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NEW YORK, April 04, 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 it will present full results from the Phase 3 ARISE-HF study evaluating AT-001 (caficrestat) in Diabetic Cardiomyopathy (DbCM) in an oral presentation at the 2024 American College of Cardiology (ACC) Annual Scientific Session to take place April 6-8, 2024 in Atlanta, Georgia. The Company announced topline results from ARISE-HF in January 2024, demonstrating a strong trend in stabilizing cardiac functional capacity with AT-001 treatment, and a statistically significant difference in cardiac functional capacity in a prespecified subgroup of patients not receiving concomitant treatment with an SGLT2 or GLP-1 while preventing clinically significant worsening. The presentation at ACC will also include important data on progression to overt heart failure and other secondary outcome measures. AT-001 treatment prevented progression to overt heart failure in patients with DbCM as compared to placebo (p=0.0285). Detailed safety data will also be presented, demonstrating that AT-001 was safe and well tolerated in a large cohort of patients, providing proof of concept that the technology has overcome the selectivity and safety issues of “old” aldose reductase inhibitors. The oral presentation at ACC will be followed by simultaneous publication of the study results in the Journal of the American College of Cardiology Journal (JACC). ACC Presentation: A Selective Aldose Reductase Inhibitor (AT-001) For the Treatment of Diabetic Cardiomyopathy: Primary Results of the Phase 3 Randomized Controlled ARISE-HF Study James L. Januzzi Jr, Javed Butler, Stefano Del Prato, Justin A. Ezekowitz, Nasrien E. Ibrahim, Carolyn S.P. Lam, Gregory D. Lewis, Thomas H. Marwick, Riccardo Perfetti, Julio Rosenstock, Scott D. Solomon, W.H. Wilson Tang, Faiez Zannad on behalf of the ARISE-HF Investigators Monday, April 8, 2024, 8:30 – 9:45 am ET, Main Tent (Hall B1) JACC Publication: Randomized Trial of a Selective Aldose Reductase Inhibitor in Patients with Diabetic Cardiomyopathy James L. Januzzi Jr, Javed Butler, Stefano Del Prato, Justin A. Ezekowitz, Nasrien E. Ibrahim, Carolyn S.P. Lam, Gregory D. Lewis, Thomas H. Marwick, Riccardo Perfetti, Julio Rosenstock, Scott D. Solomon, W.H. Wilson Tang, Faiez Zannad on behalf of the ARISE-HF Investigators Journal of the American College of Cardiology Published online April 8, 2024 About AT-001 (Caficrestat) AT-001 (caficrestat) is an investigational oral, novel, potent Aldose Reductase inhibitor in Phase 3 clinical development for the treatment of Diabetic Cardiomyopathy. The global ARISE-HF Phase 3 study evaluated the ability of AT-001 to improve or prevent worsening of disease, as measured by changes in cardiac functional capacity, in 675 patients with DbCM at high risk of progression to overt heart failure. The study demonstrated a positive impact of AT-001 treatment, which was statistically significant in a prespecified subgroup of patients not on concomitant treatment with an SGLT2 or GLP-1 inhibitor. AT-001 has been previously studied in a Phase 1/2 study in approximately 120 patients with type 2 diabetes, a subset of which had DbCM. 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. 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 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

Applied Therapeutics shared news of the FDA delay after market close on Thursday, sending the company’s stock down 14% after hours. Even after a failed phase 3 pediatric clinical trial, Applied Therapeutics forged ahead with an FDA filing for potential market approval. Now the regulatory agency has extended the review period for the rare disease prospect, pushing back a possible decision date into November and sending the biotech’s stock tumbling. The drug at question is govorestat, an aldose reductase inhibitor designed to treat classic galactosemia, an inherited metabolic disorder. In February, the FDA accepted the investigational drug for review, granting priority review, with a decision slated for Aug. 28. Now, the agency has moved that date back three months to Nov. 28, according to a March 28 release. The FDA told Applied that more time was needed to examine supplemental analyses of already submitted data and determined that the additional info constitutes a major amendment to the new drug application, according to the release. Applied shared news of the delay after market close on Thursday, sending the company’s stock down 14% after hours, dropping from $6.80 per share at close to $5.80 as of 7:57 p.m. ET, March 28. “While the PDUFA action date extension represents a delay, we remain confident in the potential for govorestat approval for galactosemia and we will continue to work closely with the FDA throughout the review process,” Applied founder and CEO Shoshana Shendelman, Ph.D., said in the release. “During this time, we are committed to maintaining the expanded access program for govorestat to ensure patients with galactosemia have the opportunity to receive this important treatment.” Last April, the biotech shared phase 3 results assessing the asset, which is the company’s lead pipeline program. The study found that govorestat was no better than placebo at improving a composite of four measures—including language skills, self-care capabilities and more—among children with galactosemia.   