An Open-label, Randomized, Three-arm Study Evaluating the Potential of BMS-984923 to Alter the Systemic Exposure of Three Orally Administered Probe Substrates in Healthy Adult Participants

The goal of this study is to learn if the investigational drug, BMS-984923 will impact the exposure and clearance of other medications when given together. Most drugs are broken down and cleared in the body via cytochrome P450 enzymes in the liver. The metabolism and clearance of certain drugs can be affected by other drugs when dosed together. To evaluate the impact of BMS-984923 on the clearance of other medications, we will investigate three known pathways which may be impacted by BMS-984923.
In this study participants will take one dose of the three known medications, midazolam, caffeine and dextromethorphan together. These drugs are known to be cleared by different cytochrome P450 enzymes. Blood will be collected to evaluate the exposure and clearance of these medications and their primary metabolites. Study participants will then be administered BMS-984923 for 18-days. On the 18th Day of BMS-984923 dosing, participants will again be co-administering midazolam, caffeine and dextromethorphan. Blood will be collected again, and the concentration of each drug will be measured. We will learn in this study if BMS-984923 changes the exposure and metabolism of the known drugs. These results will inform how BMS-984923 can be administered to patients who take multiple medications.

Start Date21 Nov 2024

Sponsor / Collaborator

Allyx Therapeutics, Inc.Startup

[+1]

NCT06309147 / RecruitingPhase 1

A Double-Blind, Single Center, Randomized, Placebo-Controlled Study of BMS-984923 in Participants With Parkinson's Disease

A Phase 1, randomized, double-blind, placebo-controlled study of BMS-984923 administered orally twice daily (BID) for 28 days in participants with Parkinson's disease.

Start Date15 Mar 2024

Sponsor / Collaborator

Allyx Therapeutics, Inc.Startup

[+1]

NCT05804383 / RecruitingPhase 1

A Phase 1B Multiple Ascending Dose Study of The Safety and Tolerability of BMS-984923 in Healthy Older Adults and Patients With Alzheimer's Disease

A Phase 1b Multiple Ascending Dose Study of the Safety and Tolerability of BMS-984923 in Healthy Older Adults and Patients with Alzheimer's Disease

Start Date28 Mar 2023

Sponsor / Collaborator

Allyx Therapeutics, Inc.Startup

[+2]

100 Clinical Results associated with BMS-984923

100 Translational Medicine associated with BMS-984923

100 Patents (Medical) associated with BMS-984923

Literatures (Medical) associated with BMS-984923

18 Oct 2024·MOLECULAR PSYCHIATRY

Aging-dependent loss of functional connectivity in a mouse model of Alzheimer's disease and reversal by mGluR5 modulator.

Article

Author: Papademetris, Xenophon ; Chakravarty, M Mallar ; O'Connor, David ; Onofrey, John ; Mukherjee, Bandhan ; Mandino, Francesca ; Strittmatter, Stephen M ; Shen, Xilin ; Qu, An ; Desrosiers-Grégoire, Gabriel ; Lake, Evelyn M R ; Owens, Ashley

Amyloid accumulation in Alzheimer's disease (AD) is associated with synaptic damage and altered connectivity in brain networks. While measures of amyloid accumulation and biochemical changes in mouse models have utility for translational studies of certain therapeutics, preclinical analysis of altered brain connectivity using clinically relevant fMRI measures has not been well developed for agents intended to improve neural networks. Here, we conduct a longitudinal study in a double knock-in mouse model for AD (App^NL-G-F/hMapt), monitoring brain connectivity by means of resting-state fMRI. While the 4-month-old AD mice are indistinguishable from wild-type controls (WT), decreased connectivity in the default-mode network is significant for the AD mice relative to WT mice by 6 months of age and is pronounced by 9 months of age. In a second cohort of 20-month-old mice with persistent functional connectivity deficits for AD relative to WT, we assess the impact of two-months of oral treatment with a silent allosteric modulator of mGluR5 (BMS-984923/ALX001) known to rescue synaptic density. Functional connectivity deficits in the aged AD mice are reversed by the mGluR5-directed treatment. The longitudinal application of fMRI has enabled us to define the preclinical time trajectory of AD-related changes in functional connectivity, and to demonstrate a translatable metric for monitoring disease emergence, progression, and response to synapse-rescuing treatment.

