A Partially Double-Blinded Phase 1 Study to Assess the Safety, Tolerability and Pharmacokinetics of AST-004 as a Short Loading Intravenous infusion Followed by AST-004 as a Continuous Infusion in Healthy Adult Subjects. - CS0398-230004 Astrocyte

开始日期2023-04-05

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Astrocyte Pharmaceuticals, Inc.初创企业

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2024-12-01·STROKE

First-in-Human Phase I Clinical Trial of the Adenosine A1R/A3R Agonist AST-004 in Healthy Subjects

Article

作者: Korinek, William S. ; Lakner, Géza ; Hernandez, Juan ; Matson, Mark A. ; Liston, Theodore E. ; Hunt, Dawn E. ; Manna, Lisa M. ; Lancey, Robert A. ; Poe, Russell B.

BACKGROUND::

AST-004 is a small-molecule adenosine A1/A3 receptor agonist that has exhibited significant cerebroprotective efficacy in preclinical models of acute ischemic stroke and traumatic brain injury. The primary objectives of this clinical phase I first-in-human study were to evaluate the safety and tolerability profile of single ascending intravenous doses in healthy subjects. The secondary objectives were to characterize the single-dose pharmacokinetic profiles in plasma, cerebrospinal fluid (CSF), and urine.

METHODS::

In part 1 of the study, AST-004 was administered in ascending dose cohorts of 5, 25, 50, 75, and 100 mg, with 6 subjects in each cohort receiving the study drug and 2 receiving placebo. In part 2, all 12 subjects received a 100 mg IV infusion of the study drug followed by a single CSF collection per subject via lumbar puncture at 20, 40, or 60 minutes after infusion.

RESULTS::

A total of 42 subjects received AST-004, with no severe or serious adverse events observed. Twelve of these subjects experienced a treatment-emergent adverse event, the most frequent across groups being headache. In part 2, pharmacokinetic analyses confirmed that AST-004 was distributed in the CSF, with the CSF-to-plasma ratio increasing over the 3 timepoints sampled. The mean half-life was 1.1 to 1.4 hours for doses of 25 to 100 mg, and the geometric mean maximum plasma concentration obtained in the highest dosing cohort (100 mg) was 2232±428 ng/mL.

CONCLUSIONS::

AST-004 was safe and well-tolerated at plasma concentrations 3 to 8× higher than those associated with significant efficacy in astrocyte’s preclinical primate stroke efficacy studies, with CSF concentrations highest at the 60-minute collection timepoint, the last timepoint tested. This study supports additional clinical investigations, including evaluation of an extended infusion to support the phase 2 program in stroke and traumatic brain injury.

2022-01-01·Stroke1区 · 医学

Adenosine A1R/A3R (Adenosine A1 and A3 Receptor) Agonist AST-004 Reduces Brain Infarction in a Nonhuman Primate Model of Stroke

1区 · 医学

Article

作者: Natsume, Takahiro ; Korinek, William S. ; Hama, Aldric ; Lechleiter, James D. ; Boltze, Johannes ; Liston, Theodore E. ; Poe, Russell B. ; Hayashi, Ikuo ; Takamatsu, Hiroyuki

Background and Purpose::

Treatment with A1R/A3R (adenosine A1 and A3 receptor) agonists in rodent models of acute ischemic stroke results in significantly reduced lesion volume, indicating activation of adenosine A1R or A3R is cerebroprotective. However, dosing and timing required for cerebroprotection has yet to be established, and whether adenosine A1R/A3R activation will lead to cerebroprotection in a gyrencephalic species has yet to be determined.

Methods::

The current study used clinical study intervention timelines in a nonhuman primate model of transient, 4-hour middle cerebral artery occlusion to investigate a potential cerebroprotective effect of the dual adenosine A1R/A3R agonist AST-004. Bolus and then 22 hours intravenous infusion of AST-004 was initiated 2 hours after transient middle cerebral artery occlusion. Primary outcome measures included lesion volume, lesion growth kinetics, penumbra volume as well as initial pharmacokinetic-pharmacodynamic relationships measured up to 5 days after transient middle cerebral artery occlusion. Secondary outcome measures included physiological parameters and neurological function.

