zagociguat (CY6463) / Tisento Therap - LARVOL DELTA

PRIZM: A Phase 2b Study of Zagociguat in Patients With MELAS (clinicaltrials.gov) - P2 | N=44 | Recruiting | Sponsor: Tisento Therapeutics | Trial completion date: Mar 2026 ➔ Jun 2026 | Trial primary completion date: Mar 2026 ➔ Jun 2026

Trial completion date • Trial primary completion date • Cardiovascular • CNS Disorders • Metabolic Disorders

An Open-label Extension Safety Study of MELAS Patients Who Completed TIS6463-203 (PRIZM) (clinicaltrials.gov) - P2 | N=44 | Enrolling by invitation | Sponsor: Tisento Therapeutics | Not yet recruiting ➔ Enrolling by invitation | Trial completion date: Mar 2028 ➔ Jul 2028 | Trial primary completion date: Mar 2028 ➔ Jul 2028

Enrollment open • Trial completion date • Trial primary completion date • Cardiovascular • CNS Disorders • Metabolic Disorders

Zagociguat prevented stressor-induced neuromuscular dysfunction, improved mitochondrial physiology, and increased exercise capacity in diverse mitochondrial respiratory chain disease zebrafish models. (PubMed, Front Pharmacol) - "Preclinical evaluation of zag demonstrated its safety, significant protection of neuromuscular dysfunction and/or acute RC stressor-induced decompensation, and improved mitochondrial physiology across multiple different genetic and/or pharmacologic models of RC-deficient PMD. Thus, zag may yield therapeutic potential for an array of diseases with mitochondrial dysfunction beyond MELAS, potentially including Leigh syndrome spectrum disorder and primary mitochondrial myopathies."

Journal • Cardiovascular • CNS Disorders • Metabolic Disorders • Myositis

Tisento Therapeutics Receives U.S. FDA Fast Track Designation for Zagociguat for the Treatment of MELAS (GlobeNewswire) - "Tisento Therapeutics today announced that the U.S. Food and Drug Administration (FDA) has granted Fast Track designation to zagociguat for the treatment of MELAS (Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like Episodes)....In the global Phase 2b PRIZM study, Tisento is evaluating the impact of zagociguat treatment on fatigue, cognitive impairment, and other key aspects of MELAS."

Fast track • Genetic Disorders

An Open-label Extension Safety Study of MELAS Patients Who Completed TIS6463-203 (PRIZM) (clinicaltrials.gov) - P2 | N=44 | Not yet recruiting | Sponsor: Tisento Therapeutics

New P2 trial • Cardiovascular • CNS Disorders • Metabolic Disorders

PRIZM: A Phase 2b Study of Zagociguat in Patients with MELAS (clinicaltrials.gov) - P2 | N=44 | Recruiting | Sponsor: Tisento Therapeutics | Trial completion date: Sep 2025 ➔ Mar 2026 | Trial primary completion date: Sep 2025 ➔ Mar 2026

Trial completion date • Trial primary completion date • Cardiovascular • CNS Disorders • Metabolic Disorders

First Participant Dosed in Tisento Therapeutics’ Global Phase 2b PRIZM Study Evaluating Zagociguat for the Treatment of MELAS (GlobeNewswire) - "Tisento Therapeutics today announced that the first patient has been dosed in its global Phase 2b PRIZM study. The study is investigating the impact of once-daily oral zagociguat treatment on fatigue, cognitive impairment, and other key aspects of the rare mitochondrial disease MELAS (Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like Episodes)."

Trial status • Cognitive Disorders • Rare Diseases

PRIZM: A Phase 2b Study of Zagociguat in Patients with MELAS (clinicaltrials.gov) - P2 | N=44 | Recruiting | Sponsor: Tisento Therapeutics | Not yet recruiting ➔ Recruiting

Enrollment open • Cardiovascular • CNS Disorders • Metabolic Disorders

A Study of the Effects of CY6463 in Participants With Alzheimer's Disease With Vascular Pathology (clinicaltrials.gov) - P2 | N=12 | Terminated | Sponsor: Tisento Therapeutics | Phase classification: P2a ➔ P2

Phase classification • Alzheimer's Disease • CNS Disorders

PRIZM: A Phase 2b Study of Zagociguat in Patients With MELAS (clinicaltrials.gov) - P2 | N=36 | Not yet recruiting | Sponsor: Tisento Therapeutics | Trial completion date: Sep 2024 ➔ Sep 2025 | Trial primary completion date: Sep 2024 ➔ Sep 2025

Trial completion date • Trial primary completion date • Cardiovascular • CNS Disorders • Metabolic Disorders

PRIZM: A Phase 2b Study of Zagociguat in Patients With MELAS (clinicaltrials.gov) - P2 | N=36 | Not yet recruiting | Sponsor: Tisento Therapeutics

New P2 trial • Cardiovascular • CNS Disorders • Metabolic Disorders

Phase 2a Study of IW-6463 in Adults Diagnosed With Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like Episodes (MELAS) (clinicaltrials.gov) - P2 | N=8 | Terminated | Sponsor: Tisento Therapeutics | Phase classification: P2a ➔ P2

Phase classification • Cardiovascular • CNS Disorders • Metabolic Disorders

A Study of the Effects of CY6463 in Participants With Alzheimer's Disease With Vascular Pathology (clinicaltrials.gov) - P2a | N=12 | Terminated | Sponsor: Cyclerion Therapeutics | N=30 ➔ 12 | Trial completion date: Jul 2022 ➔ Nov 2022 | Recruiting ➔ Terminated | Trial primary completion date: Jul 2022 ➔ Nov 2022; Due to enrollment challenges

Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Alzheimer's Disease • CNS Disorders

First-in-human trial to assess safety, tolerability, pharmacokinetics and pharmacodynamics of zagociguat (CY6463), a CNS-penetrant soluble guanylyl cyclase stimulator. (PubMed, Clin Transl Sci) - "Zagociguat was well tolerated, CNS-penetrant and demonstrated pharmacodynamic activity consistent with other sGC stimulators. The results of this study support further development of zagociguat."

