Hereditary Sensory and Autonomic Neuropathies

Interim primary endpoint met; Statistically significant correlation of sorbitol with the CMT-FOM clinical outcome composite (p=0.05) Sustained, statistically significant reduction in sorbitol in govorestat-treated patients vs. placebo (p<0.001) Highly statistically significant effects on the CMT Health Index (CMT-HI) patient reported outcome measure (p=0.01), with benefit of govorestat on categories of lower limb function, mobility, fatigue, pain, sensory function, and upper limb function Company plans to request a pre-NDA meeting with the neurology division of the US FDA regarding potential approval based on current data Company to host investor conference call and webcast today at 8:30 a.m. ET NEW YORK, Feb. 15, 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 positive interim 12-month results from the ongoing Phase 3 INSPIRE trial, in which the primary endpoints and several key secondary endpoints were achieved. The INSPIRE trial is a Phase 3 double-blind placebo-controlled registrational study evaluating the effect of once-daily (QD) oral govorestat (AT-007) in 56 patients aged 16-55 with SORD Deficiency in the US and Europe. SORD Deficiency is a debilitating, hereditary axonal neuropathy caused by mutations in the Sorbitol Dehydrogenase gene, leading to an inability to metabolize the sugar sorbitol and resulting in accumulation of high levels of toxic sorbitol, which causes motor neuron degeneration and loss of mobility and motility. Govorestat is a central nervous system penetrant Aldose Reductase Inhibitor, which blocks the conversion of glucose to sorbitol, and has previously been shown to reduce sorbitol levels in patients with SORD Deficiency. The objective of this pre-specified, 12-month interim analysis was to evaluate early indicators of govorestat treatment effect in order to inform future regulatory discussions and support a potential New Drug Application (NDA) submission, due to the urgent need for treatment and absence of any other options for patients with SORD Deficiency. The 12-month interim analysis was comprised of a clinical efficacy primary endpoint based on correlation of sorbitol with composite clinical outcome measures, and a pharmacodynamic (PD) biomarker primary endpoint based on sorbitol reduction. Interim Analysis Results: Demonstrated statistically significant correlation between sorbitol level and the prespecified CMT-FOM composite clinical endpoint (10-meter walk-run test, 4 stair climb, sit to stand test,6-minute walk test and dorsiflexion) (p=0.05). Govorestat treatment provided sustained reduction in sorbitol level in patients with SORD Deficiency over 12 months of treatment, which was statistically significant compared to placebo (p<0.001). Govorestat treatment also resulted in a highly statistically significant effect (p=0.01) on the CMT Health Index (CMT-HI), an important patient-reported outcome measure of disease severity and well-being, which was a secondary endpoint in the study. Aspects of the CMT-HI that demonstrated a treatment effect included lower limb function, mobility, fatigue, pain, sensory function, and upper limb function. Govorestat was safe and well tolerated, with similar incidence of adverse events between active and placebo-treated groups. We believe the results from the 12-month interim analysis confirm the role of sorbitol as a key driver of disease severity and progression over time. Clinical outcomes of the ongoing INSPIRE trial are expected to be assessed again at 24 months, where the 10-meter walk run test serves as the primary clinical efficacy endpoint. The Company plans to discuss a potential NDA submission with the U.S. Food and Drug Administration (FDA) based on the clinical data to date. “Our commitment to bringing first of their kind therapies to rare disease indications with no existing treatment options is at the core of our work,” said Shoshana Shendelman, PhD, Founder and CEO of Applied Therapeutics. “We are excited by the prospect of providing patients with SORD Deficiency with a treatment option that has the potential to slow disease progression and the consistent benefit demonstrated by govorestat.” “We are thrilled by the results of this 12-month interim analysis, which demonstrate govorestat’s effectiveness in reducing sorbitol levels and improving key functional measures and patient reported outcomes in SORD Deficiency, including lower limb function, upper limb function, fatigue and pain,” said Riccardo Perfetti, MD, PhD, Chief Medical Officer of Applied Therapeutics. “We look forward to meeting with regulatory agencies regarding a path to potential approval based on this data, and endeavor to bring this important treatment to patients as quickly as possible.” “As a neurologist and neuromuscular specialist, I am delighted to see such strong results from just 12 months of treatment with govorestat for this debilitating disease with no existing treatment options available,” said Michael Shy, MD, Director of the Division of Neuromuscular Medicine at Carver College of Medicine, University of Iowa Medical Center, and Principal Investigator on the INSPIRE Phase 3 trial. “The results from this interim analysis have exceeded my expectations, with a statistically significant impact on how patients feel and function, as measured by the CMT-HI patient reported outcome measure. The ability to reduce sorbitol levels, which we believe to be the pathogenic cause of damage in these patients, coupled with standardized metrics of patient function and well-being are strong indicators of treatment benefit.” Conference Call Information Applied Therapeutics will host a conference call and webcast on Thursday, February 15, 2024, at 8:30 a.m. ET to discuss the interim analysis of govorestat for the treatment of SORD Deficiency. To access the conference call, please dial +1(844) 481-2912 (local) or +1(412) 317-0695 (international) at least 10 minutes prior to the start of the call and ask to be joined into the Applied Therapeutics call. A live webcast of the call will be accessible on the Events Page under the Investor Relations section of the Applied Therapeutics website at . A replay of the webcast will be available for 90 days on the Investors section of Applied Therapeutics’ website. About Sorbitol Dehydrogenase (SORD) Deficiency Sorbitol Dehydrogenase Deficiency (SORD Deficiency) is a rare, progressive, debilitating hereditary neuropathy that affects peripheral nerves and motor neurons. SORD Deficiency 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 Europe. 