Expect Rare Disease, Cancer, Immunology Drugs to Have Big Impact

· 10 min read

While the launches of biosimilars of AbbVie Inc.’s best-selling drug Humira (adalimumab) are arguably the top entrants expected on the U.S. marketplace in 2023, numerous other specialty agents are expected to join them. AIS Health, a division of MMIT, spoke with multiple industry experts on what they’re keeping an eye on in the late-stage pipeline.

AIS Health: Are there any big specialty drugs expected to see patent expiration — and potentially generic or biosimilar competition — in 2023?

Nicole Kjesbo, Pharm.D., director of clinical program development for Prime Therapeutics LLC: Generics are expected to launch in 2023 for [AstraZeneca’s] Iressa (gefitinib), [Jazz Pharmaceuticals plc’s] Xyrem (sodium oxybate), [Novartis Pharmaceuticals Corp.’s] Sandostatin LAR (octreotide acetate) and Thalomid (thalidomide) [from Bristol Myers Squibb unit Celgene Corp.]. Stelara [(ustekinumab) from Johnson & Johnson unit Janssen Biotech, Inc.] (IV/SC) and IV Actemra [(tocilizumab) from Genentech USA, Inc., a member of the Roche Group] lose their exclusivity in 2023.

Andy Szczotka, Pharm.D., chief pharmacy officer at AscellaHealth: In addition to the introduction of Humira biosimilars, the most significant specialty drugs with expected patent loss in 2023 allowing for a first-time marketplace launch include Stelara and Actemra. While these products are part of the same autoimmune therapeutic class as Humira and the upcoming biosimilar launches, each product currently holds market share in their respective therapeutic areas.

Actemra is used to treat rheumatoid arthritis, polyarticular juvenile idiopathic arthritis (PJIA), active systemic juvenile idiopathic arthritis (SJIA) and hospitalized patients with COVID-19 and has two biosimilars awaiting FDA approval. Actemra had reported sales of more than $3 billion in 2021. Stelara, which is used to treat plaque psoriasis, psoriatic arthritis, Crohn’s disease and ulcerative colitis, also has two biosimilars awaiting FDA approval in 2023. Stelara had more than $9 billion in sales last year. It is anticipated that both products will have biosimilar competition in late 2023.

Mesfin Tegenu, CEO and chairman of RxParadigm, Inc.: Stelara is set to lose exclusivity in September 2023. Currently there is no FDA-approved biosimilar to Stelara but there are several biosimilars in the pipeline including two biosimilars pending FDA approval for the second half of 2023.

AIS Health: In terms of the specialty drug pipeline, are there particular drugs and/or therapeutic categories that should be on payers’ radar, and why?

Kjesbo: Gene therapy, both [BioMarin’s] Roctavian (valoctocogene roxaparvovec) for hemophilia A and delandistrogene moxeparvovec [from Sarepta Therapeutics, Inc.] for Duchenne muscular dystrophy (DMD) are currently being reviewed for approval by the FDA. Intercept Pharmaceuticals, Inc. has resubmitted their application for obeticholic acid for nonalcoholic steatohepatitis (NASH) to the FDA, with an anticipated decision anticipated in second-quarter 2023.

Szczotka: Three gene therapy products in the pipeline will be key to watch in 2023. While approved in November 2022, the initial product that should be on the payers’ radar is Hemgenix [(etranacogene dezaparvovec-drlb) from uniQure N.V.], currently the most expensive drug therapy available ($3.5 million). Hemgenix is a single dose adeno-associated virus vector-based gene therapy for the treatment of adults with hemophilia B who currently use FIX (factor IX) prophylaxis therapy or have current or historical life-threatening hemorrhage or have repeated, serious spontaneous bleeding episodes. The HOPE-B trial, which was a Phase III, open-label, single-arm study that included 54 male participants with severe or moderately severe hemophilia B showed that during months 7-18 post-infusion, the annualized bleeding rate was 1.9 bleeds/year compared with 4.1 bleeds/year during the lead-in period in which patients were receiving standard of care. Additionally, 94% of participants treated with Hemgenix discontinued the use of prophylactic therapy and remained free of previous continuous routine prophylaxis therapy. While the upfront cost is significant, Hemgenix potentially provides future cost savings since it may eliminate the need for prophylactic injections of FIX (approximately $700,000 to $800,000 annually).

