tovinontrine (IMR-687) / Enliven Therapeutics, Cardurion - LARVOL DELTA

A Study to Assess Safety & Effectiveness of Tovinontrine in Chronic Heart Failure With Reduced Ejection Fraction (Cycle-1-REF) (clinicaltrials.gov) - P2 | N=557 | Completed | Sponsor: Cardurion Pharmaceuticals, Inc. | Active, not recruiting ➔ Completed

Trial completion • Cardiovascular • Congestive Heart Failure • Heart Failure

Safety & Effectiveness of Tovinontrine in Chronic Heart Failure With Preserved Ejection Fraction (Cycle-2-PEF) (clinicaltrials.gov) - P2 | N=303 | Completed | Sponsor: Cardurion Pharmaceuticals, Inc. | Active, not recruiting ➔ Completed

Trial completion • Cardiovascular • Congestive Heart Failure • Heart Failure

A Study to Assess Safety & Effectiveness of Tovinontrine in Chronic Heart Failure With Reduced Ejection Fraction (Cycle-1-REF) (clinicaltrials.gov) - P2 | N=557 | Active, not recruiting | Sponsor: Cardurion Pharmaceuticals, Inc. | Recruiting ➔ Active, not recruiting | N=400 ➔ 557

Enrollment change • Enrollment closed • Cardiovascular • Congestive Heart Failure • Heart Failure

Safety & Effectiveness of Tovinontrine in Chronic Heart Failure With Preserved Ejection Fraction (Cycle-2-PEF) (clinicaltrials.gov) - P2 | N=303 | Active, not recruiting | Sponsor: Cardurion Pharmaceuticals, Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed • Cardiovascular • Congestive Heart Failure • Heart Failure

A Study of IMR-687 in Subjects With Sickle Cell Disease (clinicaltrials.gov) - P2 | N=115 | Terminated | Sponsor: Cardurion Pharmaceuticals, Inc. | Phase classification: P2b ➔ P2

Phase classification • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

A Study of IMR-687 in Healthy Adult Volunteers (clinicaltrials.gov) - P1 | N=66 | Completed | Sponsor: Cardurion Pharmaceuticals, Inc. | Phase classification: P1a ➔ P1

Phase classification • Beta-Thalassemia • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

A Study of IMR-687 in Adult Participants With Sickle Cell Anemia (Homozygous HbSS or Sickle-β0 Thalassemia) (clinicaltrials.gov) - P2 | N=100 | Completed | Sponsor: Cardurion Pharmaceuticals, Inc. | Phase classification: P2a ➔ P2

Phase classification • Anemia • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

A Study to Assess Safety & Effectiveness of Tovinontrine in Chronic Heart Failure With Reduced Ejection Fraction (Cycle-1-REF) (clinicaltrials.gov) - P2 | N=400 | Recruiting | Sponsor: Cardurion Pharmaceuticals, Inc. | Not yet recruiting ➔ Recruiting

Enrollment open • Cardiovascular • Congestive Heart Failure • Heart Failure

Safety & Effectiveness of Tovinontrine in Chronic Heart Failure With Preserved Ejection Fraction (Cycle-2-PEF) (clinicaltrials.gov) - P2 | N=240 | Recruiting | Sponsor: Cardurion Pharmaceuticals, Inc. | Not yet recruiting ➔ Recruiting

Enrollment open • Cardiovascular • Congestive Heart Failure • Heart Failure

A Study to Assess Safety & Effectiveness of Tovinontrine in Chronic Heart Failure With Reduced Ejection Fraction (Cycle-1-REF) (clinicaltrials.gov) - P2 | N=400 | Not yet recruiting | Sponsor: Cardurion Pharmaceuticals, Inc.

New P2 trial • Cardiovascular • Congestive Heart Failure • Heart Failure

Safety & Effectiveness of Tovinontrine in Chronic Heart Failure With Preserved Ejection Fraction (Cycle-2-PEF) (clinicaltrials.gov) - P2 | N=240 | Not yet recruiting | Sponsor: Cardurion Pharmaceuticals, Inc.

