Applied Therapeutics Reports Encouraging Results for Govorestat in CMT-SORD Treatment
Clinical trial findings indicate that govorestat slows disease progression and decreases sorbitol levels in patients with Charcot-Marie-Tooth Sorbitol Dehydrogenase Deficiency (CMT-SORD) over a 24-month period.
INSPIRE Trial Findings
Applied Therapeutics, Inc. has released promising interim results from the INSPIRE Phase 2/3 trial involving govorestat. This treatment targets CMT-SORD, a rare genetic disorder. Results show a meaningful reduction in blood sorbitol levels and observable slowing of disease progression via MRI scans over 24 months. Improved patient-reported outcomes were also noted. Although the primary endpoint, measured by the 10-meter walk-run test, did not achieve statistical significance, a noteworthy correlation exists between decreased sorbitol levels and enhancements in functional assessments like the CMT-Health Index. Importantly, govorestat maintained a favorable safety profile, and the company is looking to submit a New Drug Application (NDA) by 2025.
Positive Highlights
- The slowing of disease progression, as seen in MRI scans at the 24-month mark, represents a significant development for CMT-SORD patients.
- A statistically significant improvement in the CMT-Health Index reflects the treatment’s positive impact on patients’ daily lives.
- Govorestat demonstrated a significant 37% reduction in sorbitol in the sciatic nerve tissue after treatment, further evidencing its efficacy.
- A strong 90% of patients are opting for an open-label extension of the study, indicating high levels of patient commitment to the treatment.
Challenges Noted
- The primary endpoint, the 10-meter walk-run test (10MWRT), did not show statistical significance, prompting questions about govorestat’s efficacy in critical functional measures.
- The exclusion of the 10MWRT from the CMT-FOM composite score may complicate the evaluation of clinical outcomes and consistency in assessing treatment effectiveness.
- CMT-SORD is a relatively new classification established in 2020, which might introduce uncertainties surrounding treatment approaches and data reliability due to the absence of a well-defined natural history.
Frequently Asked Questions
What improvements were observed in patients treated with govorestat?
Govorestat treatment resulted in significant reductions in sorbitol levels and a slowdown in disease progression, as observed through MRI at the 24-month mark.
What is CMT-SORD?
CMT-SORD is a rare hereditary neurological condition caused by genetic mutations that disrupt the sorbitol dehydrogenase enzyme, affecting mobility and sensory functions.
When is the NDA submission for govorestat planned?
Applied Therapeutics aims to submit a New Drug Application for govorestat for CMT-SORD treatment by 2025.
How was the INSPIRE Phase 2/3 trial designed?
The trial was a randomized, double-blind, placebo-controlled study focused on evaluating the impacts of govorestat on both functional and patient-reported outcomes in CMT-SORD patients.
Why is sorbitol reduction significant in CMT-SORD treatment?
A statistically significant link exists between sorbitol reduction and improvements in clinical outcomes, highlighting its role in effectively managing CMT-SORD symptoms.
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Study Highlights
Slowing of disease progression observed via MRI at 24 months.
Improvements in outcomes and sustained reduction in sorbitol levels maintained through 24 months.
While the primary endpoint of the 10MWRT was not statistically significant, a correlation was identified with improvements in other measures.
Notably significant reduction of 37% sorbitol in tissue samples following treatment.
# Applied Therapeutics Reveals Promising Results for Govorestat in CMT-SORD
Govorestat Shows Strong Safety Profile and Tolerance
Company Aims for NDA Submission in 2025
NEW YORK, May 18, 2025 (GLOBE NEWSWIRE) — Applied Therapeutics, Inc. (Nasdaq: APLT) has unveiled comprehensive 12-month clinical results and new topline data from the 18- and 24-month periods of its INSPIRE Phase 2/3 trial for govorestat (AT-007). This treatment targets Sorbitol Dehydrogenase (SORD) Deficiency, a subtype of Charcot-Marie-Tooth (CMT) disease. Findings were shared during an oral presentation at the Peripheral Nerve Society (PNS) 2025 Annual Meeting held from May 17-20 in Edinburgh, Scotland.
CMT-SORD is a rare neuromuscular disorder resulting from genetic mutations affecting the sorbitol dehydrogenase enzyme, crucial for sorbitol metabolism. Before 2020, patients were typically diagnosed with CMT Type 2 of unknown genetic origin or distal hereditary motor neuropathy. The discovery of CMT-SORD as a distinct subtype followed a comprehensive genome sequencing initiative in 2020, leading to advancements in genetic testing for this condition.
Les Funtleyder, Interim CEO and CFO of Applied Therapeutics, remarked, “CMT-SORD is a newly identified and evolving disease, only recognized in 2020. The lack of natural history data complicates clinical trial design. Our efforts include adapting the CMT-Functional Outcome Measure composite for assessing disease progression, evidenced by the removal of the 10-meter walk-run test.”
Supporting these findings, Dr. Evan Bailey, SVP of Clinical Development, noted, “We are encouraged by the substantial data indicating govorestat significantly reduces blood sorbitol levels and improves functional and patient-reported outcomes.” At the 24-month mark, patients treated with govorestat also showed slowed disease progression through MRI scans. The study has seen a 90% conversion of remaining patients to its open-label extension study, indicating potential long-term patient benefits.
“Sustained positive trends in functional measures correlate with consistent sorbitol reductions at 18 and 24 months. Notably, improvements in the CMT-Health Index reflect the patients’ daily experiences,” stated Dr. Michael Shy, Professor of Neurology at the University of Iowa.