Results::

Administration of AST-004 resulted in rapid and statistically significant decreases in lesion growth rate and total lesion volume. In addition, penumbra volume decline over time was significantly less under AST-004 treatment compared with vehicle treatment. These changes correlated with unbound AST-004 concentrations in the plasma and cerebrospinal fluid as well as estimated brain A1R and A3R occupancy. No relevant changes in physiological parameters were observed during AST-004 treatment.

Conclusions::

These findings suggest that administration of AST-004 and combined A1R/A3R agonism in the brain are efficacious pharmacological interventions in acute ischemic stroke and warrant further clinical evaluation.

2020-12-01·Purinergic signalling3区 · 医学

Nucleotide P2Y1 receptor agonists are in vitro and in vivo prodrugs of A1/A3 adenosine receptor agonists: implications for roles of P2Y1 and A1/A3 receptors in physiology and pathology

3区 · 医学

Article

作者: Gao, Zhan-Guo ; Jacobson, Kenneth A ; Korinek, William S ; Wendling, Jay ; Müller, Christa E ; Tosh, Dilip K ; Lechleiter, James D ; Campbell, Mary ; Liston, Theodore E ; Sethre-Hofstad, Dane A ; Hinz, Sonja ; Holstein, Deborah M ; Suresh, R Rama ; Melton, Roger J

Rapid phosphoester hydrolysis of endogenous purine and pyrimidine nucleotides has challenged the characterization of the role of P2 receptors in physiology and pathology. Nucleotide phosphoester stabilization has been pursued on a number of medicinal chemistry fronts. We investigated the in vitro and in vivo stability and pharmacokinetics of prototypical nucleotide P2Y₁ receptor (P2Y₁R) agonists and antagonists. These included the riboside nucleotide agonist 2-methylthio-ADP and antagonist MRS2179, as well as agonist MRS2365 and antagonist MRS2500 containing constrained (N)-methanocarba rings, which were previously reported to form nucleotides that are more slowly hydrolyzed at the α-phosphoester compared with the ribosides. In vitro incubations in mouse and human plasma and blood demonstrated the rapid hydrolysis of these compounds to nucleoside metabolites. This metabolism was inhibited by EDTA to chelate divalent cations required by ectonucleotidases for nucleotide hydrolysis. This rapid hydrolysis was confirmed in vivo in mouse pharmacokinetic studies that demonstrate that MRS2365 is a prodrug of the nucleoside metabolite AST-004 (MRS4322). Furthermore, we demonstrate that the nucleoside metabolites of MRS2365 and 2-methylthio-ADP are adenosine receptor (AR) agonists, notably at A₃ and A₁ARs. In vivo efficacy of MRS2365 in murine models of traumatic brain injury and stroke can be attributed to AR activation by its nucleoside metabolite AST-004, rather than P2Y₁R activation. This research suggests the importance of reevaluation of previous in vitro and in vivo research of P2YRs and P2XRs as there is a potential that the pharmacology attributed to nucleotide agonists is due to AR activation by active nucleoside metabolites.

项与 Astrocyte Pharmaceuticals, Inc. 相关的新闻（医药）

2024-03-12

·BioSpace

Astrocyte Pharmaceuticals Announces FDA Clearance of its Investigational New Drug Application for AST-004Green Light for Phase 2 Trial of AST-004 in Acute Ischemic Stroke Patients

