Applied Therapeutics Presents Full 12-Month Clinical Results and New Topline Data from INSPIRE Phase 2/3 Trial of Govorestat in CMT-SORD in Late-Breaking Oral Presentation at the Peripheral Nerve Society 2025 Annual Meeting

Rhea-AI Summary

Applied Therapeutics (NASDAQ: APLT) presented full 12-month clinical results and new topline data from the INSPIRE Phase 2/3 trial of govorestat for treating CMT-SORD, a rare neuromuscular disease. While the primary endpoint of 10MWRT at 12 months wasn't statistically significant, the study showed significant correlation between sorbitol reduction and improvements in mobility measures. Key findings include: statistically significant improvement in CMT-Health Index, sustained sorbitol reduction through 24 months, and MRI evidence of slowed disease progression at 24 months. The drug remained generally safe and well-tolerated, with 90% of remaining patients continuing treatment in the open-label extension study. The company plans to pursue NDA submission in 2025.

Positive

• MRI data at 24 months shows slowing of disease progression
• Statistically significant improvement in CMT-Health Index (p=0.039)
• Significant correlation between sorbitol reduction and mobility improvements
• 90% patient retention rate in open-label extension study
• Drug demonstrated sustained safety and tolerability through 24 months

Negative

• Primary endpoint (10MWRT) at 12 months was not statistically significant (p=0.457)
• Limited patient data available for longer-term analysis (only 24 patients at 18 months and 15 at 24 months)
• 10MWRT measure was removed from CMT-FOM clinical outcomes assessment during trial

Insights

Biotechnology Clinical Trial Expert

Mixed trial results for govorestat in CMT-SORD show benefit in secondary endpoints but missed primary endpoint; NDA still planned for 2025.

Applied Therapeutics has presented its INSPIRE Phase 2/3 trial results for govorestat (AT-007) in Charcot-Marie-Tooth-SORD Deficiency (CMT-SORD), revealing a complex efficacy picture. While the primary endpoint of 10-meter walk-run test (10MWRT) at 12 months was not statistically significant (p=0.457), the company reported several positive secondary outcomes. The trial demonstrated statistically significant correlation between sorbitol reduction and improvements in 10MWRT (p=0.031) and the CMT-FOM Lower Limb domain (p=0.037).

A critical finding was the statistically significant improvement in the CMT-Health Index (p=0.039), a patient-reported outcome measure. Notably, the 10MWRT metric that served as the primary endpoint has since been removed from the CMT-FOM composite score, suggesting evolving understanding of appropriate outcome measures for this rare disease that was only officially recognized in 2020.

Longer-term data shows maintenance of benefits through 24 months, with MRI evidence suggesting slowing of disease progression in treated patients. The drug achieved its biochemical objective with highly significant reduction in blood sorbitol levels (p<0.001) and demonstrated 37% reduction of sorbitol in the sciatic nerve in an animal model (p=0.005). The safety profile remains favorable, with similar adverse event rates between treatment and placebo groups.

Importantly, 90% of remaining patients (45 of 50) opted to continue treatment in the open-label extension study, indicating perceived benefit. Despite missing the primary endpoint, the company remains committed to submitting an NDA in 2025, suggesting confidence in the overall data package and potential regulatory flexibility for this rare disease with no approved treatments.

 Slowing of progression of disease observed via MRI at 24 months

Improvements in outcomes and reduction in sorbitol maintained through 24 months

Statistically significant correlation between absolute reduction in sorbitol and change in 10MWRT and CMT-FOM Lower Limb domain at 12 months, though the primary endpoint of 10MWRT at 12 months was not statistically significant (the measure has since been removed from the CMT-FOM clinical outcomes assessment based upon the results of the ACT-CMT study*)

Statistically significant improvement in CMT-HI and statistically significant correlation between percent change in sorbitol and change in CMT-HI at 12 months

Treatment with govorestat in CMT-SORD-Null rats demonstrated a highly statistically significant 37% (p=0.005) reduction of sorbitol in the sciatic nerve, the tissue of interest, after treatment with govorestat.
Reflective of the peripheral neuropathy experienced by patients with CMT-SORD.

