After extending its review period to evaluate additional submissions, the FDA ultimately denied Applied Therapeutics’ govorestat for galactosemia, citing “deficiencies” with the application. The biotech plans to meet with the regulator to discuss the best way forward for the drug.
The FDA last week denied approval for Applied Therapeutics’ investigational aldose reductase inhibitor govorestat for the treatment of classic galactosemia, sending the New York biotech’s stocks plunging more than 80%.
Galactosemia is a rare genetic metabolic disorder that affects around 3,000 patients in the U.S. It is characterized by the inability to degrade the sugar galactose, leading to the accumulation of a toxic byproduct called galactitol, which can damage the nervous system. Patients with galactosemia manifest cognitive, speech, motor and behavioral problems. There are no approved treatments for this disease.
Applied Therapeutics’ answer to galactosemia is govorsetat, which is able to penetrate into the brain and target the aldose reductase enzyme, disabling its ability to convert galactose to galactitol.
In last week’s Complete Response Letter (CRL), the FDA said that it could not sign off on govorestat given “deficiencies” in Applied Therapeutics’ clinical application, according to last week’s press announcement.
While Applied Therapeutics is “disappointed” by the rejection, CEO Soshana Shendelman said in a statement that the company plans to “work with the FDA to address concerns in the CRL and determine an expeditious path” forward for govorestat.
In a Thursday note to investors, William Blair analysts wrote that Applied Therapeutics “suspects” that the CRL “was related to the efficacy package as opposed to [chemistry, manufacturing and controls] or safety.” The biotech’s leadership also noted to William Blair that “it was too early, at this time, to speculate whether an additional clinical trial would need to be conducted.”
To back govorestat’s drug application, Applied Therapeutics used data from the Phase III ACTION-Galactosemia Kids study, which the biotech in a 2022 research paper touted as the “1st therapeutic interventional clinical trial in children with classic galactosemia.”
However, results from the trial, unveiled in April 2023, showed that govorestat fell short of its primary efficacy endpoint, a composite of four clinical measures designed to assess various domains of galactosemia symptoms. Still, Shendelman at the time said that govorestat “demonstrated compelling evidence of clinical benefit,” referring to post-hoc results showing significant improvements in behavior and activities of daily living, as well as a reduction in tremors.
Applied Therapeutics also backed govorestat with results from the Phase I/II ACTION-Galactosemia study, which focused on adults. According to the biotech, govorestat resulted in a drop in galactitol concentrations in this patient subgroup, an effect that was apparent as soon as the first day of treatment.
The FDA had initially set a target action date of Aug. 28 for govorestat, with an advisory committee meeting planned. In March 2024, the regulator pushed back its decision date, saying it needed more time to review supplemental submissions from Applied Therapeutics. In September, the FDA announced that it would no longer convene an external expert panel for govorestat.
Aside from galactosemia, Applied Therapeutics is also advancing govorestat for sorbitol dehydrogenase (SORD) deficiency, another rare disease that affects the neuromuscular system. The biotech plans to file a New Drug Application for this indication in the first quarter of 2025.
“Importantly, we do not see the CRL as having an impact on the NDA or regulatory decision for SORD given the pivotal Inspire study achieved both co-primary endpoints and no CMC or safety issues were raised during the galactosemia review,” the William Blair analysts wrote.