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 and become toxic to the body. Intracellular sorbitol accumulation results 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) in development for the treatment of several rare neurological diseases, including Galactosemia, SORD Deficiency, and PMM2-CDG. 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 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 (i) the Company’s plans to request pre-NDA meeting with the neurology division of the FDA regarding potential approval based on the clinical data to date and (ii) the timing of assessment of clinical outcomes of the INSPIRE trial any potential submission. 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 or appliedtherapeutics@argotpartners.com Media: media@appliedtherapeutics.com

NEW YORK--( BUSINESS WIRE )-- RTW Charitable Foundation (“RTWCF”) announced today that it has awarded $900,000 in research grants to support six research studies. These studies aim to drive transformational progress in genetic therapies and align with RTWCF’s mission to power community initiatives and scientific research to improve the health of underserved communities. Grant Recipients The following studies and researchers each received $150,000 research grants from RTWCF: “ Establishing gene replacement therapy for NEDAMSS, an ultra-rare neurological disorder caused by mutations in the IRF2BPL gene” (Kathrin Meyer, Nationwide Children’s Hospital, Columbus, OH). “ Optimizing AAV-SPL gene therapy for sphingosine phosphate lyase insufficiency syndrome” (Julie Saba, University of California, San Francisco, San Francisco, CA). “Gene therapy for SURF1-related Leigh Syndrome” (Steven Gray, The University of Texas Southwestern, Dallas, TX). “ Safety and toxicity assessment of AAV-based gene therapy for creatine transporter deficiency” (Jagdeep Walia, Queen’s University, Kingston, Ontario, Canada). “Advanced therapeutics for SELENON-related myopathy” (Alan Beggs, Boston Children’s Hospital, Boston, MA). “ Preclinical studies of ASO therapy for SPTLC1-related hereditary sensory neuropathy” (Haiyan Zhou, University College London, London, UK). “ Despite considerable advancements in gene and cell therapies that deliver more targeted and effective treatments for rare diseases, a significant amount of additional research is still required to move these advances out of the lab and safely to patients,” said Juan Carlos López, PhD, Managing Director, Research Grants, RTW Charitable Foundation. “ RTW Charitable Foundation is proud to provide financial and scientific support to these six incredible researchers and their respective studies. We believe that each of these studies will help expedite the development of gene therapies for rare and ultrarare diseases, and greatly improve the lives of individuals with unmet medical needs.” Grant Recipient Commentary Julie Saba, MD, PhD, commented : “ I am honored and grateful to receive this award from RTWCF, which will support studies to optimize gene therapy for sphingosine phosphate lyase insufficiency syndrome. This newly recognized inborn error of metabolism leads to kidney failure in most of the affected children, causing more than half of them to die in their first years of life. While kidney transplantation can be lifesaving, it is invasive, costly, unavailable to many, and does not address the many other serious consequences of the disorder. Gene therapy offers a potentially lifesaving alternative treatment. The studies undertaken with RTWCF funding should improve our gene therapy potency, allowing us to advance to toxicology studies and clinical trials. I appreciate RTWCF’s dedication to advancing research in ultrarare diseases, which are overwhelmingly underfunded. Every child deserves personalized therapy!” Alan Beggs, PhD, commented: “ Our group has studied a neuromuscular condition called Multiminicore Disease or Rigid Spine Muscular Dystrophy for many years to understand how mutations of a gene called SELENON lead to weakness. We are now on the cusp of translating our laboratory experiments into a treatment that can be tested in patients. I’m thrilled that support from the RTWCF is helping us to work towards developing a next-generation gene therapy candidate designed for eventual testing in a clinical trial.” Haiyan Zhou, MD, PhD, commented: “ We are extremely grateful for the generous award from RTWCF. This grant serves as a vital catalyst in advancing our groundbreaking work on a novel nucleic acid therapy designed for an ultrarare neurodegenerative condition, currently devoid of effective treatment options. The crucial support from RTWCF will propel the preclinical development and hasten the clinical translation of this experimental therapy. Moreover, this award will play a pivotal role in elevating the impact of our translational genetic therapy program at the Great Ormond Street Institute of Child Health and NIHR GOSH Biomedical Research Centre. It also contributes to the growth of the UK platform for nucleic acid therapy in rare diseases.” To date, RTWCF has awarded over 20 research grants, totaling over $3 million in funding. In addition to delivering financial resources, RTWCF also provides grant recipients with hands-on scientific support, helping them improve or further develop their research and research tools and identify new therapeutic targets. About RTW Charitable Foundation Founded in 2018 as the charitable foundation arm of RTW Investments, LP, RTW Charitable Foundation works to power community initiatives and scientific research to improve the health of underserved communities. The Foundation is able to provide capital, manpower, and logistical support to help scientists push such projects forward. In addition, the Foundation aims to assist in advocacy, disease awareness and directly support organizations and communities in New York City. To learn more, visit www.rtwcf.org .