Govorestat remains generally safe and well tolerated

Company remains committed to potential NDA submission of govorestat for treatment of CMT-SORD in 2025

NEW YORK, May 18, 2025 (GLOBE NEWSWIRE) -- Applied Therapeutics, Inc. (Nasdaq: APLT), a clinical-stage biopharmaceutical company dedicated to creating transformative treatments for rare disease, today presented full 12-month clinical results and new topline data from 18 and 24 months from the INSPIRE Phase 2/3 trial of govorestat (AT-007) for the treatment of Sorbitol Dehydrogenase (SORD) Deficiency, a subtype of Charcot-Marie-Tooth (CMT) disease, in an oral presentation at the Peripheral Nerve Society (PNS) 2025 Annual Meeting, being held May 17-20, 2025 in Edinburgh, Scotland.

CMT-SORD is a rare, progressive, neuromuscular disease caused by genetic mutations in the sorbitol dehydrogenase enzyme, which is responsible for the metabolism of sorbitol. Prior to 2020, patients were symptomatically diagnosed as having CMT Type 2 of unknown genetic cause or distal hereditary motor neuropathy. Following a whole genome sequencing initiative in 2020, CMT-SORD was identified as a subtype of CMT and there is now commercially available sorbitol testing and genetic testing specifically for CMT-SORD.

“CMT-SORD is a slowly progressing and very newly identified disease, only becoming officially recognized in 2020. 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. This is particularly evidenced with clinical trial design for CMT-SORD, for which there is no natural history data to draw from and an evolving methodology for assessing disease progression. This is exemplified by changes to the CMT-Functional Outcome Measure composite for determining clinical outcomes in CMT-SORD patients, which following the initiation of INSPIRE no longer includes the 10-meter walk-run test,” said Les Funtleyder, Interim CEO and CFO of Applied Therapeutics. Evan Bailey MD, SVP of Clinical Development added, “In the midst of a complicated clinical landscape, 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. We have also observed slowing of disease progression at 24 months through MRI scans in patients treated with govorestat. With 90% of remaining patients converting to our open-label extension study, we believe that govorestat has the potential for long-term patient benefit. We look forward to further analyzing the results from the INSPIRE trial to inform and support future potential regulatory interactions with the FDA regarding govorestat for the treatment of CMT-SORD. We want to thank the patients, their families, the investigators and their sites for their willingness and dedication to bringing this important trial forward.”

“We were pleased to see sustained positive trends in functional measures correlated with sustained sorbitol reductions observed at 18 and 24 months with significant lowering of blood sorbitol levels associated with govorestat treatment. Additionally, a significant improvement in the CMT-Health Index, which is an important patient-reported outcome, indicates how patients with CMT-SORD are feeling in their daily lives,” Michael Shy, MD, Professor of Neurology University of Iowa.

INSPIRE Phase 2/3 Trial Design

The INSPIRE Phase 2/3 trial was a randomized, double-blind, placebo-controlled trial to evaluate the effect of govorestat in patients with CMT-SORD. 56 patients with CMT-SORD were randomized 2:1 to an active, once daily govorestat treatment versus placebo. The primary clinical endpoint of INSPIRE was the 10-meter walk-run test (10MWRT) at 12 months, which is no longer included in the CMT-FOM composite score. Additional key trial objectives included the effect of govorestat treatment on the levels of blood sorbitol, the correlation of sorbitol levels with clinical outcomes and the CMT-Health Index (HI), an important patient reported outcome measure of disease severity and well-being.

Full 12-Month Clinical Results

A reverified, interim analysis of 49 patients evaluable for efficacy as of February 2024, conducted at 12 months of active treatment. Full clinical results from 12 months include:

• Statistically significant correlation between absolute reduction in sorbitol and change in the 10MWRT (p=0.031) and the CMT-FOM Lower Limb domain (10MWRT, 6MWT, Stair Climb, Dorsiflexion, Sit-to Stand) (p=0.037) were observed.
• The primary endpoint, the 10MWRT, was not statistically significant (p=0.457). Since initiation of the INSPIRE study, the 10MWRT was removed from the CMT-FOM, which now only consists of 11 components.
• Govorestat treatment demonstrated a statistically significant improvement (p=0.039) on key secondary endpoint, CMT-HI at 12 months.
• A statistically significant correlation between percent change in sorbitol and change in CMT-HI was observed at 12 months for the total score as well as in the mobility and balance domains.
  
