ninerafaxstat (IMB-101) / Imbria Pharma - LARVOL DELTA

Comparative efficacy of pharmacological therapies in non-obstructive hypertrophic cardiomyopathy: a frequentist network meta-analysis. (PubMed, Eur J Clin Pharmacol) - "Different pharmacological therapies may provide benefits in specific physiological domains in patients with non-obstructive HCM; however, no single therapy demonstrated consistent improvements across all evaluated outcomes. These findings highlight the heterogeneity of treatment effects and suggest that targeting multiple pathophysiological pathways may be important. Larger randomized and head-to-head comparative studies are needed to define optimal management in this population."

Clinical • Journal • Retrospective data • Review • Cardiomyopathy • Cardiovascular • Hypertrophic Cardiomyopathy • Non-obstructive Hypertrophic Cardiomyopathy

Imbria Pharmaceuticals, Inc…announced that the U.S. Food and Drug Administration (FDA) has granted Orphan Drug Designation to ninerafaxstat for the treatment of symptomatic non-obstructive hypertrophic cardiomyopathy (GlobeNewswire) - Ninerafaxstat, Imbria’s first-in-class investigational oral therapy designed to improve the heart’s ability to produce energy efficiently, is currently being evaluated in the Phase 2b FORTITUDE-HCM clinical trial (NCT07023614) in patients with symptomatic nHCM.

Orphan drug • Non-obstructive Hypertrophic Cardiomyopathy

Targeting Myocardial Energetics in Nonobstructive Hypertrophic Cardiomyopathy (nHCM): The Role of Ninerafaxstat. (PubMed, J Cardiovasc Pharmacol) - "Clinical trials of novel agents, including myosin inhibitors (aficamten, mavacamten) and metabolic modulators, highlight ninerafaxstat's unique potential. Ninerafaxstat represents a paradigm shift toward precision medicine in nHCM, offering a metabolic foundation for combination strategies. Future Phase 3 trials must validate long-term benefits on functional capacity, metabolic markers, arrhythmia risk, and survival, positioning ninerafaxstat as a cornerstone therapy for restoring cardiac energetics in nHCM."

Journal • Cardiomyopathy • Cardiovascular • Gene Therapies • Hypertrophic Cardiomyopathy • Metabolic Disorders • Non-obstructive Hypertrophic Cardiomyopathy

SYSTEMATIC REVIEW OF PHARMACOLOGIC THERAPIES FOR NON-OBSTRUCTIVE HYPERTROPHIC CARDIOMYOPATHY (ACC 2026) - "Cardiac myosin inhibitors (CMIs) lowered pro-brain natriuretic peptide and troponin, improved diastolic indices, and induced modest left ventricular remodeling; aficamten improved functional status in contrast to mavacamten...Renin-angiotensin-aldosterone system (RAAS) agents were largely neutral, but valsartan improved a composite remodeling score in early nHCM. Metabolic modulators were inconsistent - perhexiline and ninerafaxstat showed some benefits, while ranolazine and trimetazidine did not. CMIs show the most consistent efficacy, followed by SGLT2is and cibenzoline; RAAS agents and metabolic modulators provide variable or limited benefit. Further trials are needed to clarify the role of SGLT2is and CMIs in nHCM."

Review • Cardiomyopathy • Cardiovascular • Hypertrophic Cardiomyopathy • Non-obstructive Hypertrophic Cardiomyopathy

IMB101-010: A randomized, double-blinded, placebo-controlled trial to evaluate the efficacy and safety of ninerafaxstat in patients with symptomatic non-obstructive hypertrophic cardiomyopathy (clinicaltrialsregister.eu) - P1/2 | N=130 | Recruiting | Sponsor: Imbria Pharmaceuticals Inc.

