Myocardial fibrosis

Five years after receiving the experimental Fabry disease gene therapy AVR-RD-01, kidney function in all five participants remains relatively stable, according to the final results of the Canadian FACTs study, which tested the treatment candidate in men with the condition.All five patients had significant and sustained increases in blood alpha-Gal A activity, an enzyme deficient in people with Fabry. At the same time, four of the patients showed a marked drop in blood lyso-Gb3, a biomarker that reflects alpha-Gal A activity.The team of North American researchers noted that alpha-gal A activity “was observed at day 6-8 in each patient following infusion [of the gene therapy] and has remained durable for 5+ years,” with “all 5 patients … eligible to come off biweekly enzyme therapy.” Three of the men did stop enzyme treatment, the researchers noted.With these results, “we demonstrate that this therapeutic approach has merit, is durable, and should be explored in a larger clinical trial,” the team wrote.The study, “Lentivirus-mediated gene therapy for Fabry disease: 5-year End-of-Study results from the Canadian FACTs trial,” was published in the journal Clinical and Translational Medicine.In Fabry disease, mutations in the GLA gene result in a lack of functional alpha-galactosidase, or alpha-Gal A, an enzyme needed to break down the fatty compound globotriaosylceramide, known as Gb3. This enzymatic defect leads to the accumulation of Gb3 in the blood and cells, causing damage to various tissues and organs, especially the kidneys and heart.AVR-RD-01 is a one-time gene therapy designed to deliver a working copy of the GLA gene to a patient’s hematopoietic stem cells, or HSCs, which give rise to different types of blood cells. Treatment involves harvesting HSCs from a patient and exposing them to the viral vector used to carry the functional GLA gene. After a procedure to eliminate existing bone marrow cells, the modified stem cells are returned to the same patient via a transplant.Canadian FACTs was a five-year Phase 1 trial (NCT02800070) that tested the gene therapy in five men, ages 29-48, with classic Fabry. All of the participants had been previously treated with enzyme replacement therapy (ERT), used to manage Fabry.Interim results reported in 2021 showed that alpha-Gal A rose to near-normal levels within a week of receiving AVR-RD-01. Although enzyme activity decreased over time, almost three years later, such activity remained above levels typically found in Fabry patients. In 2024, a follow-up analysis showed sustained reductions in Gb3 and lyso-Gb3 in treated patients.Meanwhile, the FAB-GT Phase 1/2 open-label trial (NCT03454893) was launched to evaluate AVR-RD-01 in males with Fabry, ages 16-50, who had not received previous treatment. However, some patients showed unexpected drops in alpha-Gal A activity and signs that the modified stem cells were not growing in the bone marrow as expected.Given these findings, Avrobio, the developer of AVR-RD-01, deprioritized its Fabry program in early 2022, and enrollment in the FAB-GT trial was stopped.In this report, Canadian FACTs investigators presented the final results of the study, focusing on years one through five, as earlier time points already were reported.The data showed that blood levels of alpha-Gal A significantly increased in all five patients up to five years after their stem cell transplant. Still, those levels remained below the normal range in all patients except for one, who had sustained normal levels. Enzyme activity levels in white blood cells followed a similar pattern.Throughout the study, blood Gb3 levels dropped in all patients, remaining in the normal range at year five. While all participants were eligible to do so, three chose to stop ERT during the trial.The researchers noted that pausing ERT in those three participants had saved the Canadian public health care system about $5 million at the time of the last patient visit. Moreover, ERT cost savings continue to increase as all five patients are involved in a 15-year follow-up.Blood lyso-Gb3, a recognized metabolite of interest in Fabry that correlates with disease outcomes, significantly decreased in four patients. Half had stopped ERT, and half had continued. The fifth patient, who had also stopped ERT, had a small but significant increase in lyso-Gb3.Kidney function remained relatively stable for up to five years in all patients, as measured by the estimated glomerular filtration rate (eGFR), which