01 Jul 2017·Cell reportsQ1 · BIOLOGY

Silent Allosteric Modulation of mGluR5 Maintains Glutamate Signaling while Rescuing Alzheimer’s Mouse Phenotypes

Q1 · BIOLOGY

ArticleOA

Author: Herber, Charlotte S ; Haas, Laura T ; Smith, Levi M ; Macor, John E ; Balakrishnan, Anand ; Strittmatter, Stephen M ; Degnan, Andrew P ; Albright, Charles F ; Cox, Timothy O ; Zhao, Helen R ; Salazar, Santiago V

Metabotropic glutamate receptor 5 (mGluR5) has been implicated in Alzheimer's disease (AD) pathology. We sought to understand whether mGluR5's role in AD requires glutamate signaling. We used a potent mGluR5 silent allosteric modulator (SAM, BMS-984923) to separate its well-known physiological role in glutamate signaling from a pathological role in mediating amyloid-β oligomer (Aβo) action. Binding of the SAM to mGluR5 does not change glutamate signaling but strongly reduces mGluR5 interaction with cellular prion protein (PrP^C) bound to Aβo. The SAM compound prevents Aβo-induced signal transduction in brain slices and in an AD transgenic mouse model, the APPswe/PS1ΔE9 strain. Critically, 4 weeks of SAM treatment rescues memory deficits and synaptic depletion in the APPswe/PS1ΔE9 transgenic mouse brain. Our data show that mGluR5's role in Aβo-dependent AD phenotypes is separate from its role in glutamate signaling and silent allosteric modulation of mGluR5 has promise as a disease-modifying AD intervention with a broad therapeutic window.

bioRxiv : the preprint server for biology

Aging-Dependent Loss of Connectivity in Alzheimer’s Model Mice with Rescue by mGluR5 Modulator

Author: Papademetris, Xenophon ; Mukherjee, Bandhan ; Onofrey, John ; Mandino, Francesca ; Desrosiers-Gregoire, Gabriel ; Strittmatter, Stephen M ; Shen, Xilin ; Lake, Evelyn MR ; Qu, An ; Chakravarty, M. Mallar ; O’Connor, David ; Owens, Ashley

Abstract:

Amyloid accumulation in Alzheimer’s disease (AD) is associated with synaptic damage and altered connectivity in brain networks. While measures of amyloid accumulation and biochemical changes in mouse models have utility for translational studies of certain therapeutics, preclinical analysis of altered brain connectivity using clinically relevant fMRI measures has not been well developed for agents intended to improve neural networks. Here, we conduct a longitudinal study in a double knock-in mouse model for AD (AppNL-G-F/hMapt), monitoring brain connectivity by means of resting-state fMRI. While the 4-month-old AD mice are indistinguishable from wild-type controls (WT), decreased connectivity in the default-mode network is significant for the AD mice relative to WT mice by 6 months of age and is pronounced by 9 months of age. In a second cohort of 20-month-old mice with persistent functional connectivity deficits for AD relative to WT, we assess the impact of two-months of oral treatment with a silent allosteric modulator of mGluR5 (BMS-984923) known to rescue synaptic density. Functional connectivity deficits in the aged AD mice are reversed by the mGluR5-directed treatment. The longitudinal application of fMRI has enabled us to define the preclinical time trajectory of AD-related changes in functional connectivity, and to demonstrate a translatable metric for monitoring disease emergence, progression, and response to synapse-rescuing treatment.

News (Medical) associated with BMS-984923

04 Sep 2024

·www.globenewswire.com

Allyx Therapeutics Announces First Parkinson’s Disease Patient Treated with ALX-001