• Statistically significant lowering of blood sorbitol levels (p <0.001) were observed.

• Govorestat continued to be generally safe and well tolerated, with similar incidence of adverse events between active and placebo-treated groups.
  
  

Topline 18-Month and 24-Month Patient Level Analyses

As of October 11, 2024, 24 patients were evaluable at 18 months and 15 patients were evaluable at 24 months for patient-level analyses of active treatment with govorestat compared to placebo prior to transition of the INSPIRE trial to an open-label extension (OLE). Topline results from analyses of patients following 18 and 24 months of continuous, active treatment with govorestat include:

• MRIs at 24 months demonstrate slowing of disease progression in patients treated with govorestat.
• Improvements in outcomes maintained through 24 months including the change in the CMT-HI observed at Month 12.
• Reduction in sorbitol maintained through 18 and 24 months.
• Govorestat remained generally safe and well tolerated through 24 months of treatment.
  
  

“For the first time in any CMT patient population, we are encouraged to see upon examination of the 24 month MRI data that govorestat slowed the progression of the disease versus the MRIs at 12 months. We look forward to continuing studies exploring this further in this long-term debilitating disease,” said Mary M. Reilly, MD, FRCP, FRCPI, Professor of Neurology, University College London Department of Neuromuscular Diseases.

“We were pleased to see upon examination of the 24 month MRI data that govorestat slowed the progression of the disease versus the MRIs at 12 months which 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 OLE portion of the INSPIRE trial commenced in September 2024. To-date, 90% of the remaining INSPIRE patients (45 out of 50) continue on govorestat treatment in the OLE study.  The Company remains committed to working with the U.S. Food and Drug Administration (FDA) to determine an appropriate regulatory pathway for a potential submission of a New Drug Application (NDA) 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 of the disease we live with every single day, but also in the meaningful ways it impacts our daily lives through patient-reported outcomes and our ability to perform everyday activities,” said Allison Moore, Founder and CEO of the Hereditary Neuropathy Foundation and 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, progressive, debilitating hereditary neuropathy that affects peripheral nerves and motor neurons. CMT-SORD is one of the most common forms of recessive hereditary neuropathy and affects approximately 3,300 patients in the U.S. and 4,000 patients in the EU. The disease is caused by a lack of the enzyme sorbitol dehydrogenase, responsible for the metabolism of sorbitol, which causes sorbitol to accumulate at high levels in blood and tissues. Intracellular sorbitol accumulation is implicated in significant disability, loss of sensory function, neuromuscular dysfunction, and decreased mobility.

About Govorestat (AT-007)

Govorestat is a central nervous system (CNS) penetrant Aldose Reductase Inhibitor (ARI) being developed for the treatment of multiple 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. Govorestat has also received Orphan Drug Designation from the U.S. Food and Drug Administration (FDA) for the treatment of Galactosemia, phosphomannomutase 2 deficiency, and CMT-SORD; Rare Pediatric Disease designation for Galactosemia and PMM2-CDG; and Fast Track designation for Galactosemia. 

About Applied Therapeutics

Applied Therapeutics is a clinical-stage biopharmaceutical company committed to the development of novel drug candidates against validated molecular targets in rare diseases. The Company’s lead drug candidate, govorestat, is a novel central nervous system 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).

To learn more, please visit www.appliedtherapeutics.com and follow the company on X at @Applied_Tx.

