govorestat (AT-007) / Applied Therap - LARVOL DELTA

CMT-HI Upper Limb Subscale Scores Respond to Treatment With Govorestat in Patients With CMT-SORD (AAN 2026) - "CMT-SORD is a severe progressive neuropathy caused by excess sorbitol. As a disease-specific outcome measure, the CMT-HI and its subscales are capable of detecting a reduction in disease burden in response to govorestat during a longitudinal trial."

Clinical • Genetic Disorders • Metabolic Disorders • AKR1B1

Long-term Exposure to Galactitol Leads to Progression of Symptoms in Patients with Classic Galactosemia (ACMG 2026) - "Govorestat (AT-007) is a once daily, oral, CNS penetrant aldose reductase inhibitor (ARI), which prevents conversion of galactose to galactitol... While galactitol and age each correlate to the severity of disease at baseline, accounting for both the level of galactitol and the time exposed to that level (galactitol exposure) most strongly correlates with disease severity. The findings support that the years one is exposed to elevated level of galactitol , and not simply the level of galactitol, is what drives the disease phenotype. Therefore, by lowering galactitol and maintaining a new, lower level over the course of years, the disease burden and/or progression would lessen."

Clinical • Ataxia • Metabolic Disorders • Movement Disorders • AKR1B1

Curcumin-based benzothiazepane analogues exhibit selective anti-cancer activity in HCT-116 cells via precipitated particle formation and internalisation. (PubMed, Biomed Pharmacother) - "Two analogues, AT007 and AT096, demonstrated enhanced anti-cancer selectivity compared to curcumin...Rather than direct molecular interactions typical of soluble compounds, the observed selectivity appears to result from indirect, particle-driven physical effects, potentially involving (intracellular) membrane disruption. Our findings suggest that aggregation behaviour can be a key determinant in improving the potency and selectivity of bioactive compounds, opening new opportunities for the design and screening of more selective anti-cancer therapeutics."

Journal • Colon Cancer • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

Cycle Pharmaceuticals to Acquire Applied Therapeutics (The Manila Times) - "Applied’s lead drug candidate, govorestat, is a novel central nervous system (CNS) penetrant Aldose Reductase Inhibitor (ARI) for the treatment of CNS rare metabolic diseases, including Classic Galactosemia, Charcot-Marie-Tooth Sorbitol Dehydrogenase Deficiency (CMT-SORD) and phosphomannomutase 2 congenital disorder of glycosylation (PMM2-CDG)...Under the terms of the merger agreement, Cycle will commence a tender offer to acquire all of the outstanding shares of Applied common stock for a per share price of $0.088 per share in cash payable at closing plus one non-transferrable contingent value right (CVR) that entitles the holder to receive potential additional payments."

M&A • CNS Disorders • Metabolic Disorders

Qualitative Exit Interviews in Charcot-Marie-Tooth Type-2 Sorbitol Dehydrogenase (CMT-SORD) Deficiency (ISPOR-EU 2025) - P2/3 | "Govorestat, a CNS-penetrant ARI, is being evaluated in patients with CMT-SORD in the double blind, placebo-controlled INSPIRE clinical trial (NCT05397665); exit interviews were conducted to contextualize the patient experience as part of this trial... The interviews highlighted the burden of CMT-SORD symptoms, related impacts and functional challenges. The most notable symptomatic improvements experienced by participants in the INSPIRE trial were associated with lower limb function. Patients reported that even small improvements in function and mobility were meaningful, as was no change, potentially representing slowing or stabilizing disease progression."

Interview • Fatigue • Genetic Disorders • AKR1B1

Consistent long-term clinical benefit with govorestat treatment: results of the ACTION-Galactosemia Kids trial (SSIEM 2023) - "Improvement in galactitol level was sustained throughout the trial with no impact on Gal-1p or galactose. Govorestat was generally safe and well tolerated, with no treatment-related SAEs."

Clinical • Metabolic Disorders • Movement Disorders • AKR1B1

Clinical Benefit, Safety, PK and PD Study of AT-007 in Pediatric Subjects With Classic Galactosemia (clinicaltrials.gov) - P2/3 | N=47 | Completed | Sponsor: Applied Therapeutics, Inc. | Active, not recruiting ➔ Completed | Trial completion date: Dec 2024 ➔ May 2025

Trial completion • Trial completion date • Metabolic Disorders • Pediatrics

Treatment of Single Patient With PMM2-Congenital Disorder of Glycosylation With Govorestat (AT-007), an Aldose Reductase Inhibitor. (PubMed, JIMD Rep) - "Improvements in liver transaminases, clotting factors, and whole blood sorbitol were observed along with improvements in clinical measures. These findings support further study of govorestat as a potential treatment for PMM2-CDG."