New P1/2 trial • Cardiomyopathy • Cardiovascular • Hypertrophic Cardiomyopathy • Non-obstructive Hypertrophic Cardiomyopathy

IMPROVE-DiCE, a 2-Part, Open-Label, Phase 2a Trial Evaluating the Safety and Effectiveness of Ninerafaxstat in Patients With Cardiometabolic Syndromes. (PubMed, Circulation) - P2 | "Myocardial energetics (phosphocreatine-to-ATP ratio [PCr/ATP], primary outcome) and function (rest and dobutamine stress) were assessed before and after treatment using magnetic resonance imaging, 31P- and 1H magnetic resonance spectroscopy. These mechanistic phase 2a study results show that ninerafaxstat is safely tolerated and improves myocardial energetics in participants with obesity and diabetes without or with clinically manifest HFpEF. URL: https://clinicaltrials.gov; Unique identifier: NCT04826159."

Journal • P2a data • Cardiomyopathy • Cardiovascular • Congestive Heart Failure • Diabetes • Genetic Disorders • Heart Failure • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus

A Study to Evaluate the Safety, Tolerability, and Efficacy of IMB-1018972 in Patients With Refractory Angina (clinicaltrials.gov) - P2 | N=0 | Withdrawn | Sponsor: Imbria Pharmaceuticals, Inc. | N=640 ➔ 0 | Suspended ➔ Withdrawn

Enrollment change • Trial withdrawal • Cardiovascular

FORTITUDE-HCM: A Trial to Evaluate the Efficacy and Safety of Ninerafaxstat in Patients With Symptomatic Non-obstructive Hypertrophic Cardiomyopathy (clinicaltrials.gov) - P2 | N=165 | Recruiting | Sponsor: Imbria Pharmaceuticals, Inc. | Not yet recruiting ➔ Recruiting | Initiation date: Jul 2025 ➔ Oct 2025

Enrollment open • Trial initiation date • Cardiomyopathy • Cardiovascular • Hypertrophic Cardiomyopathy • Non-obstructive Hypertrophic Cardiomyopathy

The Role of Medical Therapy in Hypertrophic Cardiomyopathy: An Updated Review. (PubMed, Heart Fail Clin) - "Emerging therapies, including sodium-glucose cotransporter 2 inhibitors, sacubitril/valsartan, and ninerafaxstat, show promising benefits. Proper management of related conditions such as atrial fibrillation and heart failure is also essential. A comprehensive approach that considers individual patient characteristics and the specific subtype of HCM is essential for achieving optimal outcomes."

Journal • Review • Atrial Fibrillation • Cardiomyopathy • Cardiovascular • Congestive Heart Failure • Heart Failure • Hypertrophic Cardiomyopathy

IMPROVE-DiCE: Study to Evaluate Effect of IMB-1018972 on Cardiac Energetics in T2DM & Obesity (Pt 1) With HFpEF (Pt 2) (clinicaltrials.gov) - P2 | N=49 | Completed | Sponsor: Imbria Pharmaceuticals, Inc. | Recruiting ➔ Completed | Trial completion date: Mar 2024 ➔ Aug 2024 | Trial primary completion date: Mar 2024 ➔ Aug 2024

Trial completion • Trial completion date • Trial primary completion date • Cardiomyopathy • Cardiovascular • Diabetes • Genetic Disorders • Heart Failure • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus

FORTITUDE-HCM: A Trial to Evaluate the Efficacy and Safety of Ninerafaxstat in Patients With Symptomatic Non-obstructive Hypertrophic Cardiomyopathy (clinicaltrials.gov) - P2 | N=165 | Not yet recruiting | Sponsor: Imbria Pharmaceuticals, Inc.

New P2 trial • Cardiomyopathy • Cardiovascular • Hypertrophic Cardiomyopathy • Non-obstructive Hypertrophic Cardiomyopathy

A de novo systematic literature review to identify the clinical effectiveness and safety of different treatments for patients with non-obstructive hypertrophic cardiomyopathy (HEART FAILURE 2025) - "A change in New York Heart Association (NYHA) class was reported in seven studies, all of which reported on 40 patients or fewer; within these the proportion of patients with ≥1 class improvement ranged from 14.7% (5/29) (ninerafaxstat arm of IMPROVE-HCM) to 79.4% (27/34) (aficamten arm of FOREST-HCM). There is a scarcity of rigorous studies reporting on non-obstructive HCM treatment and there is no significant evidence to support improved outcomes for traditional treatments, such as beta-blockers. Newer therapies which include cardiac myosin inhibitors (designed to address the underlying pathophysiology of HCM), are emerging as promising options with phase II studies demonstrating step changes in safety and efficacy, including NYHA functional class changes. Further research is needed to strengthen these findings, as current data remains limited."