Forward-Looking Statements

This press release contains “forward-looking statements” that involve substantial risks and uncertainties for purposes of the safe harbor provided by the Private Securities Litigation Reform Act of 1995. Any statements, other than statements of historical fact, included in this press release regarding the strategy, future operations, prospects, plans and objectives of management, including words such as “may,” “will,” “expect,” “anticipate,” “plan,” “intend,” “predicts” and similar expressions (as well as other words or expressions referencing future events, conditions or circumstances) are forward-looking statements. These include, without limitation, statements regarding the (i) likelihood that the Company’s ongoing NDA submissions will be approved and the timing of any decision and (ii) statements related to the scheduling or timing of any potential FDA meetings, interactions or submissions. Forward-looking statements in this release involve substantial risks and uncertainties that could cause actual results to differ materially from those expressed or implied by the forward-looking statements, and we, therefore cannot assure you that our plans, intentions, expectations or strategies will be attained or achieved.

Such risks and uncertainties include, without limitation, (i) our plans to develop, market and commercialize our product candidates, (ii) the initiation, timing, progress and results of our current and future preclinical studies and clinical trials and our research and development programs, (iii) our ability to take advantage of expedited regulatory pathways for any of our product candidates, (iv) our estimates regarding expenses, future revenue, capital requirements and needs for additional financing, (v) our ability to successfully acquire or license additional product candidates on reasonable terms and advance product candidates into, and successfully complete, clinical studies, (vi) our ability to maintain and establish collaborations or obtain additional funding, (vii) our ability to obtain and timing of regulatory approval of our current and future product candidates, (viii) the anticipated indications for our product candidates, if approved, (ix) our expectations regarding the potential market size and the rate and degree of market acceptance of such product candidates, (x) our ability to fund our working capital requirements and expectations regarding the sufficiency of our capital resources, (xi) the implementation of our business model and strategic plans for our business and product candidates, (xii) our intellectual property position and the duration of our patent rights, (xiii) developments or disputes concerning our intellectual property or other proprietary rights, (xiv) our expectations regarding government and third-party payor coverage and reimbursement, (xv) our ability to compete in the markets we serve, (xvi) the impact of government laws and regulations and liabilities thereunder, (xvii) developments relating to our competitors and our industry, (xviii) our ability to achieve the anticipated benefits from the agreements entered into in connection with our partnership with Advanz Pharma and (xix) other factors that may impact our financial results. In light of the significant uncertainties in these forward-looking statements, you should not rely upon forward-looking statements as predictions of future events. Although we believe that we have a reasonable basis for each forward-looking statement contained in this press release, we cannot guarantee that the future results, levels of activity, performance or events and circumstances reflected in the forward-looking statements will be achieved or occur at all. Factors that may cause actual results to differ from those expressed or implied in the forward-looking statements in this press release are discussed in our filings with the U.S. Securities and Exchange Commission, including those described in the “Risk Factors” section contained therein. Except as otherwise required by law, we disclaim any intention or obligation to update or revise any forward-looking statements, which speak only as of the date they were made, whether as a result of new information, future events or circumstances or otherwise.

* Mandarakas MR. et al. J Neurol. 2024;102(3).

Contacts

Investors:
Julie Seidel / Andrew Vulis
(212) 600-1902 or
appliedtherapeutics@argotpartners.com

Media:
media@appliedtherapeutics.com

FAQ

What were the main results of APLT's INSPIRE Phase 2/3 trial for govorestat?

While the primary endpoint wasn't met, the trial showed statistically significant improvement in CMT-Health Index, correlation between sorbitol reduction and mobility improvements, and MRI evidence of slowed disease progression at 24 months.

Did Applied Therapeutics' govorestat meet its primary endpoint in the CMT-SORD trial?

No, the primary endpoint of 10-meter walk-run test (10MWRT) at 12 months was not statistically significant (p=0.457).

What is the regulatory timeline for APLT's govorestat?

Applied Therapeutics remains committed to submitting a New Drug Application (NDA) for govorestat to the FDA in 2025.

How many patients continued in the APLT govorestat open-label extension study?

90% of remaining patients (45 out of 50) continued treatment with govorestat in the open-label extension study.

What is CMT-SORD and when was it identified?

CMT-SORD is a rare, progressive neuromuscular disease caused by genetic mutations in the sorbitol dehydrogenase enzyme. It was officially recognized as a subtype of Charcot-Marie-Tooth disease in 2020.