New P2 trial • Cardiovascular • Congestive Heart Failure • Heart Failure

Treatment with IMR-687, a Highly Selective PDE9 Inhibitor, Increases HbF and Reduces VOCs in Adults with Sickle Cell Disease in a Long-Term, Phase 2a, Open-Label Extension Study (ASH 2021) - P2, P2a, P2b | "In a Phase 2a, randomized, double-blind, placebo-controlled study of adult patients with SCD (N=93) (NCT03401112), IMR-687 was generally well-tolerated as a monotherapy and in combination with hydroxyurea (HU) (European Hematology Association Annual Congress 2021, Abstract S263). IMR-687 treatment reduced the annualized rate of VOCs and increased HbF (%) and F-cells (%). Based on these encouraging data, a Phase 2b study (NCT04474314) is ongoing to further explore IMR-687 at doses up to 400 mg daily as a disease-modifying therapy for SCD."

Clinical • P2a data • Back Pain • Beta-Thalassemia • Genetic Disorders • Hematological Disorders • Musculoskeletal Pain • Pain • Sickle Cell Disease

PDE9 Inhibition By IMR-687 Improves Markers of Beta-Thalassemia in the Hbbth1/th1 Experimental Mouse Model (ASH 2021) - P2 | "These results support a role for IMR-687 in beta-thalassemia by enabling RBC maturation and improving ineffective erythropoiesis, key components in ameliorating disease pathology. Clinical testing of IMR-687 (up to 400 mg) as a once daily, oral tablet is currently ongoing in a Phase 2 study of patients with beta-thalassemia (NCT04411082)."

Preclinical • Beta-Thalassemia • Genetic Disorders • Hematological Disorders • TFRC

Results of a phase 1 healthy volunteer (HV) study of the safety, tolerability, and pharmacokinetics of tovinontrine (IMR-687), an investigational, oral PDE9 inhibitor for the treatment of HFpEF (ESC 2022) - No abstract available

Clinical • P1 data • PK/PD data • Cardiovascular

SP9In-HFpEF: Selective PDE9 Inhibition With IMR-687 in Adults With Heart Failure With Preserved Ejection Fraction (clinicaltrials.gov) - P2 | N=0 | Withdrawn | Sponsor: Imara, Inc. | N=168 ➔ 0 | Not yet recruiting ➔ Withdrawn

Enrollment change • Trial withdrawal • Cardiovascular • Congestive Heart Failure • Heart Failure • IFNG • IL6 • MMP2

A Study of IMR-687 in Subjects With Sickle Cell Disease (clinicaltrials.gov) - P2b | N=115 | Terminated | Sponsor: Imara, Inc. | Active, not recruiting ➔ Terminated | Trial primary completion date: Sep 2022 ➔ Mar 2022 | Trial completion date: Sep 2022 ➔ May 2022; A recently conducted Interim analysis of IMR-SCD-301 demonstrated that while IMR-687 was generally well-tolerated, it failed to meet its primary efficacy endpoint. So, the sponsor has decided to discontinue this study.

Trial completion date • Trial primary completion date • Trial termination • Genetic Disorders • Hematological Disorders • Sickle Cell Disease • CRP • MPO • NPPB • VCAM1

A Study of IMR-687 in Subjects With Beta Thalassemia (clinicaltrials.gov) - P2 | N=122 | Terminated | Sponsor: Imara, Inc. | Trial completion date: Jan 2023 ➔ May 2022 | Active, not recruiting ➔ Terminated | Trial primary completion date: Jan 2023 ➔ Mar 2022; IMR-BTL-201demonstrated that while IMR-687 was generally well-tolerated, it failed to show any meaningful benefit in transfusion burden or improvement in most disease-related biomarkers. So, the sponsor has decided to discontinue this study

Trial completion date • Trial primary completion date • Trial termination • Beta-Thalassemia • Genetic Disorders

A Study of IMR-687 in Subjects With Sickle Cell Disease (clinicaltrials.gov) - P2b | N=99 | Active, not recruiting | Sponsor: Imara, Inc. | Trial primary completion date: Mar 2022 ➔ Sep 2022

Trial primary completion date • Genetic Disorders • Hematological Disorders • Sickle Cell Disease • CRP • MPO • NPPB • VCAM1

SP9In-HFpEF: Selective PDE9 Inhibition With IMR-687 in Adults With Heart Failure With Preserved Ejection Fraction (clinicaltrials.gov) - P2 | N=168 | Not yet recruiting | Sponsor: Imara, Inc.

