that delivers near-normal factor activity levels for most of the week, allowing for once-weekly dosing. It also significantly reduces bleeds compared to prior factor VIII prophylaxis. [Its weekly infusions] significantly improve the quality of life for many individuals and their families whose schedules currently revolve around multiple necessary prophylactic infusions each week.

Casgevy and Lyfgenia are the first cell-based gene therapies for the treatment of sickle-cell disease (SCD) in patients 12 years and older. Casgevy also becomes the first FDA-approved therapy that uses CRISPR gene-editing technology. SCD is an inherited blood disorder caused by a defective gene that affects hemoglobin, the protein that helps red blood cells transport oxygen throughout the body. The faulty gene causes some red blood cells to be rigid, sticky and shaped like sickles or crescent moons. This results in restricted blood flow, and the lack of oxygen causes significant acute pain. Current treatments aim to manage symptoms, lower the frequency of acute pain and reduce the risk of complications.

Both treatments are administered as one-time infusions and are made from a patient's own blood stem cells, which are modified and returned to the patient. In clinical trials, a single dose with either Casgevy or Lyfgenia enabled patients to make healthy hemoglobin-producing blood cells and prevented acute pain events for more than two years. By reducing or eliminating the debilitating pain often associated with the disease, both Casgevy and Lyfgenia have the potential to significantly improve the quality of life and life expectancy of SCD patients. In addition, Casgevy represents an important medical advance using new gene editing techniques that will likely be applicable for other diseases in the future.

Mesfin Tegenu, CEO and chairman of RxParadigm, Inc.: Notable FDA approvals in 2023 include Tyruko, Tofidence and Wezlana, which are biosimilars of Tysabri, Actemra and Stelara, respectively. These biosimilars are the first biosimilars to get approved for their respective reference products. Notably, before Wezlana received FDA approval, Stelara was chosen as one of the 10 drugs slated for price negotiations under the Inflation Reduction Act (IRA). According to new guidance from CMS on the IRA's drug price negotiation program, CMS can reevaluate a drug's eligibility for price negotiations if a generic or biosimilar competitor gets approved based on the availability and "bona fide marketing" of the drug. This suggests that Stelara could potentially be excluded from the list of drugs subject to price negotiations. It will be interesting to see what the outcome is; CMS's decision may impact the value of future biosimilars entering the market with high Medicare utilization.

Drew Walk, CEO of Soleo Health: Soleo Health deems the approval of Leqembi in July 2023 as among — if not, the most — important advancement in 2023 due to the role it plays in the ongoing fight against AD. Leqembi marks a major breakthrough in the AD drug class. It holds enormous potential since the addressable market for Leqembi is large, as an estimated 6.7 million Americans aged 65 and older, or about 11% of the population, were living with AD in 2023. The number of those afflicted is growing fast.

Leqembi shows promise as it demonstrates a reduction of amyloid beta plaque, a marker of AD in patients with mild cognitive impairment or mild dementia stage of the disease. This reduction may substantially slow cognitive and functional decline in patients with dementia or mild cognitive impairment due to AD, thereby enhancing quality of life.

In early 2023, Soleo Health was selected by Eisai Inc., a developer of pharmaceuticals including Leqembi, as the sole specialty pharmacy distribution partner of this treatment. To this end, Soleo Health offers Leqembi to patients across multiple sites of care including in their homes, at one of the company's 35+ ambulatory infusion centers or in provider offices.

Winston Wong, Pharm.D., president of W-Squared Group: 2023 will stand as a year of notable FDA approvals representing major advancements in several therapeutic areas, ranging from vaccines to gene therapy. Fifty-five new molecular entities were approved, not including vaccines, allergenic products, blood and blood products, plasma derivatives, and cellular and gene therapy products. On the vaccine front, three vaccines were approved for RSV [respiratory syncytial virus], as well as the full approval for Paxlovid for mild to moderate COVID-19. We also have full approval of the first clinically proven monoclonal antibody to slow the progression of Alzheimer's disease, a step forward from the previously similar medication receiving accelerated approval in 2021, but [it] still fails to show clinical benefit. We finish the 2023 year in review with several gene therapies, used for the treatment of hemophilia A and sickle cell disease. However, as with all technological advances, come the rather expensive costs, and our challenge still remains on how to keep health care affordable.

Contact Makanji via Jenine Anderson at jenine.anderson@primetherapeutics.com, Szczotka via Caroline Chambers at cchambers@cpronline.com, Tegenu at Mesfin.Tegenu@rxparadigm.com, Walk via Susan Turkell at sturkell@pairelations.com and Wong at w2sqgroup@gmail.com.

By Angela Maas