5 Highly Anticipated FDA Decisions for Rare Diseases Coming This Year

FDA Headquarters, iStock, Grandbrothers

Pictured: FDA Headquarters/iStock, Grandbrothers

The first half of 2023 saw the first approvals of therapies for a genetic subset of ALS and a pair of rare neurological disorders, Rett syndrome and Friedreich’s ataxia—and the regulator has several decisions for rare and orphan diseases on the docket in the second half of the year.   

Rare diseases are gaining recognition, and research into potential treatments for them is picking up momentum. A recently initiated FDA pilot program aimed at developing novel efficacy endpoints for rare disease research and an NIH-managed consortium intended to accelerate the development of gene therapies for rare disorders are giving patients and caregivers reason to hope.

Here, BioSpace looks at five therapies for rare indications up for FDA review later this year.

Ipsen’s Palovarotene

Fibrodysplasia ossificans progressiva

PDUFA date: August 16

Ipsen Biopharmaceuticals’ palovarotene, in development to treat fibrodysplasia ossificans progressiva (FOP), won the backing of an FDA advisory committee in June. Despite some reservations, the advisers ultimately voted 10-4 in favor of the candidate’s efficacy based on the Phase III MOVE study and 11-3 that the benefits conferred by palovarotene outweighed the associated risks.

Palovarotene is intended to reduce abnormal bone formation in people living with FOP, an ultra-rare disorder that causes the continuous and permanent formation of bone in soft and connective tissues. FOP results in severely restricted mobility and function, and patients ultimately succumb to breathing problems and cardiorespiratory failure caused by bone formation around the ribcage. There are approximately 900 cases worldwide, according to Ipsen.

While palovarotene failed its Phase III study, Ipsen has stated that this was due to the use of a particular statistical technique and the inherent biases involved with using natural history controls.

The FDA rejected palovarotene in December 2022, a decision the company said corresponded to the regulator’s previous request for additional information regarding clinical trial data. Last week, the European Commission declined to approve palovarotene, which, according to Ipsen, is the first treatment for FOP to be submitted for approval anywhere in the world.

Ipsen will find out on or before August 16 if the second time’s the charm for U.S. approval of palovarotene.

Regeneron’s Pozelimab

CHAPLE disease

PDUFA date: August 20

Also next month, the FDA will render its verdict on Regeneron’s pozelimab, which is in development to treat CHAPLE disease.  

Even more rare than FOP, CHAPLE currently affects less than 100 people worldwide, according to Regeneron. It is a hereditary immune disorder driven by overactivation of the complement system. People with the disease have mutations in the CD55 gene, leaving them unable to regulate complement activity. This causes damage to blood and lymph vessels along the upper digestive tract, putting patients at risk for potentially life-threatening abdominal and cardiovascular symptoms.

Pozelimab is an antibody designed to block the activity of complement factor C5, a protein in the innate immune system involved in complement system activation.

Regeneron is supporting its BLA with results from a Phase II/III trial that tested the therapy in 10 patients one year of age or older. At 24 weeks, Regeneron reported that all patients experienced “rapid and sustained normalization of serum albumin”—a disease biomarker—and improvement or no worsening of clinical symptoms. Mild or moderate adverse events occurred in seven of the ten patients, with the most common AEs being iron deficiency, pyrexia, rhinitis, urticaria and vomiting.

The FDA is expected to make a decision on or before August 20.

BioMarin’s Voxzogo


PDUFA date: October 21

In November 2021, the FDA greenlit BioMarin’s Voxzogo (vosoritide) as the first U.S. treatment for achondroplasia, a rare genetic disorder that causes the most common form of dwarfism. Voxzogo was approved for children five years and older. Nearly two years later, the regulator is set to decide whether to expand its use to younger children.

Voxzogo is a once-daily injection approved specifically for children who have open epiphyses, or growth plates, which gives them the potential for growth. Achondroplasia is caused by a mutation in the fibroblast growth factor receptor 3 gene involved in converting cartilage to bone during fetal development. Worldwide, the condition occurs in one out of every 20,000 to 30,000 live births, according to the National Organization for Rare Disorders (NORD).

BioMarin’s supplemental NDA is based on data from a global Phase II trial in which the company reported that Voxzogo demonstrated similar safety and efficacy profiles in children under five years compared with their older counterparts. The FDA is expected to decide on this expansion by October 21.

Voxzogo is also under review in the EU for this patient population, and if both are approved, it could open up treatment for more than 1,000 more children, BioMarin stated in a press release.

Santhera’s Vamorolone

Duchenne muscular dystrophy

PDUFA date: October 26

A regulatory submission process that began in March 2022 will culminate on or before October 26, as the FDA decides whether to grant approval to Santhera Pharmaceuticals’ vamorolone for Duchenne muscular dystrophy (DMD). While considered rare by NORD, DMD is one of the most prevalent genetic conditions, affecting around one in 3,500 male births globally, according to the organization.

Catalyst Pharmaceuticals, for one, is banking on a positive outcome for vamorolone, paying $231 million plus royalties for exclusive North American rights to the therapy in June.

Vamorolone, which is considered a dissociative anti-inflammatory drug, binds to the same receptor as glucocorticoids but modifies its downstream activity. In a press release announcing the U.S. licensing deal, Santhera said this mechanism could “dissociate” efficacy from steroid safety concerns, making it a potential alternative to current corticosteroids used to treat DMD.

SpringWorks’ Nirogacestat

Desmoid tumors

PDUFA date: November 27

A rare type of cancer, desmoid tumors are diagnosed in 900 to 1,500 people across the U.S. each year, according to the American Society of Clinical Oncology. SpringWorks Therapeutics, which focuses on developing therapies for severe rare diseases and cancer, expects a decision from the FDA on nirogacestat in this indication on or before November 27.

Nirogacestat is a small molecule inhibitor of gamma secretase that cleaves the transmembrane protein complex Notch, which is believed to play a part in activating pathways that contribute to the growth of desmoid tumors.

SpringWorks is backing its NDA—which the FDA accepted and granted Priority Review in February—with data from the Phase III DeFi trial. The study, which consisted of 142 people randomized to receive either nirogacestat or placebo twice daily, demonstrated a statistically significant advantage for nirogacestat, the company reported in May 2022. Nirogacestat reduced the risk of disease progression by 71% and showed statistically significant improvements in objective response rate and patient-reported outcomes.

SpringWorks had initially expected a decision by August 27, but in June the FDA extended the review period to allow more time to review additional analyses of data previously submitted by the company.

Heather McKenzie is a senior editor at BioSpace. You can reach her at heather.mckenzie@biospace.com. Follow her on LinkedIn and Twitter @chicat08.

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