GROTON, Conn., March 12, 2024 (GLOBE NEWSWIRE) -- Astrocyte Pharmaceuticals Inc., a clinical-stage biopharmaceutical company committed to advancing cerebroprotective therapies for individuals suffering from stroke, traumatic brain injury (TBI), and concussion, has announced today the U.S. Food and Drug Administration (FDA) has cleared the company’s Investigational New Drug (IND) application for its lead program, AST-004, for acute ischemic stroke. The company is preparing to initiate a Phase 2 clinical trial. The IND application clearance also paves the way for additional studies further exploring AST-004 in stroke, as well as TBI, and concussion. Currently, only ~5% of stroke patients receive pharmaceutical therapy, largely due to the short treatment windows of available thrombolytic medicines, as well as their need for imaging before those treatments can be initiated. AST-004 was developed with the potential to treat all stroke patients. Unlike existing therapies, treatment with AST-004 is designed for use without the need for imaging in the emergency room and for use at any point after diagnosis. And it has the potential to treat stroke occurring in any sized blood vessel in the brain. The upcoming Phase 2 trial in acute ischemic stroke patients builds upon the recent successful stroke clinical trial designs used by medical device companies, heralding a new era in patient care. “The past decade has witnessed a transformative shift in stroke trials, thanks to sophisticated imaging techniques that enable high-quality real-time characterization of stroke and ensure selection of homogeneous study groups,” said Dr. Kevin Sheth, Co-Director of the Center for Brain & Mind Health at the Yale School of Medicine and Chief Medical Advisor to Astrocyte. “The new study of AST-004 will first focus on treating those stroke patients with large vessel occlusions, offering hope to significantly diminish brain damage.” AST-004 is an innovative small molecule therapy that has demonstrated exceptional promise in preclinical studies. In a critical non-human primate stroke model, a significant reduction in brain lesion growth by 64% and an overall lesion size decrease by 45% were observed with a high dose (as reported in 'The Journal Stroke' in 2022). Astrocyte previously completed two Phase 1 safety trials in Europe, involving 80 participants in total, and saw no significant adverse effects or safety concerns. Dr. William Korinek, CEO of Astrocyte Pharmaceuticals, commented, “Since our founding in 2014, we have been focused on demonstrating the potential of cerebroprotective benefits of AST-004. Our robust preclinical program and Phase 1 studies have laid the foundation for our ongoing development efforts, and we are eager to move forward with the planned Phase 2 study. Stroke is the second leading cause of death globally, and the need for advances in treatment is enormous. We believe AST-004 can be part of that solution.” About Astrocyte Pharmaceuticals Inc. Astrocyte Pharmaceuticals Inc. is a privately held, clinical-stage drug discovery and development company dedicated to accelerating the recovery and well-being of brain injury patients. The company is committed to proving the cerebroprotective benefits of enhancing astrocyte function and advancing breakthrough therapeutic agents for treating brain injury resulting from stroke, traumatic brain injury, concussion, and neurodegenerative disorders such as Alzheimer’s disease. For more information on Astrocyte Pharmaceuticals Inc. and the AST-004 program, please visit us at Astrocyte Pharmaceuticals Inc. Forward-Looking Statement This press release contains certain forward-looking statements regarding, among other things, statements relating to goals, plans, and projections regarding the company’s financial position, results of operations, market position, product development, and business strategy. Such forward-looking statements are based on current expectations and involve inherent risks and uncertainties, including factors that could delay, divert, or change any of them and could cause actual outcomes and results to differ materially from current expectations. No forward-looking statements can be guaranteed, and actual results may differ materially from such statements. The information in this release is provided only as of the date of this release, and the company undertakes no obligation to update any forward-looking statements contained in this release on account of new information, future events, or otherwise, except as required by law. Media contact: Kimberly Macleod – kim@kmacconnect.com info@astrocytepharma.com

临床1期临床2期临床申请

2023-08-18

·BioSpace

Alzheimer's Drug Discovery Foundation Joins Astrocyte Pharmaceuticals’ $6M Pre-Series B Financing Round to Expand Development of Cerebroprotectant AST-004