Journal • Pediatrics • AKR1B1 • PMM2

Exit interviews with caregivers of pediatric patients with classic galactosemia to explore meaningfulness of changes in the ACTION-galactosemia kids trial. (PubMed, Orphanet J Rare Dis) - "The exit interviews confirmed the burden of Classic Galactosemia disease across multiple domains. Qualitative investigation suggests that observed changes are meaningful to the patient and caregiver, and changes were more commonly reported in those receiving govorestat compared to placebo. Full clinical trial findings will be published separately."

Clinical • Interview • Journal • Metabolic Disorders • Pediatrics • Sleep Disorder

Applied Therapeutics...announced that the Company completed a meeting with the U.S. Food and Drug Administration (FDA) to discuss the potential new drug application (NDA) submission for govorestat for the treatment of Charcot-Marie-Tooth Sorbitol Dehydrogenase (SORD) Deficiency (CMT-SORD) in the third quarter of 2025. (GlobeNewswire) - "The Company is awaiting the receipt of official meeting minutes from the FDA in order to determine next steps. At this time, a path forward regarding a potential submission strategy for regulatory approval, including under the accelerated approval pathway, has not been determined."

FDA event • FDA filing • Genetic Disorders

Confirmatory Study of Govorestat in CMT-SORD (clinicaltrials.gov) - P3 | N=155 | Not yet recruiting | Sponsor: Applied Therapeutics, Inc.

New P3 trial • Genetic Disorders • Metabolic Disorders

Charcot-marie-tooth disease: a review of clinical developments and its management - What's new in 2025? (PubMed, Expert Rev Neurother) - "Metabolic neuropathies are relatively easier to target, and interim analysis results from the CMT-SORD trial suggest govorestat may become the first approved CMT drug...Supportive care, including rehabilitation and orthotics, continues to improve quality of life. There is optimism that within the next decade, approved therapies will reduce disease burden."

Journal • Review • Cognitive Disorders • Gene Therapies • Genetic Disorders • Orthopedics

Genotype and phenotype spectrum of Charcot-Marie-Tooth disease due to mutations in SORD. (PubMed, Brain) - P2/3 | "Notably, a multicenter phase 2/3 study to test the efficacy of govorestat (NCT05397665), a new aldose reductase inhibitor, is currently ongoing...In conclusion, CMT-SORD is a frequent recessive form of axonal, motor predominant CMT, with prominent foot dorsiflexion and plantar flexion involvement. Fasting serum sorbitol is a reliable biomarker of the condition that can be utilized for pathogenicity assessment of identified rare SORD variants."

Journal • Genetic Disorders • Pain • AKR1B1

Results of the ACTION-Galactosemia Kids Study to Evaluate the Effects of Govorestat in Pediatric Patients with Classic Galactosemia. (PubMed, J Clin Pharmacol) - P2/3 | "Govorestat was safe and well tolerated, with adverse events well balanced between the active and placebo groups. Aldose reductase inhibition with govorestat represents a potential opportunity to lower galactitol and improve clinical outcomes in children with Classic Galactosemia."

Journal • Metabolic Disorders • Movement Disorders • Pediatrics • AKR1B1

Applied Therapeutics Provides Regulatory Update on Govorestat for the Treatment of Classic Galactosemia (GlobeNewswire) - "Applied Therapeutics, Inc...announced an update on the ongoing New Drug Application (NDA) review of govorestat for the treatment of Classic Galactosemia. The Company recently completed its late-cycle review meeting with the United States Food and Drug Administration (FDA). The FDA communicated that an Advisory Committee meeting would no longer be required, which was previously tentatively scheduled for October 9, 2024. The FDA informed the Company that the Priority Review of the NDA is continuing as planned with alignment on post-marketing requirements expected in October 2024. The previously announced Prescription Drug User Fee Act (PDUFA) target action date remains on track for November 28, 2024."

FDA event • PDUFA • Priority review • Genetic Disorders • Metabolic Disorders

Results of the ACTION-Galactosemia Kids Study, a Phase 3 Double-Blind Placebo Controlled Study Evaluating the Effects of Govorestat on Long- Term Clinical Outcomes in Pediatric Patients with Classic Galactosemia (SSIEM 2024) - "Sponsored by Applied Therapeutics"

Clinical • Clinical data • P3 data • Metabolic Disorders • Pediatrics

Development of Govorestat (AT-007), the First Potential Treatment for Patients with Classic Galactosemia (SSIEM 2024) - "Learnings on Classic Galactosemia from the first longitudinal study in children will be discussed, such as the progressive worsening of clinical function and widening gap between Classic Galactosemia patients and their normative peers. The effects of govorestat (a CNS penetrant aldose reductase inhibitor) on galactitol (a toxic metabolite of galactose formed in patients with Classic Galactosemia) and the effects of govorestat on long-term clinical outcomes will be presented."

