A Strong Year for Orphan Drug Approvals

Rare Daily Staff

The U.S. Food and Drug Administration approved 28 novel drugs for rare indications, 51 percent of all novel drug approvals last year.

It was the biggest year for orphan drug approvals since the FDA approved 34 novel orphan drugs in 2018. The approvals included the first therapies for Rett syndrome and Friedreich’s ataxia. A total of ten of the novel orphan drugs approved in 2023 were for cancer indications.

The novel orphan drug approvals included 13 first-in-class therapies and 20 drugs approved first in the United States. Six of the drugs were approved under accelerated approval, two-thirds of all accelerated approvals made for novel drugs.

In March 2023, the FDA approved Reata Pharmaceuticals’ Skyclarys as the first and only drug to treat patients with the ultra-rare neuromuscular disease Friedreich’s ataxia. The approval is for use in adults and adolescents aged 16 years and older with Friedreich’s ataxia. The FDA granted a Rare Pediatric Disease priority review voucher to Reata as a result of the approval. Skyclarys is an oral, once-daily medication that activates Nrf2 and addresses mitochondrial dysfunction, oxidative stress, and chronic inflammation.

That same month the agency also approved Acadia Pharmaceutical’s Daybue for the treatment of the rare, neurodevelopmental disorder Rett syndrome in adult and pediatric patients 2 years of age and older. With the FDA approval of Daybue, Acadia also received a Rare Pediatric Disease priority review voucher.

Among other noteworthy approvals in 2023 was Biogen’s Qalsody for the treatment of the neurodegenerative condition amyotrophic lateral sclerosis. The approval is for adults who have a mutation in the superoxide dismutase 1 (SOD1) gene, the first approval of an ALS therapy that targets a genetic cause of the disease.

The approval was based on a reduction in plasma neurofilament light chain (NfL) observed in patients treated with Qalsody. Neurofilaments are proteins that are released from neurons when they are damaged, making them a marker of neurodegeneration. It is the first time that there has been a consensus that neurofilament can be used as a surrogate marker reasonably likely to predict clinical benefit in SOD1-ALS.

On the biologics side, the FDA approved several innovative products for rare diseases.

In December 2023, on the heels of the United Kingdom’s Medicines and Healthcare Products Regulatory Agency granting of conditional marketing authorization, the FDA approved Casgevy, CRISPR Therapeutics’ and Vertex Pharmaceuticals’ CRISPR/Cas9 gene-edited therapy for the treatment of sickle cell disease. Casegevy is the first CRISPR-based therapy to win regulatory approval.

Casgevy is a one-time treatment that takes blood stem cells from a patient and, using ex vivo CRISPR/Cas9 editing, activates the production of fetal hemoglobin to compensate for the abnormal hemoglobin in people with sickle cell disease. The cells are then infused back into the patient. Fetal hemoglobin carries oxygen in the blood of a fetus, but production of it is shut off in early life as adult hemoglobin is activated. Casgevy has been shown to reduce or eliminate vaso-occlusive crises for patients with SCD. Vertex set the price of Casgevy at $2.2 million.

The same day the FDA approved Casgevy, it approved Bluebird Bio’s Lyfgenia, another cell-based therapy for SCD. Lyfgenia uses a lentiviral vector to deliver a gene therapy that modifies a patient’s blood stem cells ex vivo to produce HbA^T87Q. HbA^T87Q is similar to adult hemoglobin but has a lower risk of sickling and obstructing blood flow. The approval carried a Black Box warning because patients using Lyfgenia have developed blood cancers. Bluebird Bio set the price of Lyfgenia at $3.1 million.

The FDA also approved three gene therapies in 2023—BioMarin Pharmaceutical’s Roctavian for the blood disorder hemophilia A, Sarepta Therapeutics’ gene therapy Elevidys for the neuromuscular disease Duchenne muscular dystrophy, and Krystal Biotech’s redosable topical gene therapy for the rare connective tissue disorder dystrophic epidermolysis bullosa. They each represent the first gene therapies for the condition they treat. The approvals reflect the growing pipeline of advanced therapies that are moving toward the market.