GROTON, Conn.--(BUSINESS WIRE)-- Astrocyte Pharmaceuticals Inc., a clinical-stage drug discovery and development company advancing novel cerebroprotective therapeutics for patients with brain injuries, announced an oversubscribed pre-Series B Bridge financing round of over $6M that was led by Dreavent Capital, and joined by the Alzheimer's Drug Discovery Foundation, and other investors. The funding will accelerate the clinical development of AST-004, a highly promising therapeutic candidate aimed at treating a broad array of acute brain injuries including stroke and traumatic brain injury (TBI), and further assess its potential in preclinical models of Alzheimer's disease. “There are millions of patients living with brain injuries worldwide who face limited treatment options for these devastating conditions,” said William Korinek, Ph.D, CEO, Astrocyte Pharmaceuticals. “With this additional funding, we are poised to accelerate the clinical development of AST-004 and move one step closer to proving this novel approach can benefit patients in dire need.” Astrocyte is currently conducting Phase 1B clinical safety studies of AST-004 and preparing for Phase 2 efficacy studies in 2024. “Astrocyte has assembled an exceptional team of experts that are conducting research of the highest quality at every step,” commented Gorka Fius, CEO at Dreavent Capital who led the investment round. “Multiple preclinical studies have demonstrated the broad efficacy of AST-004 in different brain injury types and severities, and reinforces the strong belief in AST-004 and the transformative potential of this therapy.” Beyond acute brain injuries, research continues assessing the potential of AST-004 to treat chronic neurodegenerative conditions such as Alzheimer’s disease. “Finding innovative ways to target inflammation in the brain will play an important role in the future of combination therapy and precision medicine for Alzheimer's disease,” said Howard Fillit, M.D., Co-Founder and Chief Science Officer, Alzheimer's Drug Discovery Foundation. “Astrocyte's approach using AST-004 holds promise for reducing astrocyte-induced excess inflammation, which has the potential to provide a neuroprotective effect and may reduce the burden of beta-amyloid plaques in the brain, one of the traditional hallmarks of Alzheimer’s.” In addition to Dreavent Capital and the Alzheimer's Drug Discovery Foundation, the investment round was joined by Navis VB Fund I, DeepWork Capital, Mid Atlantic Bio Angels, Boston Harbor Angels, Life Science Angels, Mass Medical Angels, SideCar Angels, and others. For more information about Astrocyte Pharmaceuticals and their groundbreaking research initiatives, please visit . About Astrocyte Pharmaceuticals Inc. Astrocyte Pharmaceuticals Inc. is a privately held clinical-stage biopharmaceutical company committed to revolutionizing brain injury treatment and enhancing the lives of those affected. The company is advancing breakthrough therapeutic agents that show significant efficacy across diverse small and large animal brain injury models, encompassing stroke, traumatic brain injury, concussion, and neurodegenerative conditions like Alzheimer's disease. For more information, please visit us at Astrocyte Pharmaceuticals Inc. About The Alzheimer's Drug Discovery Foundation Founded in 1998 by Leonard A. and Ronald S. Lauder, the Alzheimer's Drug Discovery Foundation is dedicated to rapidly accelerating the discovery of drugs to prevent, treat and cure Alzheimer's disease. The ADDF is the only public charity solely focused on funding the development of drugs for Alzheimer's, employing a venture philanthropy model to support research in academia and the biotech industry. The ADDF's leadership and contributions to the field have played a pivotal role in bringing the first Alzheimer's PET scan (Amyvid®) and blood test (PrecivityAD®) to market, as well as fueling the current robust and diverse drug pipeline. Through the generosity of its donors, the ADDF has awarded more than $250 million to fund over 720 Alzheimer's drug discovery programs, biomarker programs and clinical trials in 19 countries. To learn more, please visit: . Forward-Looking Statement This press release contains certain forward-looking statements regarding, among other things, statements relating to goals, plans and projections regarding the company’s financial position, results of operations, market position, product development and business strategy. Such forward-looking statements are based on current expectations and involve inherent risks and uncertainties, including factors that could delay, divert or change any of them, and could cause actual outcomes and results to differ materially from current expectations. No forward-looking statements can be guaranteed and actual results may differ materially from such statements. The information in this release is provided only as of the date of this release, and the company undertakes no obligation to update any forward-looking statements contained in this release on account of new information, future events, or otherwise, except as required by law.

临床1期临床2期

2023-04-10

·BioSpace

Astrocyte Pharmaceuticals Announces Theodore Liston, Ph.D., Vice President of Research, as Recipient of the 2022 Innovation and Progress Award from the Journal Stroke