Allyx continues to advance clinical research of its first-in-class oral compound for neurodegenerative diseasesNEW HAVEN, Conn., Sept. 04, 2024 (GLOBE NEWSWIRE) -- Allyx Therapeutics has announced that the first patient has been dosed with its lead compound, ALX-001, in a new clinical study assessing safety, pharmacokinetics and potential therapeutic response in patients with Parkinson’s disease. ALX-001 is a highly selective, first-in-class, synapse-targeted, disease-modifying oral therapy. Allyx Therapeutics is a clinical-stage biotechnology company working to deliver a novel approach to preserve and protect synapses for people living with neurodegenerative diseases. “Allyx Therapeutics is moving forward with strong momentum to develop ALX-001 as the first-ever disease-modifying small molecule for neurodegenerative diseases, with two concurrent safety studies in patients with Parkinson’s disease and with Alzheimer’s disease, adding important information to the body of knowledge for this novel therapeutic approach,” said Tim Siegert, Ph.D. chief operating officer and co-founder of Allyx Therapeutics. The 28-day Parkinson’s disease study (NCT06309147) is assessing the safety of ALX-001 dosed twice daily at either 50 mg or 100 mg versus placebo in adults between 21 and 80 years of age, and will also investigate dopamine transporter levels in the brain measured with single photon emission computed tomography as an early marker of therapeutic response to a treatment that targets synapse restoration. The study is being conducted by the Duke Clinical Research Institute (DCRI) and is supported with grant funding awarded to Allyx Therapeutics from The Michael J. Fox Foundation for Parkinson’s Research. “I’m excited to collaborate with the Allyx team as we advance understanding of how Parkinson’s disease affects the brain and what more we might be able to do to provide a real impact for patients. Investigating the safety of this disease-modifying small molecule is a crucial first step, and one I’m proud to be a part of,” said Laurie H. Sanders, Ph.D., associate professor of Neurology at Duke University School of Medicine and DCRI. Building on twelve years of clinical research, ALX-001 continues to demonstrate promise in ongoing studies. The ALX-001 program has received more than $20 million in grant funding from the National Institutes of Health, the U.S. Government’s highly competitive Small Business Innovation Research (SBIR) programs, the Alzheimer’s Association, and The Michael J. Fox Foundation for Parkinson’s Research, among others. About ALX-001 ALX-001 (previously BMS-984923) is a silent allosteric modulator of mGluR5, and is a first-in-class compound that selectively blocks the pathogenic activation of the receptor while preserving the normal physiological glutamate signaling that is required for cognition. As such, ALX-001 has a wide therapeutic window that can saturate receptors while avoiding on-target toxicity observed with negative allosteric modulators. mGluR5 has been shown to be essential for mediating synaptic dysfunction and loss caused by multiple misfolded extracellular protein species, and as such, presents a novel approach for treating Alzheimer's and Parkinson’s disease. Importantly, ALX-001 is an orally bioavailable and brain penetrant small molecule with demonstrated mGluR5 selective engagement. The molecule was originally identified by Bristol Myers Squibb, but the mechanism of action for neurodegenerative diseases and the identification of ALX-001 as disease-modifying for Alzheimer’s disease was discovered by Allyx scientific founder Stephen Strittmatter at Yale School of Medicine. Allyx Therapeutics obtained an exclusive worldwide license for ALX-001 from Bristol Myers Squibb and Yale School of Medicine. About Allyx Therapeutics Allyx Therapeutics was founded in 2019 by a group of seasoned biopharma industry executives, venture capitalists, and scientific experts. The company aims to deliver a novel approach to preserve and protect synapses for people living with neurodegenerative diseases. Its lead compound, ALX-001, is a first-in-class oral therapy with a unique mechanism of action at mGluR5 in clinical development for Alzheimer’s disease and Parkinson’s disease. Learn more at allyxthera.com. About the Duke Clinical Research Institute The DCRI, part of the Duke University School of Medicine, is the largest academic clinical research organization in the world. Our mission is to develop, share, and implement knowledge that improves global health through innovative clinical research. The institute conducts multinational clinical trials, manages major national patient registries, and performs landmark outcomes research. The DCRI is a pioneer in cardiovascular and pediatric clinical research and conducts groundbreaking clinical research across multiple other therapeutic areas, including infectious disease, neuroscience, respiratory medicine, and nephrology. ContactMedia: Eliza Schleifstein917.763.8106Eliza@schleifsteinpr.com Investors: Tim Siegert203-691-6543tsiegert@allyxthera.com

License out/inClinical Study

11 Jun 2024

·www.globenewswire.com

Allyx Therapeutics Announces First Alzheimer’s Disease Patient Treated with Lead Compound ALX-001

