A Phase 2 Double-Blinded Placebo-Controlled Study of the Safety and Clinical Efficacy signals of AST-004 infusion for Traumatic Brain Injury (TBI)/Concussions in Australian-Rules Footballers..

Start Date31 May 2025

Sponsor / Collaborator-

NL-OMON53360

/ CompletedNot Applicable

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

Start Date05 Apr 2023

Sponsor / Collaborator

Astrocyte Pharmaceuticals, Inc.

100 Clinical Results associated with AST-004

100 Translational Medicine associated with AST-004

100 Patents (Medical) associated with AST-004

Literatures (Medical) associated with AST-004

01 Jun 2026·Purinergic Signalling

The long march towards testing the adenosine receptor agonism hypothesis for human cerebroprotection: The story of the A1R/A3R receptor agonist AST-004

Review

Author: Korinek, William S ; Liston, Theodore E ; Lechleiter, James D ; Jacobson, Kenneth A

AST-004 is an adenosine A₁R/A₃R agonist and promising cerebroprotectant currently in Phase II clinical development. Clinical evaluations have been initiated in concussion, with trials in preparation for mild complicated traumatic brain injury (TBI) and acute ischemic stroke (AIS). AST-004 was discovered as the result of basic research on the P2Y₁R-activated homeostatic roles of astrocytes in cerebroprotection, including control of edema, excitotoxicity and oxidative stress. AST-004 was identified as the active nucleoside metabolite of the P2Y₁R agonist MRS2365. Subsequent research demonstrated that astrocyte mitochondrial ATP production could be activated by AST-004, resulting in significant efficacy in rodent models of permanent and transient occlusion AIS, porcine models of TBI and a non-human primate model of AIS as well as models of neurodegeneration and addiction. The purpose of this review is to highlight the research that led to the discovery of AST-004, summarize its widespread preclinical efficacy in a variety of disease models, and describe how this compound's excellent safety and pharmaceutical profile is differentiated from prototypical A₁R and A₃R agonists formerly or currently in the clinic.

01 Dec 2024·STROKE

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

Article

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

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.

01 Jul 2024·STROKE

Lack of Interactions Between Alteplase/Tenecteplase and the Adenosine A1R/A3R Agonist AST-004

Article

Author: Korinek, William S. ; Liston, Theodore E ; Holstein, Deborah ; Lechleiter, James D ; Korinek, William S ; Lechleiter, James D. ; Liston, Theodore E. ; Lozano, Damian ; Solt, Derek

BACKGROUND::

AST-004, a small molecule agonist of the adenosine A1 and A3 receptors, is a potential cerebroprotectant for patients with acute stroke and is currently in clinical trials. Drug-drug interactions are critically important to assess in the context of acute stroke care. Lytic therapy with tPA (tissue-type plasminogen activator)–induced plasmin formation (alteplase) is the only available pharmacotherapy for acute stroke. Consequently, it is imperative to evaluate potential interactions between AST-004 and tPAs such as alteplase and tenecteplase.

METHODS::

The interactions between AST-004 and tPAs were evaluated in 3 ways in preparation for AST-004 phase II trials. First, the metabolic stability of AST-004 was determined in the presence of alteplase and plasmin. Second, the potential for AST-004 to influence the thrombolytic efficacy of alteplase and tenecteplase was evaluated with an in vitro assay system utilizing a fluorogenic substrate of plasmin. Finally, the potential for AST-004 to influence the thrombolytic efficacy of alteplase was also determined with an in vitro thrombolysis assay of human blood thrombi.

RESULTS::

Neither alteplase nor plasmin affected the stability of AST-004 in vitro. In 2 different in vitro systems, AST-004 had no effect on the ability of alteplase or tenecteplase to generate plasmin, and AST-004 had no effect on the thrombolytic efficacy of alteplase to lyse blood clots in human blood.

CONCLUSIONS::

These studies indicate that there will be no interactions between AST-004 and tPAs such as alteplase or tenecteplase in patients with stroke undergoing thrombolytic therapy.

News (Medical) associated with AST-004

13 Mar 2024

·www.globenewswire.com

Astrocyte Pharmaceuticals Announces FDA Clearance of its Investigational New Drug Application for AST-004

March 12, 2024 -- 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.” 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. The content above comes from the network. if any infringement, please contact us to modify.

IND

12 Mar 2024

·www.astrocytepharma.com

Astrocyte Pharmaceuticals Announces FDA Clearance of its Investigational New Drug Application for AST-004

Brain Injuries TBI & Concussions Stroke Neurodegenerative Disease Science Astrocytes Activating the Caretakers Reducing Damage in Stroke Healing After TBI and Concussions Portfolio News Press Releases Media Highlights Team Investors Contact TBI & Concussions Stroke Neurodegenerative Disease Astrocytes Activating the Caretakers Reducing Damage in Stroke Healing After TBI and Concussions Press Releases Media Highlights Brain Injuries TBI & Concussions Stroke Neurodegenerative Disease Science Astrocytes Activating the Caretakers Reducing Damage in Stroke Healing After TBI and Concussions Portfolio News Press Releases Media Highlights Team Investors Contact TBI & Concussions Stroke Neurodegenerative Disease Astrocytes Activating the Caretakers Reducing Damage in Stroke Healing After TBI and Concussions Press Releases Media Highlights Brain Injuries TBI & Concussions Stroke Neurodegenerative Disease Science Astrocytes Activating the Caretakers Reducing Damage in Stroke Healing After TBI and Concussions Portfolio News Press Releases Media Highlights Team Investors Contact TBI & Concussions Stroke Neurodegenerative Disease Astrocytes Activating the Caretakers Reducing Damage in Stroke Healing After TBI and Concussions Press Releases Media Highlights Brain Injuries TBI & Concussions Stroke Neurodegenerative Disease Science Astrocytes Activating the Caretakers Reducing Damage in Stroke Healing After TBI and Concussions Portfolio News Press Releases Media Highlights Team Investors Contact TBI & Concussions Stroke Neurodegenerative Disease Astrocytes Activating the Caretakers Reducing Damage in Stroke Healing After TBI and Concussions Press Releases Media Highlights Green Light for Phase 2 Trial of AST-004 in Acute Ischemic Stroke Patients Groton, CT, March 12, 2024 – 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 Press Releases Media Highlights Privacy Policy Overview Brain Injuries Science Portfolio News Team Investors Contact

Phase 1Phase 2IND

12 Mar 2024

·www.biospace.com

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

Phase 1Phase 2IND

100 Deals associated with AST-004

R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Brain Injuries, Traumatic	Phase 2	Netherlands	Astrocyte Pharmaceuticals, Inc.	11 May 2026
Acute Ischemic Stroke	Phase 1	United States	Astrocyte Pharmaceuticals, Inc.	01 Jul 2026
Alzheimer Disease	Preclinical	United States	Astrocyte Pharmaceuticals, Inc.	01 Jul 2026
Brain Concussion	Preclinical	United States	Astrocyte Pharmaceuticals, Inc.	01 Jul 2026

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


Corporate Publications Manual	Phase 1	Brain Injuries	-	AST-004	qyctoplusn(hxwxiqwxqy) = extremely well tolerated at all dose levels, and there have been no safety signals or significant adverse effects associated with AST-004 nqnwcazxly (tsnyuujlou )	Positive	14 Sep 2022

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