Clinical • Endocrine Disorders • Metabolic Disorders • Movement Disorders • Women's Health • AKR1B1

Clinical Benefit, Safety, PK and PD Study of AT-007 in Pediatric Subjects With Classic Galactosemia (clinicaltrials.gov) - P2/3 | N=47 | Active, not recruiting | Sponsor: Applied Therapeutics, Inc. | Trial completion date: Sep 2023 ➔ Dec 2024 | Trial primary completion date: Apr 2023 ➔ Dec 2024

Trial completion date • Trial primary completion date • Metabolic Disorders • Pediatrics

Safety, Pharmacokinetics, and Pharmacodynamics of the New Aldose Reductase Inhibitor Govorestat (AT-007) After a Single and Multiple Doses in Participants in a Phase 1/2 Study. (PubMed, J Clin Pharmacol) - P1/2 | "Govorestat did not affect galactose or Gal-1p levels. In conclusion, govorestat displayed a favorable safety, PK, and PD profile in humans, and reduced galactitol levels in the same magnitude (∼50%) as in a rat model of CG that demonstrated an efficacy benefit on neurological, behavioral, and ocular outcomes."

Journal • P1/2 data • PK/PD data • Metabolic Disorders • AKR1B1

Clinical meaningfulness of study outcomes in the action-galactosemia kids trial (SIMD 2024) - "The present analysis confirms the treatment benefit of govorestat (AT-007) and provides evidence of the clinical meaningfulness of clinical study outcomes."

Clinical • Endocrine Disorders • Metabolic Disorders • Movement Disorders • Women's Health • AKR1B1

Applied Therapeutics Provides FDA Update on PDUFA Target Action Date for Govorestat for the Treatment of Classic Galactosemia (GlobeNewswire) - "Applied Therapeutics...today announced that the U.S. Food and Drug Administration (FDA) has extended the review period for the New Drug Application (NDA) for govorestat (AT-007) for the treatment of Classic Galactosemia by three months. The FDA has set a new Prescription Drug User Fee Act (PDUFA) target action date of November 28, 2024....The Company expects a decision by the EMA in the fourth quarter of 2024."

European regulatory • PDUFA date • Genetic Disorders

Exit Interviews with Caregivers of Pediatric Patients with Classic Galactosemia Demonstrate the Meaningfulness of Changes in the ACTION-Galactosemia Kids Trial (ACMG 2024) - "Exit interview data confirms the treatment benefit of govorestat on clinical outcomes performance as compared to placebo, with a larger percentage of caregivers of govorestat treated patients noting improvements in behavior, cognition and motor skills, and caregivers of more placebo patients noting no change or worsening. Exit interview data was consistent with Caregiver Global Impression of Severity and Global Impression of Change data. The caregiver exit interview results support the clinical meaningfulness of the treatment effect of govorestat in children with CG."

Clinical • Interview • Endocrine Disorders • Metabolic Disorders • Movement Disorders • Pediatrics • Sleep Disorder • Women's Health • AKR1B1

Applied Therapeutics Announces FDA Acceptance and Priority Review of New Drug Application for Govorestat for the Treatment of Classic Galactosemia (GlobeNewswire) - "Applied Therapeutics, Inc...announced that the U.S. Food and Drug Administration (FDA) has accepted the filing of the New Drug Application (NDA) for govorestat (AT-007) for the treatment of Classic Galactosemia. The NDA was granted Priority Review status, and the FDA assigned a Prescription Drug User Free Act (PDUFA) target action date of August 28, 2024....The Company expects a decision by the EMA in the fourth quarter of 2024."

European regulatory • NDA • PDUFA date • CNS Disorders • Genetic Disorders • Metabolic Disorders

A Sequential, Two-Part Study to Evaluate the Clinical Benefit, Safety, Pharmacokinetics, and Pharmacodynamics of AT-007 in Pediatric Patients with Classic Galactosemia (CG) (clinicaltrialsregister.eu) - P3 | N=47 | Sponsor: Applied Therapeutics Inc.

New P3 trial • Metabolic Disorders • Pediatrics

INSPIRE: Pharmacodynamic EffIcacy and Clinical Benefit of AT 007 in Patients With Sorbitol Dehydrogenase (SORD) Deficiency (clinicaltrials.gov) - P2/3 | N=56 | Active, not recruiting | Sponsor: Applied Therapeutics, Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed • Pain