With Growing Body of Clinical Evidence, ALX-001 is Ready to Commence Phase 2 StudiesNEW HAVEN, Conn., June 11, 2024 (GLOBE NEWSWIRE) -- Allyx Therapeutics, a clinical-stage biotechnology company working to deliver a novel approach to preserve and protect synapses for people living with neurodegenerative diseases, announced that the first Alzheimer’s disease patient has been dosed with its lead compound, ALX-001, in a clinical study. ALX-001 is a highly selective, first-in-class, synapse-targeted, disease-modifying oral therapy that is ready for Phase 2 clinical development. “Administering the first dose in patients is a watershed moment for a new therapeutic, and we are pleased to begin research in Alzheimer’s disease patients as we continue to advance clinical development of ALX-001 to become the first-ever disease-modifying small molecule for neurodegenerative diseases,” commented Stephen Bloch, M.D., chief executive officer and co-founder of Allyx Therapeutics. Individuals with Alzheimer’s disease are being enrolled in a 28-day study which will evaluate the safety of ALX-001 dosed twice daily at either 50 mg or 100 mg versus placebo in adults between 50 and 80 years of age. This is the second phase of an ongoing study which previously assessed multiple ascending doses in healthy volunteers (NCT05804383) and is being conducted at Yale School of Medicine with support from the National Institute on Aging. “Every neuroscientist hopes for the moment that an asset they believe in and fight for advances to the critical stage of testing in patients,” stated Stephen Strittmatter M.D., Ph.D., scientific founder of Allyx Therapeutics and professor and chair of Neuroscience at the Yale School of Medicine. “The unique mechanism of action of ALX-001 and its promising early data have brought us to this point, and bolster our hope that it has the potential to be a difference-maker in Alzheimer’s disease.” ALX-001 is ready to proceed to phase 2 clinical development, and is not restricted by completion of ongoing studies. Building on twelve years of clinical research, ALX-001 continues to demonstrate promise in studies supported by highly reputable third parties. The ALX-001 program has received more than $20 million in grant funding from the National Institutes of Health, the U.S. Government’s highly competitive Small Business Innovation Research (SBIR) programs, the Alzheimer’s Association, and The Michael J. Fox Foundation for Parkinson’s Research, among others. About ALX-001ALX-001 (previously BMS-984923) is a silent allosteric modulator of mGluR5, and is a first-in-class compound that selectively blocks the pathogenic activation of the receptor while preserving the normal physiological glutamate signaling that is required for cognition. As such, ALX-001 has a wide therapeutic window that can saturate receptors while avoiding on-target toxicity observed with negative allosteric modulators. mGluR5 has been shown to be essential for mediating synaptic dysfunction and loss caused by multiple misfolded extracellular protein species, and as such, presents a novel approach for treating Alzheimer's and Parkinson’s disease. Importantly, ALX-001 is an orally bioavailable and brain penetrant small molecule with demonstrated mGluR5 selective engagement. The molecule was originally identified by Bristol Myers Squibb, but the mechanism of action for neurodegenerative diseases and the identification of ALX-001 as disease-modifying for Alzheimer’s disease was discovered by Allyx scientific founder Stephen Strittmatter at Yale School of Medicine. Allyx Therapeutics obtained an exclusive worldwide license for ALX-001 from Bristol Myers Squibb and Yale School of Medicine. About Allyx Therapeutics Allyx Therapeutics was founded in 2019 by a group of seasoned biopharma industry executives, venture capitalists, and scientific experts. The company aims to deliver a novel approach to preserve and protect synapses for people living with neurodegenerative diseases. Its lead compound, ALX-001, is a first-in-class oral therapy with a unique mechanism of action at mGluR5 in clinical development for Alzheimer’s disease and Parkinson’s disease. Learn more at allyxthera.com. Contact Media: Eliza Schleifstein917.763.8106Eliza@schleifsteinpr.com Investors: Tim Siegert203-691-6543tsiegert@allyxthera.com

License out/inPhase 2

11 Jun 2024

·www.biospace.com

Allyx Therapeutics Announces First Alzheimer’s Disease Patient Treated with Lead Compound ALX-001With Growing Body of Clinical Evidence, ALX-001 is Ready to Commence Phase 2 Studies

