FDA Issues CRL for Govorestat Application As Treatment for Classic Galactosemia

The FDA has issued a complete response letter (CRL) to Applied Therapeutics investigational agent govorestat, a central nervous system penetrant Aldose Reductase inhibitor (ARI), which had been submitted as a potential new treatment for patients with classic galactosemia. As of now, there are no approved therapies specifically indicated for this rare genetic metabolic disease.¹

The CRL indicates that the agency is unable to approve the NDA in its current form, citing deficiencies in the clinical application. Applied Therapeutics noted that it is "reviewing the feedback and plans to immediately request a meeting to discuss requirements for a potential resubmission of the NDA or appeal of the decision along with appropriate next steps."

“We are disappointed by the FDA’s decision today. Our strong commitment to the Galactosemia community is rooted in our belief that govorestat has the potential to change the lives of patients with Galactosemia, which we believe is evidenced by the breadth of efficacy and safety data demonstrating its ability to stop the decline on progressive clinical outcomes, including cognition and behavior,” Shoshana Shendelman, PhD, founder and CEO of Applied Therapeutics, said in a statement.¹ “Galactosemia is a progressive and debilitating disease without any existing treatment options and there remains a high unmet medical need for this community. As we move forward, we plan to work with the FDA to address the concerns in the CRL and determine an expeditious path to bring this much needed treatment to patients. We are grateful to the patients, families, and healthcare providers who participated in the govorestat clinical studies.”

The application was supported by data that included findings from the phase 3 registrational ACTION-Galactosemia Kids study (NCT05397665) in children aged 2-17 with galactosemia, the phase 1/2 ACTION-Galactosemia study in adults, and preclinical data. In ACTION-Galactosemnia Kids, treatment with govorestat resulted in clinical benefits in activities of daily living, behavioral symptoms, cognition, fine motor skills, and tremor. Throughout both studies, govorestat significantly reduced plasma galactitol levels, a toxic metabolite responsible for tissue damage and long-term complications in galactosemia.

After completing its late-cycle review meeting with the FDA, the company announced in September that the agency had no longer planned to hold an Advisory Committee meeting to discuss govorestat. With that decision, it remained on track for its November 28th PDUFA date.²

The ACTION-Galactosemia Kids Phase 3 study evaluated govorestat vs. placebo in 47 children (ages 2–17) with Galactosemia. The primary endpoint, the Global Statistical Test, combined four measures: OWLS-2 Oral Expression, OWLS-2 Listening Comprehension, BASC-3 Behavior Symptoms Index, and BASC-3 Activities of Daily Living. All told, govorestat demonstrated consistent clinical benefits across a number of outcomes, with systematic improvement over time on the primary end point (P = .1030) and a pre-specified sensitivity analysis including cognition (P = .0698), though statistical significance (P <.05) was not met.³

A post-hoc analysis of the global statistical test including behavior and activities of daily living but excluding speech and language components demonstrated a highly statistically significant benefit of active treatment vs placebo (P = .0205), which strengthened over time. In addition, govorestat provided a statistically significant benefit on tremor at 18 months (P = .0428), as measured by the Archimedes Spiral Drawing Test, and adaptive skills as assessed by the BASC-3 Adaptive Skills Index (P = .0265).

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Otherwise known as AT-007, govorestat previously received orphan medical product designation, as well as orphan drug designation for the treatment of galactosemia. It is also in development for several other conditions, including Sorbitol Dehydrogenase (SORD) Deficiency and PMM2-CDG.

Classic galactosemia is a rare genetic metabolic disorder caused by a deficiency of the enzyme galactose-1-phosphate uridylytransferase. This enzyme is essential for metabolizing galactose, a sugar found in lactose, into glucose, which the body uses for energy. The mainstay of treatment is a galactose-restricted diet, which involves eliminating lactose-containing foods to minimize galactose intake. In addition, patients will typically undergo regular monitoring of galactose-1-phosphate levels in the blood to assess dietary compliance.

ACTION-Galactosemia Kids was the first study to demonstrate a correlation between higher galactitol levels, a biochemical biomarker, and greater disease severity in patients with galactosemia. Overall, treatment with the agent resulted in a substantial reduction in mean plasma galactitol of 40%, which was statistically significant (P <.001) vs placebo. All told, children with higher plasma galactitol levels displayed greater disease severity vs children with lower plasma galactitol levels at baseline.

The phase 1/2 ACTION-Galactosemia Registrational Study evaluated govorestat in adults with Galactosemia, confirming its safety and tolerability. Govorestat significantly reduced galactitol levels, a key biomarker of Aldose Reductase activity, in all treated patients without increasing galactose or other metabolites like Gal1P. The galactitol reduction was rapid, beginning on the first day of treatment, sustained over one month, dose-dependent, and statistically significant at higher doses (20 and 40 mg/kg). At 20 mg/kg, galactitol levels decreased by approximately 50% from baseline. Pharmacokinetic analysis showed linear, dose-dependent plasma concentrations, supporting once-daily dosing.⁴

REFERENCES
1. Applied Therapeutics Receives Complete Response Letter from U.S. FDA Regarding New Drug Application for Govorestat for Classic Galactosemia. News release. Applied Therapeutics. November 27, 2024. Accessed November 27, 2024. https://www.globenewswire.com/news-release/2024/11/27/2988438/0/en/Applied-Therapeutics-Receives-Complete-Response-Letter-from-U-S-FDA-Regarding-New-Drug-Application-for-Govorestat-for-Classic-Galactosemia.html
2. Applied Therapeutics Provides Regulatory Update on Govorestat for the Treatment of Classic Galactosemia. News release. Applied Therapeutics. September 18, 2024. Accessed November 28, 2024. https://ir.appliedtherapeutics.com/news-releases/news-release-details/applied-therapeutics-provides-regulatory-update-govorestat
3. Applied Therapeutics Announces Clinical Benefit of Govorestat (AT-007) in ACTION-Galactosemia Kids Trial; Company Plans to Meet with FDA Regarding Potential NDA Submission. News release. Applied Therapeutics. April 24, 2024. Accessed November 28, 2024. https://www.biospace.com/applied-therapeutics-announces-clinical-benefit-of-govorestat-at-007-in-action-galactosemia-kids-trial-company-plans-to-meet-with-fda-regarding-potential-nda-submission
4. Govorestat. Applied Therapeutics. https://www.appliedtherapeutics.com/pipeline/govorestat/