measures how well the kidneys work.Three patients’ kidney function slightly decreased throughout the study, but their eGFR values remained normal. One patient with mild kidney disease at the time of transplant maintained kidney function without eGFR decline, while another who started with moderate kidney disease experienced a more rapid and variable decline.All patients showed slightly increasing levels of troponin, a biomarker of heart muscle inflammation. Three patients, two of whom remained on ERT, had a short-term increase in the left ventricular mass index, a measure of the heart’s left ventricle mass, which resolved at five years. No signs of heart fibrosis, or scarring, were seen in any evaluable patient, and all blood pressures were in the normal range.Although antibodies against alpha-Gal A increased in three patients after the transplant, all remained at or near pretreatment levels beyond 18 months, or 1.5 years.Two adverse events occurring during the treatment phase were previously reported: One patient experienced fever with a low white blood cell count, known as febrile neutropenia, and another had a catheter-related infection. Since then, one patient experienced a moderate incident of vomiting and another of wheezing/asthma.“Treating patients with [HSCs] engineered to express [alpha-Gal A] continues to be a safe therapy for Fabry disease patients,” the researchers wrote.The team noted that FACTs was designed as a safety study.“Future clinical trials in this area would aim to expand the patient cohort examined in this study as well as include female Fabry disease patients and younger male [patients],” the team wrote, adding that “the fact that all five treated patients responded positively to the gene therapy bodes well for outcomes in a larger study.”

- NDA and MAA for govorestat for treatment of Classic Galactosemia under FDA Priority Review and EMA review; PDUFA target action date of November 28, 2024, and EMA decision expected in Q1 2025 - NDA submission for govorestat for the treatment of SORD Deficiency under Accelerated Approval expected in early Q1 2025 NEW YORK, Nov. 07, 2024 (GLOBE NEWSWIRE) -- Applied Therapeutics, Inc. (Nasdaq: APLT) (the “Company”), a clinical-stage biopharmaceutical company developing a pipeline of novel drug candidates against validated molecular targets in indications of high unmet medical need, today reported financial results for the third quarter ended September 30, 2024. “We are proud of the significant progress we’ve made this quarter as we prepare for a transformational year ahead, with a focus on transitioning from a clinical-stage company to a commercial organization. With regulatory submissions for govorestat underway in two rare disease indications of urgent unmet need, Classic Galactosemia and SORD Deficiency, we continue to thoughtfully execute our pre-launch initiatives,” said Shoshana Shendelman, PhD, Founder and CEO of Applied Therapeutics. “As we approach the final stages of the NDA review process for Classic Galactosemia in parallel with a near-term NDA submission for SORD Deficiency, we remain confident in the promise of govorestat and its ability to address the underlying mechanisms of both diseases. We look forward to the opportunity to bring govorestat to patients in 2025.” Recent Highlights NDA Review of Govorestat for the Treatment of Classic Galactosemia Ongoing with PDUFA Target Action Date of November 28, 2024; MAA under CHMP Review by EMA. The New Drug Application (NDA) review of govorestat for the treatment of Classic Galactosemia remains ongoing within the U.S. Food and Drug Administration (FDA)’s Division of Rare Diseases and Medical Genetics with a Prescription Drug User Fee Act (PDUFA) target action date of November 28, 2024. Govorestat was previously granted Pediatric Rare Disease designation and will qualify for a Priority Review Voucher (PRV) upon approval. The Company has also submitted a Marketing Authorization Application (MAA) for govorestat for the treatment of Classic Galactosemia to the European Medicines Agency (EMA), which was validated in December 2023 and remains under review by the EMA’s Committee for Medicinal Products for Human Use (CHMP). The review remains within the Day 120 clock stop period and the Company expects a decision by the EMA early in the first quarter of 2025. The NDA and MAA submission packages are 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 packages include 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.NDA Submission