Despite the failure, the New York-based biotech argued that the data show “consistent and sustained clinical benefit on activities of daily living, behavioral symptoms, cognition, adaptive behavior and tremor,” and filed a new drug application with the FDA. Initially, Applied had planned to ask for U.S. approval on the strength of biomarker data, only for the FDA to say it would likely need evidence the drug candidate improves clinical outcomes to receive a positive decision. The phase 3 trial gave Applied evidence of the effect of govorestat, also known as AT-007, on clinical outcomes.   This isn’t the first of the company’s troubles with the drug. Back in August 2020, the FDA placed a partial clinical hold on the late-stage govorestat program, requesting more technical information to ensure patients had "access to the prospect of direct benefit of the drug." If approved, govorestat would become the first medication for treating galactosemia. The candidate has snagged orphan drug designation, fast track status and pediatric rare disease designation from the FDA in the indication.  Applied is also assessing govorestat as a potential treatment for two other rare neurological diseases: SORD Deficiency and PMM2-CDG.

Pictured: Facade of the FDA's office in Maryland/iStock, Grandbrothers Applied Therapeutics on Thursday announced that the FDA is extending the review period for its investigational aldose reductase inhibitor govorestat for the treatment of classic galactosemia. The biotech now expects a verdict by Nov. 28, 2024. The FDA will need more time to review supplemental analyses and data that Applied Therapeutics provided in response to the regulator’s routine information requests, which the FDA considered a major amendment to govorestat’s New Drug Application (NDA), according to the company. Shoshana Shendelman, founder and CEO of Applied Therapeutics, said in a statement that despite the delay the company remains “confident in the potential for govorestat approval for galactosemia and we will continue to work closely with the FDA throughout the review process.” Classic galactosemia is a rare and genetic metabolic disease characterized by the inability to properly metabolize galactose. Patients with galactosemia have a surplus of the toxic metabolite galactitol, which accumulates in tissues and organs, leading to neurological problems, such as speech, cognitive, behavior and motor deficiencies. In galactosemia, the aldose reductase enzyme is responsible for converting galactose into galactitol, according to Applied Therapeutics’ website. The biotech’s potential solution to this pathway is govorestat, a novel and selective aldose reductase inhibitor that has been designed to be able to cross the blood-brain barrier and penetrate into the central nervous system. Applied Therapeutics is supporting govorestat’s NDA—which the FDA accepted and granted Priority Review in February 2024—with data from the Phase I/II ACTION-Galactosemia and Phase III ACTION-Galactosemia Kids trials, alongside preclinical studies. ACTION-Galactosemia demonstrated that govorestat was safe to use in adult patients and elicited a reduction in galactitol levels. Govorestat’s action was rapid and its effects were apparent starting from the first day of treatment and was sustained over one month, according to the results. Govorestat also did not induce an increase in concentrations of galactose and other galactose metabolites. In ACTION-Galactosemia Kids, which enrolled more than 47 pediatric patients, govorestat treatment led to clinical benefits in terms of activities of daily living, behavioral symptoms, cognition and tremors. The original target action date for govorestat was Aug. 28, 2024, and the FDA has indicated that it plans to convene an advisory committee to discuss Applied Therapeutics’ data package. If approved, govorestat would become the first authorized therapy for galactosemia—and it would be Applied Therapeutics’ first commercial product. Tristan Manalac is an independent science writer based in Metro Manila, Philippines. Reach out to him on LinkedIn or email him at tristan@tristanmanalac.com or tristan.manalac@biospace.com.