Potential future products include Roctavian, which is another gene therapy for hemophilia that is pending approval from the FDA in early 2023. Roctavian differs from Hemgenix in that it is indicated for the one-time treatment of hemophilia A, which is the most common form of hemophilia. Results from the Phase III trial met all primary and secondary efficacy endpoints at year three. According to the three-year study results, the mean annualized bleed rate was reduced by 80% from baseline and factor VIII usage reduced by 94% compared to baseline. Approximately 92% of patients were off prophylactic therapy by the end of the three-year study. It is anticipated that if approved, pricing will be similar to Hemgenix.

Another potential key gene therapy product pending FDA approval in May 2023 is delandistrogene moxeparvovec (SRP-9001), used in the treatment of DMD. SRP-9001 would be the first gene therapy approved for the treatment of DMD,…a rare genetic disorder characterized by progressive muscle deterioration and weakness. It is the most common type of muscular dystrophy. SRP-9001 is designed to treat the proximate cause of DMD by delivering to muscle a gene that codes for a shortened, functional form of dystrophin. Combined evidence from three pooled clinical studies and an integrated analysis compared the functional results to a propensity-score-weighted external control. SRP-9001 demonstrated positive results at multiple time points, including one, two and up to four years after treatment, and has multiyear improvements on timed motor abilities assessments. The one-time treatment is anticipated to cost $2 to $3 million dollars.

On Jan. 6, 2023, the FDA approved under the accelerated approval pathway [Eisai Co., Ltd. and Biogen Inc.’s] Leqembi (lecanemab-irmb) for the treatment of Alzheimer’s disease (AD). It is administered every other week via IV infusion. Leqembi is the second anti-amyloid monoclonal antibody to be approved by the FDA for the treatment of AD, after Biogen’s Aduhelm (aducanumab) in 2021. The medication works by selectively binding to neutralize and eliminate soluble amyloid-beta plaques that are thought to contribute to the progression of AD. Leqembi’s approval was based on efficacy data from a Phase II trial (Study 201), which was an 18-month, double-blind, placebo-controlled, dose-finding study of 856 patients with AD. Treatment was initiated in patients with mild cognitive impairment or mild dementia and confirmed presence of amyloid-beta pathology. The primary endpoint — to determine the most effective dose that had 80% probability of at least 25% reduction in clinical decline compared to placebo at 12 months — was not met.

Ultimately, the most effective dose was determined to be 10mg/kg biweekly based on the Alzheimer’s Disease Composite Score (ADCOMS), which measures outcomes among patients with mild cognitive impairment and mild dementia due to AD. Results from prespecified key secondary endpoint analyses demonstrated that lecanemab reduced brain amyloid and showed early and sustained activity for the 10 mg/kg biweekly lecanemab dose across the 18-month treatment period for several clinical measures of AD. For example, patients receiving the treatment demonstrated a reduction of amyloid-beta plaque from baseline to week 79 as compared to the placebo arm, which had no reduction of amyloid-beta plaque.

In addition, lecanemab reduced clinical decline on the Alzheimer’s Disease cognitive subscale (ADAS-Cog14) over 18 months, with 47% (P=0.017) less decline compared to placebo. The amyloid hypothesis suggests that amyloid plaques, the hallmark of AD, are a primary cause of the loss of brain cells that leads to declines in memory and thinking. However, thus far, there is no direct correlation with AD progression and amyloid beta plaques. In addition, in the clinical trials that have been conducted to support Aduhelm’s and Leqembi’s approvals, success was measured not by cognitive improvement but by slowing in the rate of cognitive and functional decline. Brain impairment still occurred despite the modest decrease in amyloid-beta plaque.

Leqembi is not indicated for all types of AD. The approved labeling states that treatment with Leqembi should be initiated in patients with mild cognitive impairment or mild dementia stage of disease and patients should also have confirmed presence of amyloid-beta pathology prior to starting treatment. The labeling does state that there is no safety or effectiveness data on initiating treatment at earlier or later stages of the disease than were studied. The prescribing information for Leqembi includes a warning for amyloid-related imaging abnormalities (ARIA), which are known to occur with antibodies of this class. ARIA most commonly presents as temporary swelling in areas of the brain and usually resolves over time. It may be accompanied by small spots of bleeding in or on the surface of the brain, though some people may have symptoms such as headache, confusion, dizziness, vision changes, nausea and seizure.

