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Shares in Applied Therapeutics were down as much as 10% on Monday after the company disclosed more details of a Phase III study in sorbitol dehydrogenase (SORD) deficiency revealing the extent to which its proposed treatment, govorestat (AT-007), fell short of functional endpoints.The aldose reductase inhibitor is already under priority review at the FDA as a treatment for classic galactosemia despite failing a Phase III paediatric study last year. At the time, CEO Shoshana Shendelman said the study had nevertheless demonstrated "compelling evidence" of clinical benefit. An FDA decision on that application is due on August 28, and the agency plans to convene an advisory panel to discuss the filing. Regulators in Europe have also accepted the drug for review for galactosemia.The latest study, called INSPIRE, randomised 56 patients with SORD deficiency to receive either govorestat or placebo. The condition, an autosomal recessive form of hereditary neuropathy, results when loss of SORD prevents the body from converting sorbitol to fructose, leading to high sorbitol levels accumulating in the tissues and causing nerve damage over time.At the moment, there are no FDA-approved therapies to reduce sorbitol levels in the nervous system. Govorestat works by inhibiting the conversion of glucose to sorbitol.Last month, Applied said an interim analysis of the INSPIRE study showed a significant correlation between sorbitol levels and the prespecified CMT-FOM endpoint which measures functional ability of patients with neuropathies. The composite endpoint consists of 10m walk-run test (10MWR), 4-stair climb, sit-to-stand test, 6-minute walk test (6MWT) and dorsiflexion.However, the company said at the time that there was no effect on the final primary endpoint of 10MWR at the 12-month interim readout, so the study would continue blinded through to 24 months. The company did not give any details, but Baird analysts noted that an initial read of the data looked "reviewable.""We think the initial results from the Phase III INPSIRE study look good enough to get an FDA review for a Subpart H approval," the analysts said, adding that "govorestat has repeatedly shown the ability to substantially reduce sorbitol, the only factor with bioplausability for causality."In the interim data analysis released Monday, Applied highlighted "trends" on CMT-FOM measures linked to walking ability, such as 10MWR (p=0.258), dorsiflexion (p=0.314) and 6MWT (p=0.606), although these were not significant. There was no substantial effect on stair climb or sit-to-stand test.

PDUFA target action date of August 28, 2024 MAA validated and accepted for review by EMA in December 2023 NEW YORK, Feb. 28, 2024 (GLOBE NEWSWIRE) -- Applied Therapeutics, Inc. (Nasdaq: APLT), a clinical-stage biopharmaceutical company developing a pipeline of novel drug candidates against validated molecular targets in indications of high unmet medical need, today 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 FDA also noted that it is planning to hold an advisory committee meeting to discuss the application. Govorestat was previously granted Pediatric Rare Disease designation, and will qualify for a Priority Review Voucher (PRV) upon approval. “The FDA’s acceptance of the NDA for govorestat for the treatment of Galactosemia represents a critical milestone for Applied Therapeutics and more importantly, for patients with Galactosemia and their families. The Agency’s decision to grant Priority Review for this NDA underscores the urgent unmet medical need as there are currently no treatment options for this devastating disease,” said Shoshana Shendelman, PhD, Founder and CEO of Applied Therapeutics. “We want to thank the patients, families, collaborators and physicians involved in reaching this achievement. We look forward to continuing to work with the FDA throughout the review process, as we hope to bring govorestat to patients as quickly as possible.” “We are excited to see that the FDA has accepted the govorestat NDA for priority review,” said Nicole Casale, President of the Galactosemia Foundation. “The Galactosemia community is in urgent need of a safe and effective treatment, and the potential approval of govorestat provides hope for many families. Acceptance of the govorestat NDA brings us one step closer to availability of a first-ever treatment.” Govorestat is an investigational, novel Aldose Reductase Inhibitor (ARI) being developed for the treatment of several rare diseases. It is a potent and selective compound, which crosses the blood brain barrier into the Central Nervous System (CNS). The NDA filing of govorestat is supported by rapid and sustained reduction in galactitol, which resulted in a meaningful benefit on clinical outcomes across pediatric patients, alongside a favorable safety profile. The submission package included clinical outcomes data from the Phase 3 registrational ACTION-Galactosemia Kids study in children aged 2-17 with Galactosemia, the Phase 1/2 ACTION-Galactosemia study in adult patients with Galactosemia, and preclinical data. If approved, govorestat would be the first medication indicated for the treatment of Galactosemia and would be Applied Therapeutics’ first commercial product. The FDA grants Priority Review to applications for potential medicines that, if approved, may offer significant improvements in the treatment, prevention or diagnosis of a serious condition. Govorestat for the treatment of Galactosemia has received Orphan Medicinal Product Designation from the European Medicines Agency (EMA) and Orphan Drug Designation, Pediatric Rare Disease Designation and Fast Track Designation from the FDA. The Company has also submitted a Marketing Authorization Application (MAA) for govorestat for the treatment of Classic Galactosemia to the EMA, which was validated in December 2023 and is under review by the EMA’s Committee for Medicinal Products for Human Use (CHMP). The Company expects a decision by the EMA in the fourth quarter of 2024. About Galactosemia Galactosemia is a rare genetic metabolic disease resulting in an inability to metabolize the simple sugar galactose. Galactose is found in foods, but is also produced endogenously by the body. When not metabolized properly, galactose is converted to the toxic