GROTON, Conn.--(BUSINESS WIRE)-- Astrocyte Pharmaceuticals Inc., a private drug discovery and development company advancing novel cerebroprotective therapeutics for patients with brain injuries, today announced that Theodore Liston, Ph.D., Vice President of Research at Astrocyte, received the 2022 Progress and Innovation Award from the journal Stroke for authoring one of the journal’s top three publications in 2022. The Innovation and Progress Award recognizes research that demonstrates “a new approach, new methodology, new interpretation of existing data, or new data with far-reaching implications.” This press release features multimedia. View the full release here: Theodore E. Liston, Ph.D., Vice President of Research, Astrocyte Pharmaceuticals Inc. (Photo: Business Wire) Dr. Liston’s manuscript, Adenosine A1R/A3R (Adenosine A1 and A3 Receptor) Agonist AST-004 Reduces Brain Infarction in a Nonhuman Primate Model of Stroke, demonstrates that Astrocyte’s proprietary AST-004 drug candidate targeting adenosine A1/A3 receptors is significantly efficacious in a primate model of ischemic stroke designed to simulate a human stroke Phase 2 trial. The study showed compelling benefits for AST-004 treatment slowing stroke lesion growth, preserving at risk penumbra tissue, and substantially reducing the amount of brain tissue lost to the stroke. The research included novel pharmacokinetic/pharmacodynamic (PK/PD) modeling enabling estimates of a recommended human dose. “This research represents the first demonstration in primates that activation of specific adenosine receptors leads to significant efficacy in saving brain tissue at risk during a stroke,” remarked Dr. Liston. “This research was a truly international team effort throughout the design, planning, conduct, data analysis and publication, much of which happened during the challenging times of the COVID-19 pandemic, and will propel AST-004 into Phase 2 clinical studies.” An interview with Dr. Liston regarding the research is available online conducted by Sarah Y. Song, M.D., M.P.H., Associate Professor in the Section of Cerebrovascular Disease in the Department of Neurological Sciences at Rush University Medical Center, and Stroke Digital Media Editor. The Progress and Innovation Award is given to the publication’s first author and is comprised of a cash prize and a trophy. The award is made possible by funding from the American Heart Association | American Stroke Association. Co-authors of the publication include Aldric Hama, Ph.D.; Johannes Boltze, M.D., Ph.D.; Russell B. Poe, Ph.D.; Takahiro Natsume, Ph.D.; Ikuo Hayashi, Ph.D.; Hiroyuki Takamatsu, Ph.D.; William S. Korinek, Ph.D.; and James D. Lechleiter, Ph.D., representing Astrocyte Pharmaceuticals and the University of Texas Health San Antonio in the USA, Hamamatsu Pharma Research in Japan, and the University of Warwick in the UK. “The ongoing excitement of endovascular reperfusion has heralded a resurgence of scientific development aimed at improving acute stroke outcomes. The prestigious awarding of this year’s Stroke Progress & Innovation prize to Dr. Liston’s paper in Stroke, the flagship cerebrovascular journal of the American Heart Association, embodies this enthusiasm,” added Kevin Sheth, M.D., Chief of Yale’s Division of Neurocritical Care & Emergency Neurology, Director of the Yale Center of Brain & Mind Health, and Chief Medical Advisor to Astrocyte. “The paper is exciting because a novel concept, astrocyte protection, is tested in a non-human primate model of stroke that closely mirrors the clinical condition, and the positive results set the stage for immediate clinical translation.” AST-004 is currently being evaluated in Phase 1B human safety studies, with Phase 2 efficacy studies in stroke patients planned to start in 2024. About Astrocyte Pharmaceuticals Inc. Astrocyte Pharmaceuticals Inc. is a privately held, clinical stage, drug discovery and development company dedicated to accelerating the recovery and well-being of brain injury patients. The company is committed to proving the cerebroprotective benefits of enhancing astrocyte function, and advancing breakthrough therapeutic agents for treating brain injury resulting from stroke, traumatic brain injury, concussion, and neurodegenerative disorders such as Alzheimer’s disease. For more information, please visit us at Astrocyte Pharmaceuticals Inc. Forward Looking Statement This press release contains certain forward-looking statements regarding, among other things, statements relating to goals, plans and projections regarding the company’s financial position, results of operations, market position, product development and business strategy. Such forward-looking statements are based on current expectations and involve inherent risks and uncertainties, including factors that could delay, divert or change any of them, and could cause actual outcomes and results to differ materially from current expectations. No forward-looking statements can be guaranteed and actual results may differ materially from such statements. The information in this release is provided only as of the date of this release, and the company undertakes no obligation to update any forward-looking statements contained in this release on account of new information, future events, or otherwise, except as required by law.

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