BRUSSELS, Belgium I July 18, 2023 I UCB, a global biopharmaceutical company, today announced that the European Medicines Agency (EMA) has accepted for review the marketing authorization application for bimekizumab, an IL-17A and IL-17F inhibitor, for the treatment of adults with moderate to severe hidradenitis suppurativa (HS). “This EU regulatory submission for bimekizumab reflects our pursuit to address unmet patient needs and to advance standards of care in hidradenitis suppurativa, especially given that few treatment options are available today. If approved, this would represent the fourth indication for bimekizumab in the European Union across a range of IL-17 mediated diseases,” said Emmanuel Caeymaex, Executive Vice President, Immunology Solutions and Head of U.S., UCB. The application for HS is supported by data from the Phase 3 BE HEARD I and BE HEARD II studies which were previously communicated . 1 In both studies, bimekizumab demonstrated statistically significant and clinically meaningful improvements over placebo in signs and symptoms of HS at week 16, as measured by HiSCR50, the primary endpoint in the two studies, with maintained response to Week 48. 1* Patients treated with bimekizumab also achieved deep levels of clinical response with a greater proportion achieving HiSCR75, a key secondary endpoint, at week 16 than placebo. 1 The safety profile of bimekizumab across BE HEARD I and BE HEARD II was consistent with previous bimekizumab studies with no new safety signals observed. 1 In August 2021, bimekizumab▼ first received marketing authorization in countries of the European Union (EU)/European Economic Area (EEA) for the treatment of moderate to severe plaque psoriasis in adults who are candidates for systemic therapy. 2 In June 2023, bimekizumab was approved in countries of the EU/EEA for the treatment of adults with active psoriatic arthritis, and for the treatment of adults with active axial spondyloarthritis (axSpA), including non-radiographic axSpA and ankylosing spondylitis, also known as radiographic axSpA. 2 The safety and efficacy of bimekizumab in HS have not been established, and it is not approved for use in HS by any regulatory authority worldwide. Notes to editors: *p=0.006 and p=0.003 for BE HEARD I and BE HEARD II, respectively with bimekizumab every two weeks (Q2W); p=0.030 and p=0.004 for BE HEARD I and BE HEARD II, respectively with bimekizumab every four weeks (Q4W). About Hidradenitis Suppurativa (HS) Hidradenitis suppurativa (HS) is a chronic, recurring, painful, and debilitating inflammatory skin disease, that is associated with systemic manifestations. 3,4 The main symptoms are nodules, abscesses, and pus-discharging fistulas (channels leading out of the skin) which typically occur in the armpits, groin and buttocks. 3,4 People with HS experience flare-ups of the disease as well as severe pain, which can have a major impact on quality of life. 3,4 HS develops in early adulthood, affects approximately one percent of the population in most studied countries. 3,4 Approximately one third of people with HS have a family history of HS, and lifestyle factors such as smoking and obesity can also play a crucial role in the clinical course of HS. 5 The symptoms of pain, discharge and scarring are not only a physical burden. People with HS also experience stigma: worrying about or directly experiencing negative attitudes and reactions from society in response to their symptoms. 6 These feelings can lead to embarrassment, social isolation, low self-esteem and sexual life impairment, and impact all areas of life, including interpersonal relationships, education and work. 3,5 About BE HEARD I and BE HEARD II BE HEARD I is a randomized, double-blind, placebo-controlled, parallel group, multicenter, Phase 3 study designed to evaluate the efficacy and safety of bimekizumab in adults with moderate to severe hidradenitis suppurativa (HS). 7 BE HEARD II is a randomized, double-blind, placebo-controlled, parallel group, multicenter, Phase 3 study designed to evaluate the efficacy and safety of bimekizumab in adults with moderate to severe HS. 8 The two studies had a combined enrolment of 1,014 participants with a diagnosis of moderate to severe HS. 7,8 The primary endpoint in both studies was HiSCR50 at week 16. 8 A key secondary endpoint was HiSCR75 at week 16. HiSCR50 and HiSCR75 are defined as at least either a 50 or 75 percent reduction from baseline in the total abscess and inflammatory nodule count, with no increase from baseline in abscess or draining tunnel count. 