metabolite, galactitol, which causes neurological complications, including deficiencies in speech, cognition, behavior, and motor skills, and also results in juvenile cataracts and ovarian insufficiency (in women). There are approximately 3,000 patients with Galactosemia in the US and 80 new births per year, and approximately 4,000 patients with Galactosemia in the EU and 120 new births per year. Newborn screening for Galactosemia is mandatory in the US and most EU countries, leading to rapid identification of affected patients. About Govorestat (AT-007) Govorestat is a central nervous system (CNS) penetrant Aldose Reductase Inhibitor (ARI) in development for the treatment of several rare neurological diseases, including Galactosemia, SORD Deficiency, and PMM2-CDG. In a study in children with Galactosemia aged 2-17, treatment with govorestat demonstrated clinical benefit on activities of daily living, behavioral symptoms, cognition, fine motor skills and tremor. Govorestat also significantly reduced plasma galactitol levels in both adults and children with Galactosemia. Galactitol is a toxic metabolite responsible for tissue damage and long-term complications in Galactosemia. Govorestat is also being studied in the ongoing Phase 3 INSPIRE trial, which is evaluating the effect of AT-007 vs. placebo in patients with SORD Deficiency on sorbitol reduction as well as clinical outcomes in approximately 50 patients aged 16-55 in the U.S. and Europe. In an interim analysis at 12 months, govorestat achieved statistical significance on the prespecified primary endpoint of correlation of sorbitol with the clinical outcome composite and demonstrated sustained, statistically significant reduction in sorbitol level vs. placebo. Govorestat also demonstrated highly statistically significant effects on the CMT Health Index (CMT-HI) patient reported outcome measure, with benefit of govorestat on categories of lower limb function, mobility, fatigue, pain, sensory function, and upper limb function. Govorestat has received Orphan Medicinal Product Designation from the European Medicines Agency (EMA) for both Galactosemia and SORD Deficiency. Govorestat has also received Orphan Drug Designation from the U.S. Food and Drug Administration (FDA) for the treatment of Galactosemia, PMM2-CDG, and SORD Deficiency; Pediatric Rare Disease designation for Galactosemia and PMM2-CDG; and Fast Track designation for Galactosemia. About Applied Therapeutics Applied Therapeutics is a clinical-stage biopharmaceutical company developing a pipeline of novel drug candidates against validated molecular targets in indications of high unmet medical need. 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 Galactosemia, SORD Deficiency, and PMM2-CDG. The Company is also developing AT-001, a novel potent ARI, for the treatment of Diabetic Cardiomyopathy, or DbCM, a fatal fibrosis of the heart. The preclinical pipeline also includes AT-003, an ARI designed to cross through the back of the eye when dosed orally, for the treatment of Diabetic retinopathy. To learn more, please visit www.appliedtherapeutics.com and follow the company on Twitter @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 likelihood that the NDA submission will be approved. 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 (xiv) 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 the “Risk Factors” 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. Contacts Investors:Maeve Conneighton (212) 600-1902 orappliedtherapeutics@argotpartners.com Media:media@appliedtherapeutics.com

Govorestat is forecast to generate $81m in sales in 2029, according to GlobalData. Credit: adike via Shutterstock. Applied Therapeutics has announced plans to discuss a potential new drug application (NDA) submission with the US Food and Drug Administration (FDA) after the Phase III trial (NCT05397665) investigating its sorbitol dehydrogenase (SORD) deficiency drug Govorestat (AT-007) had positive interim results. Treatment with Govorestat resulted in a statistically significant improvement on the primary endpoint at 12 months – the correlation of sorbitol with the Charcot Marie Tooth functional outcome measure (CMT-FOM), which includes a ten-metre walk-run test, four stair climb, sit-to-stand test, six-minute walk test and dorsiflexion. The Phase III INSPIRE trial enrolled 56 patients aged 16-55 years with SORD deficiency. The treatment also demonstrated significant improvements in secondary endpoints, including a statistically significant effect on the CMT health index with various aspects such as lower limb function, mobility, fatigue, pain, sensory function, and upper limb function showing improvement. Applied reported that Govorestat shows a favourable safety profile with no adverse events reported. At the 24-month mark, the ongoing INSPIRE trial will reevaluate clinical outcomes, focusing on the ten-metre walk-run test as the primary measure of clinical effectiveness. Applied is now requesting a pre-new drug application (NDA) meeting with the FDA’s neurology division for Govorestat, which has both orphan drug and fast track designations. See Also: Ultimovacs bags EMA orphan drug status for cancer vaccine Pfizer’s VELSIPITY receives EC approval for ulcerative colitis SORD deficiency is a genetic condition where the body lacks enough of the enzyme sorbitol dehydrogenase, which is needed to break down sorbitol, a sugar found in many fruits and artificial sweeteners. This deficiency can lead to symptoms such as developmental delay, intellectual disability, and seizures. Govorestat acts as an inhibitor for aldose reductase, which catalyses the reduction of galactose to galactitol. Galactosaemia is characterised by the inability of the body to convert galactose to glucose. The drug candidate acts by inhibiting aldose reductase and alleviates the disease condition. According to GlobalData’s Pharma Intelligence Center, Govorestat is forecast to generate $81m in sales in 2029. GlobalData is the parent company of Clinical Trials Arena. In the announcement accompanying the positive results, Applied chief medical officer Riccardo Perfetti said: “We look forward to meeting with regulatory agencies regarding a path to potential approval based on this data, and endeavour to bring this important treatment to patients as quickly as possible.”