Leqembi entered the U.S. market on Jan. 17, and Eisai has stated that it will be priced at $26,500 per year, based on an average patient weight. This price is just under Aduhelm’s current price of $28,200 per year and above the Institute for Clinical and Economic Review’s (ICER’s) suggested cost-effective annual list price of $8,500 to $20,600. Utilization of Leqembi is expected to be low until CMS modifies the National Coverage Determination (NCD) that was outlined in April 2022.

Unconvinced by the evidence of Aduhelm and due to its accelerated approval, CMS restricted coverage of Aduhelm and other AD medications like it to patients currently participating in a clinical trial. Because lecanemab was granted accelerated approval, it falls under CMS’s existing NCD. If lecanemab subsequently receives a traditional FDA approval, CMS would likely provide broader coverage in a variety of treatment settings. According to CMS, an FDA traditional approval indicates the drug has demonstrated evidence of efficacy from a direct measure of clinical benefit. On the same day that Leqembi received accelerated approval, the manufacturer announced that it submitted the supplemental Biologics License Application (sBLA) to the FDA to convert Leqembi to a traditional approval based on data from the confirmatory Phase III CLARITY AD clinical trial. A decision on Leqembi’s traditional approval is expected in late 2023.

On Jan. 19, 2023, the FDA declined to grant accelerated approval to a third potential antibody for AD, donanemab, and requested additional data from Eli Lilly and Co. The company plans to file Phase III clinical trial data later this year for a traditional FDA approval. Donanemab is administered once monthly via IV infusion and works by targeting a modified form of deposited beta amyloid called N3pG. In November 2022, Lilly announced that donanemab met all primary and secondary endpoints for the six-month primary outcome analysis in the Phase III TRAILBLAZER-ALZ 4 study. The main purpose of the study was to compare donanemab to Aduhelm on amyloid plaque clearance in participants with early AD.

Brain amyloid plaque clearance was achieved in 37.9% of donanemab-treated participants (25 of 66) compared with 1.6% of Aduhelm-treated patients (1 of 64) at six months. In a key secondary outcome, donanemab reduced brain amyloid levels versus baseline by 65.2% compared with 17.0% for Aduhelm at six months. ARIA was the most common adverse event in both groups, occurring in approximately one-quarter of patients with symptoms appearing in 2% to 4%. Treatment with donanemab led to greater amyloid clearance than Aduhelm; however, it was not associated with a higher rate of ARIA. The TRAILBLAZER-ALZ 4 trial will continue with 12- and 18-month secondary analysis. If approved later in 2023, the pricing for donanemab is anticipated to be comparable to the prior AD agents, Aduhelm and Leqembi.

Omaveloxolone [from Reata Pharmaceuticals, Inc.] is pending approval for Friedreich’s ataxia (FA). It is an activator of Nrf2, a transcription factor that induces molecular pathways that decrease inflammation via restoring mitochondrial function, reducing oxidative stress and inhibiting pro-inflammatory signaling. This would be the first FDA-approved treatment for FA, and current treatment entails symptomatic and supportive care. FA is the most common hereditary ataxia in the U.S. The cost is anticipated to be between $300,000 and $500,000 per year.

Zilucoplan [from UCB] is a complement inhibitor pending FDA approval for the treatment of generalized myasthenia gravis and could be available by the end of 2023. Myasthenia gravis is an autoimmune disorder characterized by muscle weakness and fatigue. This treatment is a self-administered, once-daily subcutaneous injection which would be at-home treatment option for patients. The two other competitors include Ultomiris [(ravulizumab-cwvz) from AstraZeneca unit Alexion Pharmaceuticals, Inc.] (a complement inhibitor) and Vyvgart [(efgartigimod alfa-fcab) from argenx] (a neonatal Fc receptor antagonist), both of which need to be administered by a physician. The cost is estimated to be approximately $300,000 to $500,000 per year.

Vyjuvek [(beremagene geperpavec) from Krystal Biotech, Inc.] is a redosable topical gel gene therapy in development for dystrophic epidermolysis bullosa, a type of epidermolysis bullosa (EB), in patients 6 months of age and older. EB is a rare, inherited skin disease with four major types and multiple subtypes that vary in severity. Vyjuvek met the primary endpoint of complete wound healing at week 24 compared with vehicle-treated control wounds in the Phase III GEM-3 trial. Currently, there are no FDA-approved treatment for EB. Management is currently supportive and is centered around wound care and prevention of new wounds and complications. The cost is estimated to be around $100,000 to $300,000, with cost being a bit higher in the first year while wounds heal and until application reaches a maintenance phase.