7,8 The two studies evaluated two dose regimens of bimekizumab (320 mg every two weeks [Q2W] and 320 mg every four weeks [Q4W]) versus placebo over the 16-week initial and the 32-week maintenance treatment periods. 7,8 About bimekizumab Bimekizumab is a humanized monoclonal IgG1 antibody that is designed to selectively inhibit both interleukin 17A (IL-17A) and interleukin 17F (IL-17F), two key cytokines driving inflammatory processes. 9 The therapeutic indications in the European Union are: BIMZELX ® ▼ (bimekizumab) EU/EEA* Important Safety Information The most frequently reported adverse reactions with bimekizumab were upper respiratory tract infections (14.5%, 14.6%, 16.3% in plaque psoriasis (PSO), psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA), respectively) and oral candidiasis (7.3%, 2.3%, 3.7% in PSO, PsA and axSpA, respectively). Common adverse reactions (≥1/100 to <1/10) were oral candidiasis, tinea infections, ear infections, herpes simplex infections, oropharyngeal candidiasis, gastroenteritis, folliculitis, headache, rash, dermatitis and eczema, acne, injection site reactions, fatigue. Elderly may be more likely to experience certain adverse reactions such as oral candidiasis, dermatitis and eczema when using bimekizumab. Bimekizumab is contraindicated in patients with hypersensitivity to the active substance or any of the excipients and in patients with clinically important active infections (e.g. active tuberculosis). Bimekizumab may increase the risk of infections. Treatment with bimekizumab must not be initiated in patients with any clinically important active infection. Patients treated with bimekizumab should be instructed to seek medical advice if signs or symptoms suggestive of an infection occur. If a patient develops an infection the patient should be carefully monitored. If the infection becomes serious or is not responding to standard therapy, treatment should be discontinued until the infection resolves. Prior to initiating treatment with bimekizumab, patients should be evaluated for tuberculosis (TB) infection. Bimekizumab should not be given in patients with active TB. Patients receiving bimekizumab should be monitored for signs and symptoms of active TB. Cases of new or exacerbations of inflammatory bowel disease have been reported with bimekizumab. Bimekizumab is not recommended in patients with inflammatory bowel disease. If a patient develops signs and symptoms of inflammatory bowel disease or experiences an exacerbation of pre-existing inflammatory bowel disease, bimekizumab should be discontinued and appropriate medical management should be initiated. Serious hypersensitivity reactions including anaphylactic reactions have been observed with IL-17 inhibitors. If a serious hypersensitivity reaction occurs, administration of bimekizumab should be discontinued immediately and appropriate therapy initiated. Live vaccines should not be given in patients treated with bimekizumab. Please consult the summary of product characteristics in relation to other side effects, full safety and prescribing information. European SmPC date of revision: June 2023. http://www.ema.europa.eu/en/documents/product-information/bimzelx-epar-product-information_en.pdf *EU/EEA means European Union/European Economic Area ▼ This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. For further information, contact UCB: Investor Relations Antje Witte T +32.2.559.94.14 email This email address is being protected from spambots. You need JavaScript enabled to view it. // Corporate Communications Laurent Schots T +32.2.559.92.64 email This email address is being protected from spambots. You need JavaScript enabled to view it. // Brand Communications Eimear O’Brien T +32.2.559.92.71 email This email address is being protected from spambots. You need JavaScript enabled to view it. // About UCB UCB, Brussels, Belgium (www.ucb.com) is a global biopharmaceutical company focused on the discovery and development of innovative medicines and solutions to transform the lives of people living with severe diseases of the immune system or of the central nervous system. With approximately 8,700 people in approximately 40 countries, the company generated revenue of €5.5 billion in 2022 UCB is listed on Euronext Brussels (symbol: UCB). Follow us on Twitter: @UCB_news. References SOURCE: UCB