Clinical • Review • Atrial Fibrillation • Cardiomyopathy • Cardiovascular • Congestive Heart Failure • Heart Failure • Hypertrophic Cardiomyopathy • Non-obstructive Hypertrophic Cardiomyopathy

EFFECTS OF NINERAFAXSTAT ON MYOCARDIAL ENERGETICS, EXERCISE CAPACITY, AND CARDIAC FUNCTION IN HEART FAILURE WITH PRESERVED EJECTION FRACTION, TYPE 2 DIABETES AND OBESITY- A PHASE 2A CLINICAL TRIAL - Sarah Birkhoelzer (ACC 2025) - "In cardiometabolic HFpEF Ninerafaxstat resulted in significant improvement in cardiac energetics. This was associated with clinically meaningful improvements in cardiac function, HF-related health status and exercise capacity."

Clinical • P2a data • Cardiomyopathy • Cardiovascular • Congestive Heart Failure • Diabetes • Genetic Disorders • Heart Failure • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus

Erratum: Ninerafaxstat in the Treatment of Diabetic Cardiomyopathy and Nonobstructive Hypertrophic Cardiomyopathy. (PubMed, Cardiol Rev) - No abstract available

Journal • Cardiomyopathy • Cardiovascular • Hypertrophic Cardiomyopathy • Non-obstructive Hypertrophic Cardiomyopathy

Modulating energy metabolism to treat non-obstructive hypertrophic cardiomyopathy? Insights from IMPROVE-HCM. (PubMed, Heart Fail Rev) - "The study assessed the safety (primary endpoint) and efficacy (secondary endpoint) of ninerafaxstat, a novel cardiac mitotrope drug that increases adenosine triphosphate production. We highlighted the main findings of the trial, contextualizing these results within the larger landscape of completed and ongoing trials in nHCM."

Clinical • Journal • Cardiomyopathy • Cardiovascular • Heart Failure • Hypertrophic Cardiomyopathy • Non-obstructive Hypertrophic Cardiomyopathy • Obstructive Hypertrophic Cardiomyopathy

"Emerging clinical approaches in diabetic cardiomyopathy: insights from clinical trials and future directions". (PubMed, Acta Diabetol) - "Pharmacological treatments like GLP-1 agonists, SGLT-2 inhibitors, NHE-1, NHE-3, and PPAR-γ agonists show promise for treating DCM. These treatments improve myocardial glucose absorption, address dysregulated glucose and lipid metabolism, and lower heart failure and cardiovascular events. Further research is needed to confirm effectiveness and safety."

Journal • Review • Cardiomyopathy • Cardiovascular • Congestive Heart Failure • Diabetes • Heart Failure • Metabolic Disorders • AKR1B1

Ninerafaxstat in the Treatment of Diabetic Cardiomyopathy and Nonobstructive Hypertrophic Cardiomyopathy. (PubMed, Cardiol Rev) - "These findings support a larger phase 3 study in symptomatic nonobstructive HCM patients to further investigate ninerafaxstat. Several drugs that also improve glucose utilization including fatty acid oxidation inhibitors, carnitine palmitoyltransferase I inhibitors, and glucagon-like peptide-1 receptor agonists are presently under investigation in clinical trials."