New P2 trial • Cardiovascular • Congestive Heart Failure • Heart Failure • IFNG • IL6 • MMP2

Imara Announces FDA Clearance of Investigational New Drug Application (IND) for Tovinontrine (IMR-687) for Heart Failure with Preserved Ejection Fraction (HFpEF) (GlobeNewswire) - "In addition to Imara's internal development team, led by cardiologist...this trial will be overseen by an executive committee of key opinion leaders in heart failure including...Sanjiv Shah, M.D..."

Regulatory

An Extension Study of IMR-687 in Adult Patients With Sickle Cell Anemia (clinicaltrials.gov) - P2 | N=30 | Active, not recruiting | Sponsor: Imara, Inc. | Enrolling by invitation ➔ Active, not recruiting

Enrollment closed • Anemia • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

A Study of IMR-687 in Subjects With Beta Thalassemia (clinicaltrials.gov) - P2 | N=120 | Active, not recruiting | Sponsor: Imara, Inc. | Recruiting ➔ Active, not recruiting | Trial completion date: May 2022 ➔ Jan 2023 | Trial primary completion date: May 2022 ➔ Jan 2023

Enrollment closed • Trial completion date • Trial primary completion date • Beta-Thalassemia • Genetic Disorders

β-Thalassemia: evolving treatment options beyond transfusion and iron chelation. (PubMed, Hematology Am Soc Hematol Educ Program) - "Luspatercept, a transforming growth factor-β inhibitor, has demonstrated efficacy in reducing ineffective erythropoiesis, improving anemia, and possibly reducing iron loading...Several medications in development aim to induce hemoglobin F (HbF): sirolimus, benserazide, and IMR-687 (a phosphodiesterase 9 inhibitor). Another group of agents seeks to ameliorate ineffective erythropoiesis and improve anemia by targeting abnormal iron metabolism in thalassemia: apotransferrin, VIT-2763 (a ferroportin inhibitor), PTG-300 (a hepcidin mimetic), and an erythroferrone antibody in early development. Mitapivat, a pyruvate kinase activator, represents a unique mechanism to mitigate ineffective erythropoiesis...One such product, betibeglogene autotemcel (beti-cel), has reached phase 3 trials with promising results. In addition, 2 gene editing techniques (CRISPR-Cas9 and zinc-finger nucleases) are under investigation as a means to silence BCL11A to induce HbF with agents designated..."

Journal • Beta-Thalassemia • Bone Marrow Transplantation • Genetic Disorders • Hematological Disorders • Transplantation

[VIRTUAL] Selective Phosphodiesterase-9 Inhibition With IMR-687 Mitigates Cardiac Hypertrophy and Renal Injury in Preclinical Mouse Models of Heart Failure With Preserved Ejection Fraction (AHA 2021) - "Selective PDE9 inhibition with IMR-687 was effective for prevention and treatment of cardiac hypertrophy and renal dysfunction in 3 different preclinical models of HFpEF. IMR-687 may be a promising candidate therapy for testing in clinical trials of human HFpEF."

Preclinical • Cardiovascular • Congestive Heart Failure • Fibrosis • Heart Failure • Immunology • Nephrology • Renal Disease • IL1B

A Study of IMR-687 in Subjects With Sickle Cell Disease (clinicaltrials.gov) - P2b; N=99; Active, not recruiting; Sponsor: Imara, Inc.; Recruiting ➔ Active, not recruiting; Trial primary completion date: Dec 2021 ➔ Mar 2022

Clinical • Enrollment closed • Trial primary completion date • Genetic Disorders • Hematological Disorders • Sickle Cell Disease • CRP • MPO • NPPB • VCAM1