A RandomIzed, Double-Blind, Placebo-CoNtrolled, Two-Part Study to Evaluate the Pharmacodynamic EffIcacy and Clinical Benefit of AT 007 in Patients With SoRbitol Dehydrogenase (SORD) DEficiency

This study is designed to assess the efficacy and safety of AT-007 treatment in patients with SORD Deficiency. This randomized, double-blind study will assess the effect of AT-007 compared to Placebo in SORD Deficiency patients for 24 months.

Start Date01 Jan 2022

Sponsor / Collaborator

Applied Therapeutics, Inc.

NCT05418829 / Active, not recruitingPhase 3

An Open-Label Study to Evaluate the Long-Term Safety and Pharmacodynamic Efficacy of AT-007 in Adult Subjects With Classic Galactosemia (CG)

This study is a 12-month open-label extension (OLE) study of AT-007 in adult subjects with CG who previously participated in Study AT-007-1001 Part D and/or Part D Extension.
The study is designed to assess the long-term safety of AT-007 in subjects with CG as well as the pharmacodynamics (PD) (inhibition of galactitol) and PK of AT-007. The effect of 12-month treatment with AT-007 on the levels of galactose and other galactose metabolites in subjects with CG will also be evaluated.

Start Date01 Oct 2021

Sponsor / Collaborator

Applied Therapeutics, Inc.

NCT04902781 / Active, not recruitingPhase 2/3

A Sequential, Two-Part Study to Evaluate the Clinical Benefit, Safety, Pharmacokinetics, and Pharmacodynamics of AT-007 in Pediatric Patients With Classic Galactosemia (CG)

This study is designed to assess the clinical benefit as well as the safety, pharmacokinetics (PK), and pharmacodynamics (PD) (reduction of galactitol levels) of AT-007 in pediatric subjects with Classic Galactosemia (CG).

Start Date20 Mar 2021

Sponsor / Collaborator

Applied Therapeutics, Inc.

100 Clinical Results associated with Govorestat

100 Translational Medicine associated with Govorestat

100 Patents (Medical) associated with Govorestat

Literatures (Medical) associated with Govorestat

01 Nov 2024·The Journal of Clinical Pharmacology

Safety, Pharmacokinetics, and Pharmacodynamics of the New Aldose Reductase Inhibitor Govorestat (AT‐007) After a Single and Multiple Doses in Participants in a Phase 1/2 Study

Article

Author: Shendelman, Shoshana ; Perfetti, Riccardo ; Mohanlal, Ramon ; Bailey, Evan ; Wang, Stella ; Mills, Richard

AbstractIn classic galactosemia (CG) patients, aldose reductase (AR) converts galactose to galactitol. In a phase 1/2, placebo‐controlled study (NCT04117711), safety, pharmacokinetics (PK), and pharmacodynamics (PD) of govorestat were evaluated after single and multiple ascending doses (0.5‐40 mg/kg) in healthy adults (n = 81) and CG patients (n = 14). Levels of govorestat in plasma and cerebrospinal fluid (CSF) and blood levels of galactitol, galactose, and galactose‐1‐phosphate (Gal‐1p) were measured for population PK and PK/PD analyses. Govorestat was well tolerated. Adverse event frequency was comparable between placebo and govorestat. Govorestat PK displayed a 2‐compartment model with sequential zero‐ and first‐order absorption, and no effect of demographic factors. Multiple‐dose PK of govorestat was linear in the 0.5‐40 mg/kg range, and CSF levels increased dose dependently. Elimination half‐life was ∼10 h. PK/PD modeling supported once‐daily dosing. Change from baseline in galactitol was −15% ± 9% with placebo and −19% ± 10%, −46% ± 4%, and −51% ± 5% with govorestat 5, 20, and 40 mg/kg, respectively, thus was similar for 20 and 40 mg/kg. Govorestat did not affect galactose or Gal‐1p levels. In conclusion, govorestat displayed a favorable safety, PK, and PD profile in humans, and reduced galactitol levels in the same magnitude (∼50%) as in a rat model of CG that demonstrated an efficacy benefit on neurological, behavioral, and ocular outcomes.

