Friedrich’s ataxia, an ultra-rare disease characterized by progressively worsening muscle function that ultimately leads to death, now has its first FDA-approved therapy. The regulator has given the green light to a Reata Pharmaceuticals drug that addresses a cellular component impaired by the inherited disorder.
The approval announced Tuesday evening covers the treatment of adults as well as adolescents 16 and older. The recommended dose is three capsules taken once daily. Known in development as omeveloxolone, Plano, Texas-based Reata will commercialize its new drug as “Skyclarys.”
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“It is gratifying to have received this approval on Rare Disease Day,” Reata CEO Warren Huff said, speaking during a Tuesday evening conference call. “That underscores the progress that has been made by many patient groups, researchers, investigators, regulators, and others in the development of therapeutics for rare diseases.”
Friedreich’s ataxia is a neuromuscular disorder caused by mutations to the FXN gene, which encodes a protein called frataxin. This protein is important to function of mitochondria, the energy powerhouses of cells. In Friedreich’s ataxia, low frataxin levels lead to degeneration of nerve fibers in the spinal cord and peripheral nerves. The disease also affects the cerebellum, the part of the brain key to balance and movement.
Though Friedreich’s ataxia is inherited, it may not be diagnosed until childhood, when symptoms appear that include worsening coordination, muscle weakness, and fatigue. By the time patients reach their 20s, they require the use of a wheelchair. Based on an analysis of insurance claims data, Reata estimates that 5,000 patients in the U.S. have been diagnosed with Friedreich’s ataxia. That makes it rarer than Duchenne muscular dystrophy and spinal muscular atrophy.
Reata aims to treat Friedreich’s ataxia by restoring mitochondrial function. Its drug is a small molecule that targets and activates Nrf2, a transcription factor that the company says plays a key role in resolving inflammation. The Reata drug is intended to stabilize Nrf2 and increase its activity.
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Reata sought FDA approval based on the results of a pivotal, placebo-controlled, double-blind Phase 2 study that enrolled 103 patients. The main goal was to show at 48 weeks a change in score according to a neurological rating scale used to measure disease progression in Friedreich’s ataxia patients. Reata reported results showing on average a statistically significant improvement in score from baseline measures, while patients in the placebo group showed worsening scores.
In clinical testing, common adverse effects included elevated liver enzymes, which can be a sign of drug toxicity. Other side effects reported were headache, nausea, abdominal pain, fatigue, diarrhea, and muscle pain. The drug’s label does not carry a boxed warning, but it does recommend that clinicians obtain liver enzyme levels before starting patients on the therapy and monitoring those levels during treatment.
The FDA accepted Reata’s new drug application for Skyclarys last May, setting a Nov. 30 target date for a decision. But in a subsequent meeting to update the company on the status of the review, Reata said the FDA expressed concerns about the strength of the evidence supporting the drug’s efficacy. Reata responded by submitting additional data from an extension study of patients who participated in the pivotal trial.
Last August, the FDA told Reata that this additional information constituted a major amendment to the application, which extended the review period to Feb. 28. These additional data factored into the approval decision. The regulator said an analysis of data from patients who continued in the open-label study for up to three years showed better scores compared to a natural history of untreated patients.
Skyclarys’s approval does come with post-marketing requirements, according to an investor presentation. The company must conduct additional testing to assess the risks to the heart as well as potential drug interactions. Reata must also conduct a lactation study to assess the effects on breast milk, though Skyclarys’s label notes that there are no data showing the presence of the drug or its components in breast milk. In addition, Reata said it will conduct a long-term, real-world study to further assess Skyclarys’s safety.
Reata set an annual wholesale price of $370,000 for Skyclarys, which it plans to launch in the second quarter of this year. Acknowledging that symptoms of Friedreich’s ataxia can appear earlier in life, Huff said it is a “top priority” to work with the FDA to expand the drug’s label to include patients younger than 16.
An application seeking marketing authorization in Europe was submitted in late 2022. The company reported having a $387.5 million cash position as of the end of last year. With Skyclarys’s approval, the FDA also awarded Reata a pediatric disease priority review voucher. Though Reata can use it to speed up review of a future rare disease drug candidate, companies typically sell these vouchers to raise additional cash. Vouchers have fetched prices of $100 million or more.
Reata will be first to market with a Friedreich’s ataxia therapy, but competitors are on its heels. PTC Therapeutics expects its small molecule, vatiquinone, will have data from a Phase 2/3 test in the second quarter of this year. Meanwhile, Larimar Therapeutics has reached mid-stage testing with CTI-1601, a fusion protein engineered to penetrate the cell membrane. In 2021, the FDA placed a full clinical hold on the Larimar drug’s dose-escalation study after the report of monkey deaths in a separate toxicology study. The regulator lifted the full clinical hold last September but left in place a partial hold. Larimar is cleared to begin the study at the 25 mg dose but the FDA must review the data from this group before the study escalates to the next dose. Preliminary data are expected in the second half of this year.
[Update: The following three paragraphs added with analyst comment.] Skyclarys’s approval came the day after the FDA announced the immediate retirement of Billy Dunn, the director of FDA’s Office of Neuroscience. Under Dunn, the regulator bucked a negative advisory committee vote and approved Biogen Alzheimer’s drug Aduhelm. His “regulatory flexibility” was also stamped on last September’s approval of Amylyx amyotrophic lateral sclerosis drug Relyvrio. In a note sent to investors Wednesday, William Blair analyst Myles Minter said the flexibility of the FDA’s neuroscience division could change with the departure of Dunn, who will be succeeded by Teresa Buracchio, the office’s deputy director.
However, Minter said the full approval of Reata’s new drug establishes that a single, one-year pivotal study with a placebo control, along with open-label safety and efficacy data, is enough to pass FDA muster. The approval should have a positive read-through to other disease-modifying therapies in development for Friedreich’s ataxia, such as Larimar’s, he added.
“It seems to us that not only is this a favorable regulatory path for [Friedreich’s ataxia] drug developers and rare neuro disease more broadly, but the FDA also does not want to restrict patient access on label given the unmet need,” Minter wrote.
Photo: wir0man, Getty Images