Journal • Cardiomyopathy • Cardiovascular • Hypertrophic Cardiomyopathy • Non-obstructive Hypertrophic Cardiomyopathy

A randomized, double-blind, placebo-controlled, mechanistic trial on the safety, tolerability and pharmacodynamics of ninerafaxstat in patients with angina and chronic coronary syndrome (ESC 2024) - "The study randomized 58 subjects (mean age 68.6±7.1 years) with symptomatic stable angina and inducible hypoperfusion from 4 sites across 3 countries (Denmark, Finland, Sweden). 22% had type 2 diabetes and 50% had undergone percutaneous and/or surgical coronary revascularization. The majority (68%) were on ≥2 (up to 4) regular anti-anginals."

Clinical • PK/PD data • Cardiovascular • Myocardial Ischemia

Ninerafaxstat in the Treatment of Cardiometabolic Disease: Shifting Metabolic Paradigms. (PubMed, Cardiol Rev) - "While still completing clinical trials, ninerafaxstat must undergo further safety and efficacy evaluation before it can be used as a standard of care. If, however, the drug makes it to market, it might offer a unique way to improve both the symptoms and quality of life of the millions of Americans who suffer from CVDs."

Journal • Cardiovascular • Congestive Heart Failure • Heart Failure • Metabolic Disorders

Benefits of ninerafaxstat in non-obstructive hypertrophic cardiomyopathy. (PubMed, Nat Rev Cardiol) - No abstract available

Journal • Cardiomyopathy • Cardiovascular • Hypertrophic Cardiomyopathy • Non-obstructive Hypertrophic Cardiomyopathy

IMPROVE-HCM: A Study to Evaluate the Safety, Tolerability, and Efficacy of IMB-1018972 in Patients With Non-obstructive Hypertrophic Cardiomyopathy Trial (clinicaltrials.gov) - P2 | N=67 | Completed | Sponsor: Imbria Pharmaceuticals, Inc. | Active, not recruiting ➔ Completed

Trial completion • Cardiomyopathy • Cardiovascular • Hypertrophic Cardiomyopathy • Non-obstructive Hypertrophic Cardiomyopathy

Exploratory Study on the Safety, Tolerability, and Pharmacodynamics of IMB-1018972 in Subjects With Angina Due to Obstructive Coronary Artery Disease (IMPROVE-Ischemia) (clinicaltrials.gov) - P2 | N=58 | Completed | Sponsor: Imbria Pharmaceuticals, Inc. | Active, not recruiting ➔ Completed

Trial completion • Cardiovascular • Coronary Artery Disease

Efficacy And Safety Of Ninerafaxstat, A Novel Cardiac Mitotrope, In Patients With Symptomatic Nonobstructive Hypertrophic Cardiomyopathy: Results Of IMPROVE-HCM (ACC 2024) - "Abstract is embargoed at this time."

Clinical • Late-breaking abstract • Cardiomyopathy • Cardiovascular • Hypertrophic Cardiomyopathy • Non-obstructive Hypertrophic Cardiomyopathy

Safety and Efficacy of Metabolic Modulation With Ninerafaxstat in Patients With Nonobstructive Hypertrophic Cardiomyopathy. (PubMed, J Am Coll Cardiol) - "In symptomatic nHCM, novel drug therapy targeting myocardial energetics was safe and well tolerated and associated with better exercise performance and health status among those most symptomatically limited. The findings support assessing ninerafaxstat in a Phase 3 study."

Journal • Cardiomyopathy • Cardiovascular • Hypertrophic Cardiomyopathy • Non-obstructive Hypertrophic Cardiomyopathy

HCMS In the Thick of It Ep. 5 - What's Next for Non-obstructive Hypertrophic Cardiomyopathy (YouTube) - "Host Dr. Eli Friedman chats with Dr. Ahmad Masri...Join us in this gripping episode as we dive into the world of non-obstructive Hypertrophic Cardiomyopathy with two experts who are on a mission to unravel its mysteries. Dr. Friedman and Dr. Masri share their insights on groundbreaking clinical trials and the potential game-changer, Cardiac Mitotrope Ninerafaxstats. Together, we'll explore the challenges, the breakthroughs, and how science is paving the way for a brighter future in cardiac care! In the Thick of It is brought to you by the HCM Society, and is produced by Earfluence."

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