22 May 2023·JCI insight

Sorbitol reduction via govorestat ameliorates synaptic dysfunction and neurodegeneration in sorbitol dehydrogenase deficiency.

Article

Author: Züchner, Stephan ; Rebelo, Adriana P ; Yanick, Christopher ; Saporta, Mario ; Ortiz-Vega, Natalie ; Zhu, Yi ; Zhai, R Grace ; Shendelman, Shoshana ; Lobato, Amanda G ; Shy, Michael ; Canic, Tijana ; Perfetti, Riccardo ; Syed, Sheyum ; Tao, Xianzun

Sorbitol dehydrogenase (SORD) deficiency has been identified as the most frequent autosomal recessive form of hereditary neuropathy. Loss of SORD causes high sorbitol levels in tissues due to the inability to convert sorbitol to fructose in the 2-step polyol pathway, leading to degenerative neuropathy. The underlying mechanisms of sorbitol-induced degeneration have not been fully elucidated, and no current FDA-approved therapeutic options are available to reduce sorbitol levels in the nervous system. Here, in a Drosophila model of SORD deficiency, we showed synaptic degeneration in the brain, neurotransmission defect, locomotor impairment, and structural abnormalities in the neuromuscular junctions. In addition, we found reduced ATP production in the brain and ROS accumulation in the CNS and muscle, indicating mitochondrial dysfunction. Applied Therapeutics has developed a CNS-penetrant next-generation aldose reductase inhibitor (ARI), AT-007 (govorestat), which inhibits the conversion of glucose to sorbitol. AT-007 significantly reduced sorbitol levels in patient-derived fibroblasts, induced pluripotent stem cell-derived (iPSC-derived) motor neurons, and Drosophila brains. AT-007 feeding in Sord-deficient Drosophila mitigated synaptic degeneration and significantly improved synaptic transduction, locomotor activity, and mitochondrial function. Moreover, AT-007 treatment significantly reduced ROS accumulation in Drosophila CNS, muscle, and patient-derived fibroblasts. These findings uncover the molecular and cellular pathophysiology of SORD neuropathy and provide a potential treatment strategy for patients with SORD deficiency.

01 Jan 2017·Journal of Pathogens

A Laboratory Assessment of Two Local Strains of the Beauveria bassiana (Bals.) Vuill. against the Tetranychus urticae (Acari: Tetranychidae) and Their Potential as a Mycopesticide

Article

Author: Algur, Omer Faruk ; Ortucu, Serkan

This study was conducted to assess highly pathogenic Beauveria bassiana isolates to be used in biocontrol and to determine their potentials as mycopesticide. For this purpose, two B. bassiana isolates, which were locally isolated from T. urticae, were chosen. Firstly, three suspensions were investigated at the degree of humidity of 65 ± 5% and 100% RH. Secondly, these strains were selected according to their tendency to mass production, tolerance to UV radiation, and capability of producing spore at the different temperatures. Finally, identification of the selected isolate was performed by using ITS rDNA analysis. Both tested fungal isolates were pathogenic to the T. urticae. Mycelial growths of isolate AT076 at 20°C and 30°C were found to be greater than isolate AT007. It was observed that isolate AT076 had more spore production with 1.61 × 107 spore/disc at 30°C and 44.33% germination after UV radiation for 15 min. The numbers of spores per 5 mm disk area for isolates AT076 and AT007 were found to be 1.2 × 106 and 1.0 × 106. These results show that isolate AT076 was more virulent and more UV-tolerant and had higher tendency to mass production compared to isolate AT007 against T. urticae. As a result of this study, isolate AT076 can be used in the biocontrol as mycopesticide.