INSPIRE Phase 2/3 Trial Overview
The INSPIRE trial is a randomized, double-blind, placebo-controlled study assessing govorestat’s effectiveness in CMT-SORD patients. Of the 56 participants, they were randomized 2:1 to receive either the active treatment or a placebo. The primary endpoint was the 10-meter walk-run test (10MWRT) at 12 months, though this measure has since been excluded from the CMT-Functional Outcome Measure composite, which now consists of 11 components. Key objectives also included evaluating govorestat’s impact on blood sorbitol levels and its correlation with various clinical outcomes.
Clinical Results After 12 Months
A reverified interim analysis of 49 efficacy-evaluable patients as of February 2024 yielded significant results at 12 months:
- A statistically significant correlation was found between sorbitol reduction and improvements in the 10MWRT (p=0.031) and CMT-FOM Lower Limb domain (p=0.037).
- The primary endpoint, 10MWRT, did not show statistical significance (p=0.457) after its removal from the CMT-FOM.
- Govorestat demonstrated a statistically significant improvement on the key secondary endpoint, CMT-Health Index (p=0.039).
- There was a statistically significant correlation between changes in sorbitol levels and improvements in CMT-Health Index scores at 12 months.
- Blood sorbitol levels significantly decreased (p < 0.001).
- Govorestat remained generally safe and well tolerated, with a comparable incidence of adverse events in both treatment groups.
Topline Patient-Level Analyses at 18 and 24 Months
As of October 11, 2024, 24 patients were evaluable at 18 months, while 15 patients were evaluable at 24 months before transitioning to the open-label extension study. Key findings from these analyses include:
- MRIs at 24 months showed slowed disease progression in govorestat-treated patients.
- Improvements observed at 12 months in CMT-Health Index persisted through 24 months.
- Sorbitol reductions were maintained at 18 and 24 months.
- Govorestat continued to demonstrate a good safety profile after 24 months of treatment.
“For the first time in any CMT patient population, we are excited to see from the 24-month MRI data that govorestat has slowed disease progression compared to results at 12 months. We eagerly anticipate continuing studies in this long-term condition,” stated Dr. Mary M. Reilly, MD, FRCP, FRCPI.
Progress in CMT-SORD Trial: Govorestat Shows Promise in Slowing Disease
Professor of Neurology at University College London, specializing in Neuromuscular Diseases, remarked on the INSPIRE trial results:
“We were pleased to see upon examination of the 24-month MRI data that govorestat slowed the progression of the disease compared to the MRIs at 12 months. This is an important finding for patients living with this long-term debilitating disease,” said Suzanne Bruhn, PhD, CEO of the Charcot-Marie-Tooth Association.
The open-label extension (OLE) of the INSPIRE trial began in September 2024. Currently, 90% of remaining INSPIRE patients (45 out of 50) are continuing treatment with govorestat in this extension study. The company is dedicated to collaborating with the U.S. Food and Drug Administration (FDA) to establish an appropriate regulatory pathway for a potential New Drug Application (NDA) submission in 2025.
“The application of the CMT-HI tool and the statistically significant improvement observed in the INSPIRE trial allows our patient voice to be heard and measured—not only on the challenges we face every day but also in how it significantly impacts our daily lives,” stated Allison Moore, Founder and CEO of the Hereditary Neuropathy Foundation and a CMT patient.
PNS Presentation Details
Title: CMT-SORD Clinical Trial: Month 18 and Month 24 INSPIRE Trial Results and Designing the Next Randomized Study
Oral Presentation Number: 597
Presenter: Evan Bailey, MD, Senior Vice President, Clinical Development, Applied Therapeutics Inc.
Date and Time: Sunday, May 18, 2025, 12:25 – 12:40 p.m. BST
About Charcot-Marie-Tooth Sorbitol Dehydrogenase Deficiency (CMT-SORD)
CMT-SORD is a rare and progressive hereditary neuropathy that primarily affects peripheral nerves and motor neurons. It represents one of the most common forms of recessive hereditary neuropathy, impacting approximately 3,300 patients in the U.S. and 4,000 in the EU. The disease arises from a deficiency in the enzyme sorbitol dehydrogenase, crucial for sorbitol metabolism, leading to harmful sorbitol accumulation in the body. This accumulation can cause significant disability, loss of sensory function, neuromuscular dysfunction, and reduced mobility.
About Govorestat (AT-007)
Govorestat is a central nervous system (CNS) penetrant Aldose Reductase Inhibitor (ARI) being developed to treat several rare diseases, including Charcot-Marie-Tooth Sorbitol Dehydrogenase Deficiency (CMT-SORD), Classic Galactosemia, and phosphomannomutase 2 congenital disorder of glycosylation (PMM2-CDG).
Govorestat has received Orphan Medicinal Product Designation from the European Medicines Agency (EMA) for both Galactosemia and CMT-SORD. It has also received Orphan Drug Designation from the U.S. FDA for these conditions, along with Rare Pediatric Disease designation for Galactosemia and PMM2-CDG, in addition to Fast Track status for Galactosemia.
About Applied Therapeutics
Applied Therapeutics is a clinical-stage biopharmaceutical company focused on developing novel drug candidates targeting validated molecular pathways in rare diseases. Their lead candidate, govorestat, is specifically designed to address CNS rare metabolic diseases including Classic Galactosemia, CMT-SORD, and PMM2-CDG.
Forward-Looking Statements
This press release contains “forward-looking statements” that involve significant risks and uncertainties regarding the company’s strategy, operations, and potential future outcomes. These statements incorporate language such as “may,” “will,” “expect,” and similar terms reflecting future events. Actual results could materially differ due to a variety of factors, including but not limited to the company’s development and commercialization plans and regulatory approvals. For an in-depth examination of these uncertainties, refer to the risk factors in the company’s filings with the U.S. Securities and Exchange Commission.
* Mandarakas MR. et al. J Neurol. 2024;102(3).
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