Under Accelerated Approval for Govorestat for the Treatment of SORD Deficiency Anticipated in Early Q1 2025. Following a Type C meeting with the Neurology I Division of the FDA to align on the regulatory path forward for govorestat for the treatment of SORD Deficiency, the Company expects to submit an NDA early in the first quarter of 2025. The review and potential approval of govorestat for the treatment of SORD is independent of the ongoing review of govorestat for Classic Galactosemia. If govorestat is approved for the treatment of Classic Galactosemia, the regulatory submission for the treatment of SORD will be submitted as a supplementary New Drug Application (sNDA). Patients in the Phase 3 INSPIRE study have been transitioned to open-label govorestat treatment and will be followed for additional safety data generation. Highlighted Clinical Data and Development Characterization of Govorestat for the Treatment of Classic Galactosemia at Medical Conferences. In the third and fourth quarters of 2024, the Company presented at the 2024 Annual Symposium of the Society for the Study of Inborn Errors of Metabolism (SSIEM) and the American Society of Human Genetics (ASHG) Annual Meeting 2024. The presentations highlighted the mechanism of disease pathogenesis for Classic Galactosemia, the design of the first clinical outcomes study in Classic Galactosemia and the results of the ACTION-Galactosemia Kids study. Financial Results Cash and cash equivalents and short-term investments totaled $98.9 million as of September 30, 2024, compared with $49.9 million at December 31, 2023.Research and development expenses for the three months ended September 30, 2024, were $14.8 million, compared to $10.8 million for the three months ended September 30, 2023. The increase of approximately $4.0 million was primarily related to an increase in clinical, pre-clinical and regulatory expense related to govorestat, an increase in drug manufacturing and formulation costs related to the release of legacy accruals in prior year that did occur in current year, and an overall increase in personnel and stock-based compensation expenses.General and administrative expenses were $15.0 million for the three months ended September 30, 2024, compared to $4.7 million for the three months ended September 30, 2023. The increase of approximately $10.3 million was primarily related to an increase in legal and professional fees of $1.7 million, an increase in commercial expenses to support planned commercialization of govorestat of $6.8 million, an increase in personnel and stock-based compensation expenses of $1.4 million due to increased headcount, and an increase in other miscellaneous expense of $0.5 million due to an overall increase in data storage costs to support planned commercialization, offset by a decrease in insurance expenses.Net loss for the third quarter of 2024 was $68.6 million, or $0.48 per basic and diluted common share, compared to a net loss of $42.4 million, or $0.47 per basic and diluted common share, for the third quarter 2023. 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 (i) likelihood that the Company’s ongoing NDA and MMA submissions will be approved and the timing of any decision and (ii) statements related to the scheduling or timing of any potential FDA or EMA 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 (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:Julie Seidel/Andrew Vulis646-970-0543appliedtherapeutics@argotpartners.com Media:media@appliedtherapeutics.com Applied Therapeutics, Inc.Condensed Balance Sheets(in thousands, except share and per share data)(Unaudited) As of As of September 30, December 31, 2024 2023 ASSETS CURRENT ASSETS: Cash and cash equivalents $98,867 $49,898 Security deposits and leasehold improvements 253 254 Prepaid expenses and other current assets 5,483 4,234 Total current assets 104,603 54,386 Operating lease right-of-use asset 1,963 447 TOTAL ASSETS $106,566 $54,833 LIABILITIES AND STOCKHOLDERS’ EQUITY/(DEFICIT) CURRENT LIABILITIES: Current portion of operating lease liabilities $264 $429 Accounts payable 2,837 1,742 Accrued expenses and other current liabilities 13,489 15,286 Warrant liabilities 82,377 53,725 Total current liabilities 98,967 71,182 NONCURRENT LIABILITIES: Noncurrent portion of operating lease liabilities 1,707 38 Clinical holdback - long-term portion — 759 Total noncurrent liabilities 1,707 797 Total liabilities 100,674 71,979 STOCKHOLDERS’ EQUITY/(DEFICIT): Common stock, $0.0001 par