News (Medical) associated with Govorestat

07 Nov 2024

·www.globenewswire.com

Applied Therapeutics Reports Third Quarter 2024 Financial Results

- 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

NDAFinancial StatementPhase 3

06 Oct 2024

·medcitynews.com

J&J Backs Down From 340B Rebates, But Maintains They’re ‘Legally Permissible’ Per Statute - MedCity News

The federal 340B program has become a thorn in the side of pharmaceutical companies, who point to the drug discount program’s sprawling growth amid what they contend is lack of oversight. After initially proposing changes to the way the company offers drugs under this program, Johnson & Johnson has backed down, averting further confrontation with federal officials and hospitals on the matter. For now. When the 340B program was established in 1992, the intent was to help underserved communities. Under the program, eligible hospitals and clinics serving low-income and uninsured patients may purchase outpatient prescription medications at discounts of up to 50%. In August, J&J proposed a major change. Starting on Oct. 15, entities covered under 340B would have to pay full price, then make a claims submission for a rebate. This proposal would apply to two drugs, the plaque psoriasis medication Stelara and the blood thinner Xarelto. The Health Resources and Services Administration (HRSA), which administers the 340B program, told J&J the proposed changes are “inconsistent” with the statute and would need approval before they could take effect. In a Sept. 27 letter to J&J, HRSA Administrator Carole Johnson noted that the company had not requested such approval and proceeding with the rebate change would violate the 340B statute. The administrator added that implementations of the rebates would lead to termination of the company’s pharmaceutical pricing agreement and a referral to the Department Health and Human Services’ Office of the Inspector General. presented by Health Tech What’s Keeping Healthcare CIOs Up at Night: How to Improve Patient Satisfaction by Handling Calls More Efficiently Health systems have spent billions on portals while investments in modernizing the voice channel — the dominant preference of healthcare consumers — have taken a backseat. By Stephanie Baum In a letter of response, J&J maintained that the statute allows for rebates as a mechanism for drug manufacturers to offer the 340B price to covered entities. Furthermore, the company said its rebate proposal will target duplicate discounts, transactions in which a covered entity receives a 340B discount and then submits a claim for a Medicaid rebate — a violation of the statute. J&J says audits to uncover such duplicates have not solved the problem. “As HRSA knows, J&J’s efforts to identify and address program abuse through HRSA-approved audits of covered entities have been thwarted; nearly all of the entities for whom HRSA approved J&J audit requests have violated federal law by refusing to cooperate,” the company’s letter said. “Some have gone so far as to file suit against HRSA to invalidate the audit approvals. Plainly, audits alone are not a viable means for J&J to obtain information necessary to detect unlawful duplicate discounts and diversion as they occur.” Nevertheless, J&J said HRSA’s threat to terminate the company’s participation in the program would have the effect of cutting off millions of Medicare and Medicaid patients from necessary medicines. The company’s commitment to these patients leaves it “no choice but to forego implementation of the rebate model pending resolution of these issues.” J&J hints that litigation could be a next step. The company says it continues to believe its rebate model is “legally permissible” and “sorely needed” for drugmakers to comply with requirements of both the Inflation Reduction Act and the 340B statute. “J&J reserves all of its legal rights with respect to this matter,” the company said. presented by Health IT Accelerating Claim Processing: Strategies to Shorten the Life of a Claim These strategies and practices can significantly shorten the life cycle of claims, leading to quicker resolutions and improved financial outcomes. By Greenway Health In other regulatory news, we have FDA decisions for drugs (mostly approvals), some clinical holds, and one product withdrawal. Here’s a recap of recent regulatory developments: Regulatory Decisions —Exact Sciences’ Cologuard Plus now has FDA approval. The product is a next-generation version of Cologuard, the company’s non-invasive colorectal cancer test. Cologuard Plus offers greater sensitivity for colorectal cancer and advanced precancerous lesions. Like Cologuard, Cologuard Plus is approved for use in adults age 45 and older who are at average risk of colorectal cancer. Exact Sciences said it expects to launch