Applied Therapeutics' Rare Disease Drug Govorestat Fails Another Late-Stage Trial

Applied Therapeutics has announced that its rare disease drug govorestat has failed to meet its primary endpoint in a Phase II/III clinical trial for sorbitol dehydrogenase deficiency (SORD), a recently identified subtype of Charcot-Marie-Tooth (CMT) disease. This setback comes just months after the U.S. Food and Drug Administration (FDA) rejected the same drug for a similar indication.

Trial Results and Implications

The INSPIRE trial, which involved 56 patients, evaluated the efficacy of once-daily govorestat compared to a placebo over 12 months. The primary endpoint, a 10-meter walk-run test (10MWRT), did not show a statistically significant difference between the treatment and control groups.

Despite this failure, Applied Therapeutics highlighted positive outcomes in secondary endpoints. The drug demonstrated a statistically significant improvement in the Charcot Marie Tooth Health Index, a patient-reported outcome measure of mobility and quality of life. Additionally, govorestat successfully lowered blood sorbitol levels, a key biomarker for the disease.

Evan Bailey, M.D., Senior Vice President of Clinical Development at Applied, expressed optimism about the drug's potential: "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."

Regulatory Challenges and Future Plans

This latest setback follows a series of regulatory hurdles for govorestat. In December 2024, the FDA rejected the drug for the treatment of children with classic galactosemia, citing "deficiencies" in the application. The rejection also included criticism of Applied Therapeutics' trial conduct, including issues with electronic data deletion by a third-party vendor and mishandling of a dosing error.

Despite these challenges, Applied Therapeutics remains committed to pursuing FDA approval for govorestat in both SORD and galactosemia. The company plans to submit a New Drug Application (NDA) for SORD treatment later in 2025, focusing on the positive secondary outcomes and additional data from the INSPIRE trial.

Les Funtleyder, Applied's Chief Financial Officer and Interim CEO, acknowledged the complexities of clinical trials for newly discovered rare diseases: "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."

Financial Implications and Market Response

The news of govorestat's trial failure has had a significant impact on Applied Therapeutics' stock price, which dropped 16% after the market opened following the announcement. With cash and cash equivalents of $50.8 million as of March 31, analysts from William Blair have expressed concerns about the company's financial risk and limited cash runway.

As Applied Therapeutics navigates these challenges, the pharmaceutical industry watches closely to see how the company will address its regulatory setbacks and advance its rare disease pipeline in an increasingly complex clinical landscape.