NEW HAVEN, Conn., June 11, 2024 (GLOBE NEWSWIRE) -- Allyx Therapeutics, a clinical-stage biotechnology company working to deliver a novel approach to preserve and protect synapses for people living with neurodegenerative diseases, announced that the first Alzheimer’s disease patient has been dosed with its lead compound, ALX-001, in a clinical study. ALX-001 is a highly selective, first-in-class, synapse-targeted, disease-modifying oral therapy that is ready for Phase 2 clinical development. “Administering the first dose in patients is a watershed moment for a new therapeutic, and we are pleased to begin research in Alzheimer’s disease patients as we continue to advance clinical development of ALX-001 to become the first-ever disease-modifying small molecule for neurodegenerative diseases,” commented Stephen Bloch, M.D., chief executive officer and co-founder of Allyx Therapeutics. Individuals with Alzheimer’s disease are being enrolled in a 28-day study which will evaluate the safety of ALX-001 dosed twice daily at either 50 mg or 100 mg versus placebo in adults between 50 and 80 years of age. This is the second phase of an ongoing study which previously assessed multiple ascending doses in healthy volunteers (NCT05804383) and is being conducted at Yale School of Medicine with support from the National Institute on Aging. “Every neuroscientist hopes for the moment that an asset they believe in and fight for advances to the critical stage of testing in patients,” stated Stephen Strittmatter M.D., Ph.D., scientific founder of Allyx Therapeutics and professor and chair of Neuroscience at the Yale School of Medicine. “The unique mechanism of action of ALX-001 and its promising early data have brought us to this point, and bolster our hope that it has the potential to be a difference-maker in Alzheimer’s disease.” ALX-001 is ready to proceed to phase 2 clinical development, and is not restricted by completion of ongoing studies. Building on twelve years of clinical research, ALX-001 continues to demonstrate promise in studies supported by highly reputable third parties. The ALX-001 program has received more than $20 million in grant funding from the National Institutes of Health, the U.S. Government’s highly competitive Small Business Innovation Research (SBIR) programs, the Alzheimer’s Association, and The Michael J. Fox Foundation for Parkinson’s Research, among others. About ALX-001 ALX-001 (previously BMS-984923) is a silent allosteric modulator of mGluR5, and is a first-in-class compound that selectively blocks the pathogenic activation of the receptor while preserving the normal physiological glutamate signaling that is required for cognition. As such, ALX-001 has a wide therapeutic window that can saturate receptors while avoiding on-target toxicity observed with negative allosteric modulators. mGluR5 has been shown to be essential for mediating synaptic dysfunction and loss caused by multiple misfolded extracellular protein species, and as such, presents a novel approach for treating Alzheimer's and Parkinson’s disease. Importantly, ALX-001 is an orally bioavailable and brain penetrant small molecule with demonstrated mGluR5 selective engagement. The molecule was originally identified by Bristol Myers Squibb, but the mechanism of action for neurodegenerative diseases and the identification of ALX-001 as disease-modifying for Alzheimer’s disease was discovered by Allyx scientific founder Stephen Strittmatter at Yale School of Medicine. Allyx Therapeutics obtained an exclusive worldwide license for ALX-001 from Bristol Myers Squibb and Yale School of Medicine. About Allyx Therapeutics Allyx Therapeutics was founded in 2019 by a group of seasoned biopharma industry executives, venture capitalists, and scientific experts. The company aims to deliver a novel approach to preserve and protect synapses for people living with neurodegenerative diseases. Its lead compound, ALX-001, is a first-in-class oral therapy with a unique mechanism of action at mGluR5 in clinical development for Alzheimer’s disease and Parkinson’s disease. Learn more at allyxthera.com. Contact Media: Eliza Schleifstein 917.763.8106 Eliza@schleifsteinpr.com Investors: Tim Siegert 203-691-6543 tsiegert@allyxthera.com

License out/inPhase 2

100 Deals associated with BMS-984923

R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Parkinson Disease	Phase 1	US	Allyx Therapeutics, Inc.Startup	15 Mar 2024
Alzheimer Disease	Phase 1	US	Bristol Myers Squibb Co.	18 Mar 2021

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT04805983 (CTgov)	Phase 1	Alzheimer Disease	36	BMS-984923 (10 mg BMS-984923)	mjqjwdepgw(vlypbrstks) = kxejlicpiq boyavpouto (mtcjusfcqg, izxbvbxkqd - nvqzlarlvq) View more	-	13 Apr 2023
				BMS-984923 (40 mg BMS-984923)	mjqjwdepgw(vlypbrstks) = dvegtgkmys boyavpouto (mtcjusfcqg, jwhwljxery - orvosdsccz) View more

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