this new test in 2025. —Partners Fresenius Kabi and Formycon received FDA approval for Otulfi, a biosimilar referencing the Johnson & Johnson biologic drug Stelara. The regulatory decision for Otulfi covers all of the approved uses of Stelara, which include Crohn’s disease, ulcerative colitis, moderate-to-severe plaque psoriasis, and active psoriatic arthritis. Separately, the European Union approved Otulfi in late September. Otulfi will jostle for market share with Pyzchiva from Samsung Bioepis and Sandoz, and Wezlana from Amgen, two Stelara biosimilars that have received FDA approvals in the past year. —Eli Lilly drug Retevmo is now FDA approved for treating adults and pediatric patients age 2 and older who have advanced cases of medullary thyroid cancer carrying a RET mutation. The drug has been available in this indication under accelerated approval. The latest regulatory decision converts Retevmo’s status to traditional approval. —Dupixent, a blockbuster immunology drug from Sanofi and Regeneron Pharmaceuticals, expanded its approved uses to include chronic obstructive pulmonary disease (COPD). Dupixent is the first FDA-approved biological treatment for COPD. Dupixent approved uses now span six dermatological and respiratory conditions. —FDA approval of Bristol Myers Squibb drug Cobenfy makes the drug the first novel schizophrenia drug in decades. The twice-daily capsule is designed to target a different receptor than currently available antipsychotic drugs, offering better efficacy and tolerability. Cobenfy comes from Karuna Therapeutics, which BMS acquired for $14 billion. —Eli Lilly drug Kisunla is now approved in Japan for the treatment of patients in the early stages of Alzheimer’s disease. Kisunla is part of a class of antibody drugs that work by reducing plaques of amyloid proteins that form in the brains of Alzheimer’s patients. Japan marks the second major market approval for Kisunla, which was approved by the FDA in July. —In other Japanese regulatory news, Takeda Pharmaceutical’s Fruzaqla won approval for the treatment of advanced or recurrent colorectal cancer. The Japanese pharma giant acquired the oral small molecule from Hutchmed in early 2023. Nearly a year ago, the FDA approved the drug for treating colorectal cancer. —Ipsen landed European Union approval for Kayfanda as a treatment for cholestatic pruritus (severe itching) associated with the rare liver disease Alagille syndrome. The approval was made under “exceptional circumstances” that permits marketing authorization when comprehensive efficacy and safety data are not available. The Ipsen drug won FDA approval for Alagille patients last year; in the U.S., the once-daily capsule is marketed as Bylvay. Ipsen added the drug to its pipeline via its $952 million acquisition of Albireo. —Ipsen’s rare liver disease portfolio also welcomed European Union approval of Iqirvo for treating primary biliary cholangitis (PBC), a chronic disorder that damages the liver’s bile ducts. The approval covers use of the once-daily pill in combination with ursodeoxycholic acid (UDCA) for patients whose disease does not adequately respond to that standard of care drug. Iqirvo may be used as a monotherapy for patients who cannot tolerate UDCA. European approval comes nearly four months after the FDA greenlit Iqirvo for PBC. —Zevra Therapeutics drug Miplyffa became the first FDA-approved treatment for Niemann-Pick disease type C, a rare inherited lysosomal storage disorder that can become fatal by the time patients reach adolescence. The approval specifically covers the neurological effects of the disease. Zevra acquired the rights to Miplyffa from Orphazyme, which failed to win FDA approval for the small molecule in 2021. —Days after Miplyffa’s approval, the FDA approved levacetylleucine, brand name Aqneursa, making the drug from privately held IntraBio the second approved treatment for Niemann-Pick disease type C. Similar to Miplyffa, the regulatory decision for the IntraBio drug covers the treatment of neurological effects of the rare disease. —The European Union approved Astellas drug zolbetuximab, brand name Vyloy, as a treatment for advanced gastric and gastroesophageal junction cancer. The approval covers use of the drug in combination with chemotherapy. The FDA turned down Astellas’s submission for the drug early this year, citing manufacturing issues. Astellas resubmitted its application, which now has a Nov. 9 target date for a regulatory decision. —FluMist, an intranasally dosed influenza vaccine that’s been available in the U.S. for two decades, is now FDA-approved for self- or caregiver administration. The regulatory decision makes the AstraZeneca product the first influenza vaccine that does not need to be given by a healthcare provider. For those choosing this option, the