An Applied Therapeutics drug widely expected to secure FDA approval has been turned down by the agency, a setback for the company’s bid to bring to market the first therapy for a rare inherited metabolic disorder that currently has no treatments.
Applied offered few details about the FDA’s reasons for the complete response letter (CRL), which the company disclosed late last Wednesday ahead of the Thanksgiving holiday weekend. New York-based Applied said the agency cited non-specific “deficiencies in the clinical application” for the drug, govorestat.
The Applied drug was developed as a treatment for galactosemia, a rare inherited disease that leads to severe deficiency of enzymes needed to metabolize galactose. This sugar is produced by the body but is also a metabolic byproduct of lactose in dairy products, including breast milk. The disease can become fatal in infants, which is why it’s included in newborn screening tests in the U.S.
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Galactosemia is managed by maintaining a dairy-free diet. But even with dietary restrictions, galactose produced by the body cannot be metabolized, resulting in complications such as cognitive dysfunction, seizures, and speech and motor pathologies. Applied estimates there are about 3,300 galactosemia patients in the U.S. and 4,400 in the European Union.
Govorestat is a small molecule designed to penetrate the central nervous system to inhibit aldose reductase. This enzyme, when under oxidative stress conditions, converts glucose to sorbitol, a sugar alcohol associated with many diseases. In the Phase 2 portion of the Phase 1/2 clinical trial that was the basis for govorestat’s new drug application, the study drug did not meet the main goal of showing a statistically significant improvement according to a composite endpoint comprised of four measures of the disease. Nevertheless, the company pointed to systemic improvement on these measures over time along with reduction in blood levels of galactitol, a metabolic byproduct of galactose.
The FDA initially said it would hold an advisory committee meeting to discuss the govorestat application. In September, the company issued a status update stating the agency said an advisory meeting was no longer needed and the drug was on track to receive a regulatory decision by Nov. 28. Analysts and investors viewed that development as a sign govorestat was on its way to approval.
In a note sent to investors on Thanksgiving, analysts for William Blair said they expected approval “based on the totality of clinical data demonstrating efficacy in a rare disease with no approved therapies.” There were other encouraging signs. Applied’s management told William Blair that discussions about the drug’s labeling occurred before the FDA issued its letter. Such discussions are among the last steps before a drug is approved.
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“We see the CRL as unexpected and disappointing,” the William Blair analysts said. “Given the lack of information in the CRL, it is unclear what the path forward for govorestat in galactosemia is and whether an additional clinical trial will be necessary for approval in this indication.”
Applied said it will request a meeting with the FDA to discuss the deficiencies in govorestat’s application and the potential path forward in galactosemia. The company is also developing govorestat for sorbitol dehydrogenase (SORD) deficiency, a rare and progressive neuromuscular disease that has no FDA-approved treatments. The company said it expects to submit a new drug application in this indication early in the first quarter of 2025.
The William Blair analysts said they do not see the galactosemia decision affecting Applied’s plans in SORD, given that the pivotal study in this indication met both of its main goals. Furthermore, the review of the drug in galactosemia raised no manufacturing or safety issues that could affect a submission in SORD. The analysts also noted govorestat’s application in SORD will be reviewed by the FDA’s neurology division, with whom Applied had already aligned on plans for an accelerated approval application. The galactosemia submission was reviewed by the FDA’s Division of Rare Diseases and Medical Genetics, which has had many leadership change in the past year.
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