Rare Disease: Update and Gene Therapy Pipeline

As an increasing number of first-in-class medications are approved and become available for rare disease patients, closing the gap in knowledge with all stakeholders will be key to appropriate management and utilization.

Advances in treating rare diseases continue to be a priority for those in the industry. A rare disease is defined as one affecting less than 200,000 people in the U.S. Approximately 30 million people in the U.S. live with rare diseases, with about 7,000 identified rare diseases.1, 2

Lindsay Speicher, JD Project Manager, Specialty Magellan Rx Management

Since the enactment of the Orphan Drug Act of 1983, more than 600 orphan drugs and biological products have been approved in the U.S.3 Exciting progress continues to be made despite challenges in researching and developing treatments for rare diseases. Challenges include the complex biology of many rare diseases, as well as variation or subtypes within a particular rare disease.3 Determining endpoints or outcome measures in trials can be difficult if knowledge of the natural history of the disease is limited.1 Additionally, populating the trials can be difficult, as rare diseases have small patient populations.1 Even in the face of these challenges, promising advancements continue. Some include the first treatments directed at the underlying causes of cystic fibrosis, advances in targeted therapies for blood cancers, and therapies that prevent or slow extremely rare conditions such as pulmonary arterial hypertension, hereditary angioedema, and Gaucher disease.3 Many rare pediatric diseases, such as hypophosphatasia and neuroblastoma, now have available treatments.3

The U.S. Food & Drug Administration (FDA)’s Center for Drug Evaluation and Research (CDER) is focused on facilitating the development of therapies for rare diseases.1 In 2022, more than half of CDER’s novel drug approvals were treatments for rare, or orphan, diseases. See Table 1 for a breakdown of the rare disease drug approvals in 2022.1

Gene therapies represent more innovation, with an expansive pipeline of therapies for the rare disease space. See Table 2 for a breakdown of the rare disease gene therapy pipeline.

Payer Impact and Management

As an increasing number of first-in-class medications are approved and become available for rare disease patients, closing the gap in knowledge with all stakeholders — especially providers — will be key to appropriate management and utilization.2 Additionally, these therapies can be costly, which creates an increasing need for payers to closely manage and strategize in this space.2

Priorities for rare disease management differ depending on the disease; for example, acute and chronic rare diseases will require different management priorities.2 For chronic rare diseases, cost

Table 1. Rare Disease Drug Approvals 20224

management strategies typically focus on policies outside of the benefit, such as stop-loss or reinsurance. Meanwhile, for acute disease treatments, plans may seek ways to mitigate the cost of a one-time claim.2

Ultimately, access to appropriate therapies is crucial for patients with rare diseases. Determining the patients who can most benefit or unresectable melanoma in patients age 12 years or older ganaxolone (ZTALMY®) Marinus Pharmaceuticals oral first therapy for seizures associated with cyclin-dependent kinaselike 5 deficiency disorder in patients age 2 or older vutrisiran (AMVUTTRA™) Alnylam Pharmaceuticals injectable polyneuropathy (damage of multiple nerves throughout the body) in adults with hereditary transthyretin-mediated amyloidosis olipudase alfa-rpcp (XENPOZYME™) Sanofi IV first therapy for Niemann-Pick disease type A, B, A/B spesolimab-sbzo (SPEVIGO®) Boehringer Ingelheim injectable first therapy for flares in patients with generalized pustular psoriasis 9/1/2022 terlipressin (TERLIVAZ®) Mallinckrodt Pharmaceuticals injectable improve kidney function in adults with hepatorenal syndrome 9/14/2022 taurursodiol/sodium phenylbutyrate (RELYVRIO™) Amylyx Pharmaceuticals oral amyotrophic lateral sclerosis teclistamab-cqyv (TECVAYLI™) Janssen Biotech, Inc. injectable relapsed and refractory multiple myeloma in adults who have received at least four prior therapies tremelimumab-actl (IMJUDO®) AstraZeneca injectable unresectable hepatocellular carcinoma, together with IMFINZI® mirvetuximab soravtansinegynx (ELAHERE™) ImmunoGen, Inc. injectable recurrent ovarian cancer, resistant to platinum therapy mosunetuzumab-axgb (Lunsumio™) Roche injectable relapsed or refractory follicular lymphoma in adults

Table 2. Pipeline: Gene Therapies for Rare Diseases

Epidermolysis bullosa

Beremagene geperpavec (Vyjuvek) Krystal Biotech topical epidermolysis bullosa pending debcoemagene autoficel (D-Fi) Castle Creek Biosciences; Paragon Biosciences injectable

EB-101 Abeona Therapeutics other

Hemophilia epidermolysis bullosa phase 3 epidermolysis bullosa phase 3

Valoctocogene roxaparvovec (ROCTAVIAN™) BioMarin IV hemophilia A pending (03/31/2023) giroctocogene fitelparvovec (SB-525) Sangamo Therapeutics/Pfizer IV hemophilia A phase 3 fidanacogene elaparvovec (PF06838435) Spark Therapeutics/Pfizer IV

DMD

Delandistrogene moxeparvovec (SRP-9001) hemophilia B phase 3

Sarepta Therapeutics IV DMD pending (05/29/2023) fordadistrogene movaparvovec (PF-06939926) Pfizer IV DMD phase 3

Other exagamglogene autotemcel (Exa-cel) timrepigene emparvovec (AAV2-REP1) olenasulfigene relduparvovec (LYS-SAF302) lenadogene nolparvovec (GS010) simoladagene autotemcel (OTL-101) onasemnogene abeparvovec (ZOLGENSMA® IT)

CRISPR Therapeutics/Vertex Pharmaceuticals IV beta thalassemia;

SCID phase 3

Novartis Gene Therapies intrathecal SMA phase 3

OTL-103 Orchard Therapeutics; GSK IV WAS phase 3 pariglasgene brecparvovec (DTX401) Ultragenyx IV

UX701 Ultragenyx IV botaretigene sparoparvovec (AAV-RPGR) laruparetigene zosaparvovec (AGTC-501)

MeiraGTx; Janssen Biotech, Inc. other

Applied Genetic Technologies Corporation injectable atidarsagene autotemcel (OTL-200) Orchard Therapeutics; GSK IV von Gierke disease (glycogen storage disease type 1) phase 3

Wilson’s disease phase 3 retinitis pigmentosa phase 3 retinitis pigmentosa phase 3 metachromatic leukodystrophy phase 3 avolotcagene ontaparvovec (DTX301) Ultragenyx IV urea cycle disorders phase 3

Abbreviations: DMD = Duchenne muscular dystrophy; IV = intravenous; LHON = Leber hereditary optic neuropathy; SCD = sickle cell disease; SCID = severe combined immunodeficiency; SMA = spinal muscular atrophy; WAS = Wiskott-Aldrich syndrome from these therapies and ensuring them access and coverage are challenges that fall to payers.2 This includes determining whether these specialty drugs should be billed through medical or pharmacy benefit, providing leverage to providers to ensure treatment is covered based on the place of administration.2

Because of the high cost, input from medical specialists can help with understanding the value of certain therapies. Particularly in the space of rare diseases, informed decisions can be challenging to reach as sample sizes in trials are small, data is limited, and outcomes and impact of therapy are difficult to assess.2

In rare diseases where only one treatment is available, the top priority of payers will likely be to ensure patients are receiving the appropriate treatment for their diagnosis. Care managers can be a useful resource to guide patients through the healthcare system