vaccine will be available through a third-party pharmacy following a screening and eligibility assessment completed when patients order the vaccine. —The FDA rejected Vanda Pharmaceuticals’ tradipitant as a treatment of gastroparesis. This delayed gastric emptying is associated with diabetes but can also develop in those who do not have diabetes. According to Vanda, the FDA disregarded clinical evidence for the drug and asked the company to conduct additional clinical testing. The company said it still plans to seek marketing authorization for this drug. A separate new drug application is also planned for tradipitant later this year for preventing vomiting from motion sickness. —An experimental Applied Therapeutics drug for the rare genetic metabolic disease classic galactosemia will not be discussed by an FDA advisory committee. After completing a late-cycle review meeting, the agency told the company a meeting was no longer needed for the drug, govorestat. The Nov. 28 target date for a regulatory decision still stands. —The FDA authorized the first over-the-counter hearing aid software. Called Hearing Aid Feature, this Apple software is compatible with the company’s AirPods Pro headphones. The software was reviewed through the regulator’s De Novo premarket review pathway. FDA authorization is based on a clinical trial enrolling 118 patients with mild-to-moderate hearing loss. Results showed those who self-fit the software and device achieved similar benefit as those who received a professional fitting. —Eli Lilly won FDA approval for lebrikizumab, brand name Ebglyss, a new treatment for atopic dermatitis. It will compete with biologic drugs Dupixent from Sanofi and Regeneron Pharmaceuticals, and Adbry from LEO Pharma. Compared to those every-other-week injectable drugs, Lilly’s new product offers patients less burdensome once-monthly maintenance dosing. —Roche landed FDA approvals for subcutaneously injectable drugs that were originally developed as intravenous infusions. Tecentriq Hybreza is the injectable version of the cancer immunotherapy Tecentriq; Ocrevus Zunovo is the injectable version of the multiple sclerosis drug Ocrevus. Both drugs employ drug delivery technology from Halozyme that enables biologic drugs to be administered as injections. —Travere Therapeutics drug Filspari converted its accelerated approval into a full FDA approval for the treatment of the rare kidney disease immunoglobulin A nephropathy. The regulatory decision came nearly a year after Travere reported the drug narrowly failed its Phase 3 confirmatory study. The approval is based on longer-term data showing the once-daily pill significantly slowed the kidney function decline. One Clinical Hold Placed, Two Lifted —Following the report of patient deaths, the FDA formally placed a clinical hold on zetomipzomib, a Kezar Life Sciences drug in development for treating lupus nephritis. Kezar had voluntarily stopped dosing and enrollment in the study after emerging safety data showed four Grade 5 (fatal) serious adverse events over the course of the study so far. The company said that three of those fatalities showed a common pattern of symptoms and proximity to dosing; additional non-fatal complications also showed a proximity to dosing. —The FDA lifted a clinical hold on Biomea Fusion’s Phase 1/2 clinical trial testing BMF-219 in type 1 and type 2 diabetes. Redwood City, California-based Biomea said review of the clinical data to date found that concerning safety signals observed in the Phase 2a escalation study did not translate to the larger Phase 2b expansion study. BMF-219 is a small molecule that forms a covalent bond and inhibits menin, a protein thought to suppress the pancreatic beta cells that produce and secrete insulin. —The FDA removed the partial clinical hold placed on an Avidity Biosciences’ delpacibart etedesiran, or del-disiran, an RNA therapy in development for the rare muscular disorder myotonic dystrophy type 1. The partial hold was placed in 2022 following the report of a serious adverse event in a single patient. Del-disiran is currently in Phase 3 testing. A Rare Disease Drug Withdrawal —Pfizer is voluntarily withdrawing Oxbryta from the market and discontinuing all clinical tests of the drug, which won accelerated FDA approval for sickle cell disease in 2019. The pharma giant said its decision is based on the totality of data now indicating higher rates of complications and deaths in patients treated with the oral drug. The FDA issued an alert about the withdrawal and said it has been conducting its own safety review of postmarketing data. When the review concludes, the agency said it will communicate additional findings, if necessary. Oxbryta was the centerpiece of Pfizer’s $5.4 billion acquisition of Global Blood Therapeutics in 2022.