Journal • P1 data • PK/PD data • CNS Disorders

Phase 2a Study of IW-6463 in Adults Diagnosed With Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like Episodes (MELAS) (clinicaltrials.gov) - P2a | N=8 | Terminated | Sponsor: Cyclerion Therapeutics | Completed ➔ Terminated; Study terminated due to enrollment challenges.

Trial termination • Cardiovascular • CNS Disorders • Metabolic Disorders

CY6463 ADMINISTRATION IN HEALTHY PARTICIPANTS WAS ASSOCIATED WITH IMPROVEMENTS IN ALZHEIMER’S DISEASE-RELEVANT BIOMARKERS BASED ON A SYSTEMATIC ANALYSIS OF MULTIPLE PHASE 1 CLINICAL TRIALS USING KEM® EXPLAINABLE AI. (CTAD 2022) - P1 | "Results for safety endpoint associations were consistent with the favorable safety profile of CY6463 previously reported. On pharmacodynamics, this analysis identified CY6463 treatmentassociated, positive effects on endpoints that have been linked with AD. For example, AD patients have been described in All abstracts are embargoed until the day and time of presentation at the CTAD Conference S102 previous studies as showing increased theta and decreased alpha power by EEG as well as increased MMP3 and decreased cGMP levels."

Biomarker • Clinical • P1 data • Alzheimer's Disease • CNS Disorders • Pain • MMP3

Study to Assess the Safety and Pharmacokinetics of CY6463 in Participants With Stable Schizophrenia (clinicaltrials.gov) - P1 | N=48 | Completed | Sponsor: Cyclerion Therapeutics | Recruiting ➔ Completed

Trial completion • CNS Disorders • Psychiatry • Schizophrenia

Phase 2a Study of IW-6463 in Adults Diagnosed With MELAS (clinicaltrials.gov) - P2a | N=8 | Completed | Sponsor: Cyclerion Therapeutics | Recruiting ➔ Completed | N=20 ➔ 8

Enrollment change • Trial completion • Cardiovascular • CNS Disorders • Metabolic Disorders

Design and methods of a Phase 2a study evaluating the safety, tolerability, pharmacokinetics, and CNS activity of CY6463 in participants with Alzheimer’s disease with vascular pathology (AAN 2022) - "Results from this study will inform the design of larger, longer studies evaluating the potential for CY6463 to improve cognition in ADv."

Clinical • P2a data • PK/PD data • Alzheimer's Disease • Cardiovascular • CNS Disorders • Immunology • Inflammation

Cyclerion Announces CY6463 Clinical Pipeline and Corporate Updates (GlobeNewswire) - “Cognitive Impairment Associated with Schizophrenia (CIAS): The Phase 1 CIAS trial (NCT04972227) is a randomized, placebo-controlled, multiple-ascending-dose study of oral, once-daily CY6463 in adults aged 18-50 diagnosed with schizophrenia….Clinical sites are actively enrolling study participants and topline data are expected in H2 2022.”

P1 data • CNS Disorders • Cognitive Disorders • Schizophrenia

Cyclerion Therapeutics and Ariana Pharma Announce an Artificial Intelligence-driven Precision Medicine Collaboration (Gurufocus) - "Cyclerion Therapeutics, Inc. ( CYCN) and Ariana Pharma today announced an artificial intelligence-driven, precision medicine collaboration. This collaboration is expected to identify biomarkers of response to refine patient selection to guide and accelerate the clinical development of Cyclerion’s investigational therapeutics for neurological and neuropsychiatric diseases associated with cognitive impairment....Cyclerion expects to obtain clinical results from...CIAS studies in...2H 2022...The ADv study initiated patient dosing in January 2022 and enrollment is ongoing."

Licensing / partnership • P1 data • CNS Disorders • Cognitive Disorders • Schizophrenia

Cyclerion Therapeutics Announces Initiation of Patient Dosing in CY6463 Phase 2a Study in Alzheimer’s Disease with Vascular Pathology (GlobeNewswire) - “Cyclerion Therapeutics, Inc…today announced that patient dosing has begun in its Phase 2a study in Alzheimer’s Disease with Vascular Pathology (ADv).”

Trial status • Alzheimer's Disease • CNS Disorders

Study to Assess the Safety and Pharmacokinetics of CY6463 in Participants With Stable Schizophrenia (clinicaltrials.gov) - P1; N=60; Recruiting; Sponsor: Cyclerion Therapeutics; Not yet recruiting ➔ Recruiting

Clinical • Enrollment open • CNS Disorders • Psychiatry • Schizophrenia

Cyclerion Therapeutics Reports Second Quarter 2021 Financial Results and Corporate Update (Yahoo Finance) - "CIAS Clinical Trial Start-up: The Company received notification from the FDA that its Ph1b clinical trial in participants with CIAS may proceed and study start-up activities are ongoing."

Trial status • CNS Disorders • Schizophrenia

[VIRTUAL] A Phase 2a study evaluating the safety, tolerability, pharmacokinetics, and central nervous system activity of CY6463 when administered to participants with Alzheimer’s disease with vascular pathology (AAIC 2021) - "Results from this study in patients with ADv will inform the design of larger, longer studies evaluating the potential for CY6463 to improve cognition in this patient population."

Clinical • P2a data • PK/PD data • Alzheimer's Disease • Cardiovascular • CNS Disorders • Immunology • Inflammation • MRI • sGC HDA+