While Applied Therapeutics has vowed to reapply or appeal the FDA’s recent rejection of its rare disease candidate govorestat, deeper issues with the New York biotech’s clinical trial conduct could put a damper on those plans.
In a warning letter published Tuesday, the FDA scolded Applied on two counts related to its 47-patient study of govorestat in kids with classic galactosemia.
Specifically, agency investigators took issue with electronic data deletion by a third-party vendor and the mishandling of a dosing error that led to some patients initially receiving lower levels of govorestat than intended.
The reprimand was issued around the same time the FDA rejected govorestat’s approval bid in classic galactosemia, which causes developmental delays, speech problems and motor function abnormalities.
A phase 3 trial of Applied’s drug missed its primary endpoint in 2023—which isn’t always a dealbreaker for rare disease approvals—but the company’s clinical data package still fell short of the FDA’s standards last week. The FDA's recent rejection sent Applied’s share price tumbling some 80% in post-Thanksgiving trading.
Applied previously received a Form 483—a less severe FDA reprimand—around its trial conduct and responded to that write-up in May. That earlier wrist-slap did not include details on the dosing issue, the FDA explained in its warning letter.
Applied acknowledged the letter in a securities filing this week, noting that the regulator’s complaints come down to “issues related to electronic data capture,” which the biotech believes it addressed in prior communications, as well as a “dosing error in the dose escalation phase of the study” that the company said was “remedied prior to achieving maintenance dosing.”
Applied said that it plans to respond to the FDA’s warning letter within 15 business days.
Digging deeper into the FDA’s concerns, the agency stated that two days after preannouncing an inspection of one of Applied’s clinical trial sites in late April, a third-party vendor contracted by Applied deleted electronic data in a web-based data capturing platform.
In previous written correspondence with the FDA, Applied argued that the vendor deleted the data without consulting the company.
As for the dosing mishap, the FDA said that due to a labeling error, “clinical sites administered 80% of the protocol-required dose to subjects” between March and June of 2021. Applied alerted clinical sites about the error and provided a new formulation at the correct concentration in June of that same year, according to the warning letter.
Still, the FDA alleges that the company failed to provide the regulator with “any description or analysis of the information describing the nature and extent of the dosing errors.”
In turn, the FDA says it lacked sufficient information at the time of Applied’s approval submission to make an informed decision on the impact of the error on study data.
Govorestat, which is an aldose reductase inhibitor, has had something of a troubled history. Following the phase 3 miss last year, the FDA in March of this year delayed its decision deadline on the drug by three months, citing the need to further examine supplemental analyses of previously submitted data.
Regarding govorestat’s fate in classic galactosemia, Applied has said it’s reviewing feedback after the FDA’s snub and plans to immediately request to meet with the regulator to “discuss requirements for a potential resubmission … or appeal of the decision.”
The company has also maintained plans to file for approval of the drug in sorbitol dehydrogenase (SORD) deficiency in the first quarter of 2025.