value; 250,000,000 shares authorized as of September 30, 2024 and 200,000,000 shares authorized as of December 31, 2023; 116,356,474 shares issued and outstanding as of September 30, 2024 and 84,869,832 shares issued and outstanding as of December 31, 2023 11 8 Preferred stock, par value $0.0001; 10,000,000 shares authorized as of September 30, 2024 and December 31, 2023; 0 shares issued and outstanding as of September 30, 2024 and December 31, 2023 — — Additional paid-in capital 624,098 451,432 Accumulated deficit (618,217) (468,586)Total stockholders' equity/(deficit) 5,892 (17,146)TOTAL LIABILITIES AND STOCKHOLDERS’ EQUITY/(DEFICIT) $106,566 $54,833 Applied Therapeutics, Inc.Condensed Statements of Operations(in thousands, except share and per share data)(Unaudited) Three Months Ended Nine Months Ended September 30, September 30, 2024 2023 2024 2023 REVENUE: License revenue $— $— $— $10,660 Research and development services revenue 122 — 455 — Total revenue 122 — 455 10,660 COSTS AND EXPENSES: Research and development 14,828 10,785 37,049 38,602 General and administrative 15,037 4,710 34,683 15,585 Total costs and expenses 29,865 15,495 71,732 54,187 LOSS FROM OPERATIONS (29,743) (15,495) (71,277) (43,527)OTHER (EXPENSE) INCOME, NET: Interest income 1,357 392 2,572 1,020 Change in fair value of warrant liabilities (40,184) (27,277) (80,845) (39,611)Other (expense) income, net (21) 10 (81) 34 Total other expense, net (38,848) (26,875) (78,354) (38,557)Net loss $(68,591) $(42,370) $(149,631) $(82,084)Net loss per share attributable to common stockholders $(0.48) $(0.47) $(1.09) $(1.09)Weighted-average common stock outstanding 144,345,781 90,669,969 137,893,249 75,482,234

NASHVILLE, Tenn., Nov. 6, 2024 /PRNewswire/ -- Cumberland Pharmaceuticals Inc. (NASDAQ: CPIX), a specialty pharmaceutical company, announced today that the United States (U.S.) Food and Drug Administration (FDA) granted Orphan Drug Designation and Rare Pediatric Disease Designation to Ifetroban for the treatment of cardiomyopathy associated with Duchenne muscular dystrophy (DMD). Cumberland is completing the FIGHT DMD™ trial, a multicenter, double-blind, placebo-controlled Phase II study investigating the pharmacokinetics, safety and efficacy of once daily oral Ifetroban in patients with DMD. Results will be announced later this year. "For Duchenne muscular dystrophy, a devastating genetic disorder affecting young boys, securing both Orphan Drug and Rare Pediatric Disease Designations for Ifetroban from the FDA is a critical step forward," said A.J. Kazimi, chief executive officer of Cumberland Pharmaceuticals. "These designations not only recognize the urgent need for effective treatments but also provide vital support to accelerate research and development. These important regulatory milestones represent hope for families and a pathway to bring transformative medicines to a vulnerable patient population more quickly and efficiently." The U.S. FDA grants Rare Pediatric Disease Designation to incentivize drug development for life-threatening diseases affecting less than 200,000 children in the U.S. As these diseases pose unique challenges to drug development, special focus is needed to provide therapeutic options to these children. Companies that receive approval for a drug or biologic with this designation may be eligible for a voucher which may be redeemed for priority review of a different product. Additionally, this voucher may be transferred or sold to another sponsor. Orphan Drug Designation is granted by the U.S. FDA to encourage development of new therapies for rare diseases or conditions affecting fewer than 200,000 people in the U.S. This designation offers sponsors multiple incentives, which include exemption from user fees, tax credits for qualified clinical trials and potential market exclusivity for seven years following approval of the product. About Duchenne Muscular Dystrophy DMD is a rare and fatal genetic disorder which affects about 1 in every 3,300 male births worldwide. Characterized by mutations in the gene responsible for producing dystrophin, DMD causes damage to the skeletal and cardiac muscle of DMD patients, with cardiomyopathy recognized as the primary cause of death. Ifetroban is being evaluated to treat the heart disease associated with DMD, which has received limited attention with current therapies. About Ifetroban Ifetroban is a potent and selective thromboxane-prostanoid receptor (TPr) antagonist. Ifetroban exhibits high affinity for TPr