Applied Therapeutics’ rare disease drug has failed another late-stage clinical trial, adding to the woes of a candidate that was rejected by the FDA five months ago.
The drug in question, a selective aldose reductase inhibitor called govorestat, was being evaluated in the phase 2/3 Inspire study of 56 patients with a progressive neuromuscular disease called sorbitol dehydrogenase deficiency (SORD), which is a type of Charcot-Marie-Tooth (CMT) disease.
The study missed the primary endpoint of demonstrating an improvement in the 10-meter walk-run test (10MWRT) at 12 months when compared to placebo. Applied caveated this failure by pointing out that since the trial was launched, 10MWRT has been removed as an element of the Charcot-Marie-Tooth Functional Outcome Measure.
In fact, CMT-SORD was only identified as a subtype of CMT in 2020 thanks to the ability of a genome sequencing to pinpoint the genetic cause of this specific disease, the biotech explained.
“With newly discovered and rare diseases comes an ever-changing landscape of emerging hypotheses and research, requiring the need for flexibility and fluidity in the clinic,” Applied’s chief financial officer and interim CEO Les Funtleyder said in the May 18 release. “This is particularly evidenced with clinical trial design for CMT-SORD, for which there is no natural history data to draw from and an evolving methodology for assessing disease progression.”
The company instead tried to focus on the study’s secondary objectives at the 12-month mark, where it had some success. These included a statistically significant improvement in the Charcot Marie Tooth Health Index, a patient-reported outcome measure, as well as lowering blood sorbitol levels and demonstrating a correlation between the change in sorbitol and change in 10MWRT.
In this context, the company said it is still hopeful of submitting an approval request to the FDA for govorestat in CMT-SORD this year.
“In the midst of a complicated clinical landscape, we are encouraged by the breadth of data supporting govorestat’s ability to significantly lower blood sorbitol levels and positively impact both functional and patient-reported outcomes including stability and mobility at up to two years of treatment,” Evan Bailey, M.D., senior vice president of clinical development at Applied, said in the same release.
“We have also observed slowing of disease progression at 24 months through MRI scans in patients treated with govorestat,” Bailey added. “We look forward to further analyzing the results from the INSPIRE trial to inform and support future potential regulatory interactions with the FDA regarding govorestat for the treatment of CMT-SORD.”
Even before yesterday’s latest failure, Applied had struggled to get govorestat to market. In December 2024, the FDA rejected an application for the drug in children with classic galactosemia, while using its response to scold the biotech regarding 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 application was itself based on a failed phase 3 trial from 2023, but Applied had held out hopes it still had the data needed for the rare disease approval.
Applied has not abandoned its ambition to get govorestat approved for classic galactosemia, although the company’s request for a meeting with the FDA’s Office of Scientific Investigations to discuss the remaining issues was not granted.
In a note published ahead of the Inspire readout, William Blair analysts said it remained unclear when applications for govorestat in galactosemia or SORD deficiency will be rectified or submitted to regulators.
“Given Applied had cash and cash equivalents of $50.8 million as of March 31, we also see the company as bearing increased financial risk given its limited cash runway,” the analysts added in the May 14 note.