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

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

Applied Therapeutics Announces Successful Pre-NDA Meeting with the FDA and Confirms Plans to Submit NDA for Govorestat (AT-007) for Treatment of Classic Galactosemia to FDA in Q4 2023 (GlobeNewswire) - "Applied Therapeutics, Inc...announced successful completion of a recent pre-New Drug Application ('NDA') meeting with the Food and Drug Administration (FDA) regarding its govorestat (AT-007) Galactosemia program. Based on discussions with the FDA, the Company believes they are aligned with the FDA and plans to submit an NDA for govorestat (AT-007) for the treatment of Galactosemia in the fourth quarter of this year."

FDA event • NDA • CNS Disorders • Genetic Disorders • Metabolic Disorders

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

Govorestat (AT-007) Receives Orphan Medicinal Product Designation from the EMA for Treatment of SORD Deficiency (GlobeNewswire) - "Applied Therapeutics, Inc...today announced that AT-007 (govorestat) has been granted orphan medicinal product designation by the European Medicines Agency (EMA) for treatment of Sorbitol Dehydrogenase (SORD) Deficiency."

Orphan drug • CNS Disorders • Genetic Disorders • Metabolic Disorders

Sorbitol reduction via AT-007 (govorestat) ameliorates synaptic dysfunction and neurodegeneration in models of sorbitol dehydrogenase deficiency. (PubMed, JCI Insight) - "Moreover, AT-007 treatment significantly reduced ROS accumulation in Drosophila CNS, muscle, and patient-derived fibroblasts. These findings uncover the molecular and cellular pathophysiology of SORD neuropathy and provide a potential treatment strategy for patients with SORD deficiency."

Journal • CNS Disorders • Genetic Disorders • Metabolic Disorders • Pain • 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: Jun 2023 ➔ Sep 2023 | Trial primary completion date: Apr 2022 ➔ Apr 2023

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

AT-007 in Adult Subjects With Classic Galactosemia (CG) (clinicaltrials.gov) - P3 | N=7 | Active, not recruiting | Sponsor: Applied Therapeutics, Inc.

New P3 trial • Metabolic Disorders

Safety and Pharmacokinetics of AT-007 in Healthy Subjects and in Adult Subjects With Classic Galactosemia (clinicaltrials.gov) - P1/2 | N=100 | Completed | Sponsor: Applied Therapeutics, Inc. | Active, not recruiting ➔ Completed | Trial completion date: May 2022 ➔ Dec 2021

Trial completion • Trial completion date • Metabolic Disorders

INSPIRE: Pharmacodynamic EffIcacy and Clinical Benefit of AT 007 in Patients With Sorbitol Dehydrogenase (SORD) Deficiency (clinicaltrials.gov) - P2/3 | N=72 | Recruiting | Sponsor: Applied Therapeutics, Inc.

New P2/3 trial • Pain

Qualitative interviews with adults with Classic Galactosemia and their caregivers: disease burden and challenges with daily living. (PubMed, Orphanet J Rare Dis) - "The impact on both patients and caregivers underscores the severity of the unmet medical need and the importance of pharmacological intervention to halt or prevent disease progression. Any treatment that could reduce symptoms or slow functional decline would ease the burden of this condition on patients and caregivers."

Interview • Journal • CNS Disorders • Depression • Metabolic Disorders • Mood Disorders • Movement Disorders • Psychiatry

Safety and Pharmacokinetics of AT-007 in Healthy Subjects and in Adult Subjects With Classic Galactosemia (clinicaltrials.gov) - P1/2 | N=100 | Active, not recruiting | Sponsor: Applied Therapeutics, Inc. | Recruiting ➔ Active, not recruiting | Trial completion date: Dec 2021 ➔ May 2022 | Trial primary completion date: Jun 2020 ➔ Dec 2021

Enrollment closed • Trial completion date • Trial primary completion date • Metabolic Disorders

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. | Recruiting ➔ Active, not recruiting | Trial primary completion date: Sep 2021 ➔ Apr 2022

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