Tegenu: Immunology, oncology and diabetes are therapeutic categories that should be on payers’ radars because these will see the most impact on cost as a result of biosimilar competition.

AIS Health: What therapeutic classes are likely to see new therapies?

Kjesbo: If approved, obeticholic acid will be the first medication approved for NASH. Vyjuvek (beremagene geperpavec) would be the first for dystrophic epidermolysis bullosa, with more to follow. Nirsevimab [from AstraZeneca and Sanofi] would provide a prevention option for RSV [i.e., respiratory syncytial virus] for a broader population than Synagis [(palivizumab) from Swedish Orphan Biovitrum (Sobi) covers now. There are currently three subcutaneous medications looking for an indication in generalized myasthenia gravis.

Szczotka: Numerous new specialty medication therapies are likely to receive FDA approval in 2023. The oncology and autoimmune therapeutic areas are expected to see the greatest impact with numerous key products expected to be FDA approved.

  • Oncology: There are five IV administered oncology medications and three oral oncology medications awaiting FDA approval in 2023 that will potentially treat numerous cancers including breast cancer, multiple myeloma, lymphoma, bladder cancer and leukemia. One notable investigational oncology medication is elacestrant for the treatment of advanced or metastatic estrogen receptor-positive, HER2-negative breast cancer. [Editor’s note: The FDA approved the agent, known as Orserdu, from Stemline Therapeutics, Inc., a Menarini Group Company, on Jan. 27, after AIS Health’s deadline.] It could be the first approved agent in a new therapy class called the selective estrogen receptor degraders, with the potential to become the preferred endocrine monotherapy regimen in second-line or later estrogen receptor-positive HER2-negative breast cancer. This would allow patients to avoid chemotherapy until later lines of therapy and potentially provide an alternative treatment option than intramuscular fulvestrant (Faslodex) [from AstraZeneca].
  • Autoimmune: Five autoimmune medications with new or different mechanisms of action are expected to be approved in 2023 including [Lilly’s] mirikizumab (IL-23 inhibitor) and [Pfizer Inc.’s] etrasimod (S1P1 antagonist) for ulcerative colitis, [UCB’s] bimekizumab (IL-17 inhibitor) for plaque psoriasis, [Pfizer’s] ritlecitinib (JAK3/TEC kinase inhibitor) for alopecia areata and [Lilly’s] lebrikizumab (IL-13 inhibitor) for atopic dermatitis. Each product will need to clearly differentiate how their mechanism of action will enhance the safety and/or efficacy as compared to the multitude of agents already available. Most will be entering a crowded therapeutic and disease category where numerous brands and biosimilars are already available with proven outcomes and value propositions.

Additionally, new, novel treatment options are expected in other therapeutic areas to treat migraine and Rett syndrome:

  • Zavegepant [from Biohaven Pharmaceutical Holding Company Ltd.] is the first intranasal CGRP inhibitor for treating migraines and is expecting FDA approval in 2023. Some migraine patients may prefer an intranasal option for headache treatment. It appears to have a faster onset of action compared with other migraine products and is expected to be premium priced as compared to other CGRP inhibitors due to its unique mode of administration.
  • Trofinetide [from Acadia Pharmaceuticals Inc.] could be the first medication approved in the United States to treat Rett Syndrome, a progressive neurological disorder in young girls. In clinical trials, the therapy has demonstrated improvement in behavior and emotional features. The estimated annual price is between $100,000 and $300,000.

Tegenu: Therapeutic classes that are expected to see new drug approvals this year include oncology, hematology, nephrology and orphan drugs for rare central nervous system disorders.

Winston Wong, Pharm.D., president of W-Squared Group: The quick and simple answer to this is that I am sure we will see new entries in all therapeutic areas. Some will have incremental benefit, while others will fulfill a definite need. However, the significance and impact of these new entries will most likely not be significant unless they are within the top therapeutic areas of oncology, immunology, diabetes or rare diseases, at least from a financial standpoint. From an outcomes perspective, advances in rare diseases or rare cancers will most likely have the greatest impact, and it is in these situations where the need will override the finances.

Contact Kjesbo through Jenine Anderson at jenine.anderson@primetherapeutics.com, Szczotka through Caroline Chambers at cchambers@cpronline.com, Tegenu at Mesfin.Tegenu@rxparadigm.com and Wong at w2sqgroup@gmail.com.

By Angela Maas

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