Drug ApprovalPhase 2Phase 3Acquisition

18 Sep 2024

·endpts.com

FDA cancels Applied Therapeutics adcomm, shares skyrocket 65%

New York-based Applied Therapeutics disclosed on Wednesday that the FDA has canceled an October advisory committee meeting for its potential treatment for the genetic disorder classic galactosemia, sending shares $APLT of the company up by more than 65%. The announcement follows an FDA delay in April , when the agency said it needed additional time “to review supplemental analyses of previously submitted data,” according to the biotech. A clinical study with children ages 2 to 17 who received govorestat missed its primary endpoint, but Applied Therapeutics pointed to improvements in behavior, tremors and other endpoints as evidence of efficacy. Biotech analysts at Leerink Partners and William Blair believe the treatment will be approved. “Although the FDA’s decision to not host an AdCom meeting for govorestat is unexpected, we view this outcome as favorable for Applied as it suggests that the regulators are comfortable with the totality of the clinical data,” analysts at William Blair wrote on Wednesday. “After speaking with management, we highlight that the additional data the company previously submitted caused the sensitivity analysis for the primary endpoint to be positive. We suspect this data gave the agency greater confidence in govorestat’s efficacy and was a major contributor to the FDA’s decision to no longer hold an AdCom.” If approved, govorestat would also come with a priority review voucher, which Applied could sell for about $100 million and further extend its cash runway. “Collectively, we continue to think the galactosemia data are supportive of approval based on: the significant reduction in galactitol, the consistency of the data across several clinical endpoints, and the increasing separation of the govorestat group from placebo over time, especially in the context of a severe, rare disease with no other treatment options,” a Leerink analyst wrote Wednesday.

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Indication	Highest Phase	Country/Location	Organization	Date
Galactosemias	NDA/BLA	EU	Applied Therapeutics, Inc.	01 Dec 2023
Sorbitol dehydrogenase deficiency	Phase 3	GB	Applied Therapeutics, Inc.	01 Jan 2022
Sorbitol dehydrogenase deficiency	Phase 3	US	Applied Therapeutics, Inc.	01 Jan 2022
Sorbitol dehydrogenase deficiency	Phase 3	IT	Applied Therapeutics, Inc.	01 Jan 2022
Sorbitol dehydrogenase deficiency	Phase 3	CZ	Applied Therapeutics, Inc.	01 Jan 2022
Congenital Disorder of Glycosylation Type 1A	Phase 1	-	Applied Therapeutics, Inc.	-

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT05397665 (INSPIRE, Biospace) Manual	Phase 2/3	Sorbitol dehydrogenase deficiency	56	Govorestat	(liomefzntf) = 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). fbkrlzbknl (evczyqcqpy ) Met View more	Positive	15 Feb 2024
				Placebo
Corporate Publications Manual	Phase 3	Galactosemias	-	AT-007	npzbmtecbg(ibaiytgdmg) = Review of the data at 12 months of treatment by the DMC indicated that while the study primary endpoint has not yet reached statistical significance, a trend exists favoring AT-007 vs. placebo. kxihgwvcko (xiaayqhzil )	Positive	06 Oct 2022
				Placebo

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