on many cell types including cardiomyocytes, platelets, vascular and airway smooth muscle, and fibroblasts, and lacks agonistic activity. In several preclinical models of muscular dystrophy, including limb-girdle and Duchenne, ifetroban prevented cardiac fibrosis and cardiac dysfunction and improved mortality. Cumberland previously announced the acquisition of the ifetroban program in collaboration with Vanderbilt University and Cumberland Emerging Technologies. Cumberland is also evaluating ifetroban for systemic sclerosis and pulmonary fibrosis. The ongoing FIGHTING FIBROSIS Trial is a multicenter, randomized placebo-controlled Phase II study in patients with idiopathic pulmonary fibrosis (IPF), a progressive interstitial lung disease. IPF is marked by inflammation and fibrosis of the lungs, resulting in rapidly declining lung function and reduced survival within five years of diagnosis. The study is evaluating the safety and efficacy of once daily oral Ifetroban for 52 weeks. About Cumberland Pharmaceuticals Cumberland Pharmaceuticals Inc. is a specialty pharmaceutical company focused on the delivery of high-quality prescription brands to improve patient care. The Company develops, acquires, and commercializes brands for the hospital acute care, gastroenterology and rheumatology market segments. The Company's portfolio of FDA-approved brands includes: Acetadote® (acetylcysteine) Injection, for the treatment of acetaminophen poisoning; Caldolor® (ibuprofen) Injection, for the treatment of pain and fever; Vaprisol® (conivaptan) Injection, to raise serum sodium levels in hospitalized patients with euvolemic and hypervolemic hyponatremia; Vibativ® (telavancin) Injection, for the treatment of certain serious bacterial infections including hospital-acquired and ventilator-associated bacterial pneumonia, as well as complicated skin and skin structure infections; Kristalose® (lactulose) for Oral Solution, a prescription laxative, for the treatment of chronic and acute constipation; and Sancuso® (granisetron) Transdermal delivery system, for the treatment of nausea and vomiting associated with chemotherapy. For more information on Cumberland's approved products, including full prescribing information, please visit the individual product websites, links to which can be found on the Company's website . About Cumberland Emerging Technologies Cumberland Emerging Technologies, Inc. () is a joint initiative between Cumberland Pharmaceuticals Inc., Vanderbilt University, Launch Tennessee and WinHealth Pharma. The mission of CET is to bring biomedical technologies and products conceived at Vanderbilt and other regional research centers to the marketplace. CET helps manage the development and commercialization process for select projects and provides expertise on intellectual property, regulatory, manufacturing and marketing issues that are critical to successful new biomedical products. CET's Life Sciences Center, located in Nashville, Tennessee, provides laboratory space, equipment and infrastructure to early-stage life sciences companies. Forward-Looking Statements This press release contains forward-looking statements, which are subject to certain risks and reflect Cumberland's current views on future events based on what it believes are reasonable assumptions. No assurance can be given that these events will occur. As with any business, all phases of Cumberland's operations are subject to factors outside of its control, and any one or combination of these factors could materially affect Cumberland's results of operations. These factors include market conditions, competition, an inability of manufacturers to produce Cumberland's products on a timely basis or failure of manufacturers to comply with regulations applicable to pharmaceutical manufacturers, maintaining an effective sales and marketing infrastructure, natural disasters, public health epidemics, and other events beyond our control, as more fully discussed in the Company's most recent Form 10-K and subsequent 10-Qs as filed with the SEC. There can be no assurance that results anticipated by the Company will be realized or that they will have the expected effects. Readers are cautioned not to place undue reliance on forward-looking statements, which speak only as of the date hereof. The Company does not undertake any obligation to publicly revise these statements to reflect events after the date hereof. SOURCE Cumberland Pharmaceuticals Inc. WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED