PDE9A

Cardurion also plans to use the funding to expand the indications outlined for the two candidates and acquire additional assets for treating cardiovascular disorders. Image Credit: VectorMine / Shutterstock. US-based cardiology biotech Cardurion Pharmaceuticals has raised $260m in Series B financing to advance its drug pipeline. The proceeds will fund the late-stage trials for two of the company’s lead candidates, CRD-750, a phosphodiesterase 9 (PDE9) inhibitor for heart failure; and CRD-4730, a calmodulin-dependent protein kinase II (CaMKII) inhibitor for treating catecholaminergic polymorphic ventricular tachycardia. Both therapies are being evaluated in Phase II trials. The company also plans to use the fund to expand the number of indications being explored for the two candidates and acquire additional assets for treating cardiovascular disorders. The investors in the Series B round included Bain Capital, Ascenta Capital, and other US-based investment companies. CRD-750 is being evaluated in two Phase II trials (NCT06215586 and NCT06215911) to treat two types of heart failure – heart failure with preserved ejection fraction (HFpEF) and reduced ejection fraction (HFrEF). Both placebo-controlled trials are currently recruiting patients across multiple locations in the US and Canada. In May, the company presented positive data for another PDE9 inhibitor, CRD-740, in patients with heart failure. The CARDINAL-HF Phase IIa trial (NCT05409183) met its primary endpoint in patients with HFrEF by demonstrating a statistically significant median increase in plasma cyclic guanosine monophosphate (cGMP). See Also: Sumitomo Pharma’s DSP-5336 gains FDA fast track for AML AstraZeneca completes Amolyt Pharma acquisition CRD-4730 is being evaluated in a Phase II trial (NCT06005428) as a treatment for catecholaminergic polymorphic ventricular tachycardia—a rare genetic arrhythmic disease. The company also plans to develop CaMKII inhibitors to target additional cardiovascular indications. There has been an increased interest in developing novel cardiovascular therapies in recent months. In February, Novo Nordisk agreed to pay up to $1.46bn to license multiple molecular glue degraders for treating cardiometabolic disorders and rare diseases from Neomorph. As part of the agreement, Neomorph would bear discovery and preclinical research responsibilities while Novo Nordisk would have exclusive rights to further clinical development and commercialisation. Another approach that has emerged as a promising treatment in the cardiovascular space is drugs targeting the glucagon-like peptide-1 (GLP-1) receptor. Last year, Novo Nordisk reported that its GLP-1 therapy Wegovy (semaglutide) reduced the incidence of cardiovascular events in obese and overweight patients by 20% compared to placebo.

July 19, 2022 12:00 UTC CARDINAL-HF is the first Phase 2 proof-of-concept trial of a PDE9 inhibitor in heart failure Large-scale trial builds upon encouraging data generated in Cardurion’s Phase 1b trial CARDINAL-HF will examine the effects of CRD-740, Cardurion’s PDE9 inhibitor, in both types of heart failure and in key subsets of these patients BOSTON--(BUSINESS WIRE)-- Cardurion Pharmaceuticals, Inc. (“Cardurion” or “the Company”), a clinical-stage biotechnology company developing next-generation therapeutics for the treatment of cardiovascular diseases, today announced it has opened multiple sites and commenced dosing patients in a Phase 2 clinical trial of CRD-740, a phosphodiesterase-9 (“PDE9”) inhibitor for the treatment of heart failure. Initiated in May 2022, CARDINAL-HF is the first Phase 2 proof-of-concept trial of a PDE9 inhibitor in heart failure, and will assess the effects of CRD-740 on key subsets of these patients. Based on the mechanism of PDE9 action, inhibition by CRD-740 is expected to have benefit both alone and in combination with all standard of care heart failure treatments. CARDINAL-HF is a randomized, placebo-controlled trial that will enroll over 650 patients at more than 100 trial sites around the world. The trial will include chronic, stable patients with both reduced (HFrEF) and preserved ejection fraction heart failure (HFpEF). In addition, CRD-740 is being tested on a background of standard of care therapies to provide important information on the potential for benefit of CRD-740 when combined with guideline-directed treatments. The target of CRD-740 is PDE9, the enzyme that metabolizes cardiac cGMP generated by the natriuretic peptide receptor (NPR) pathway. Activation of this pathway is of proven clinical benefit in both forms of heart failure. PDE9 activity is increased in heart failure patients, which limits the beneficial effects of the NPR pathway. PDE9 inhibition with CRD-740 is a novel approach capable of maximizing NPR pathway activation and the beneficial effects of cGMP generated by this pathway, by blocking its breakdown by the PDE9 enzyme. “The launch of this large-scale trial is a significant milestone for Cardurion and for millions of patients who suffer from heart failure and are underserved by currently available therapies. We are gratified to have assembled a world-class group of cardiovascular experts to help oversee its execution,” said Peter Lawrence, Chief Executive Officer of Cardurion Pharmaceuticals. “We believe that CARDINAL-HF will rigorously test CRD-740 in both HFrEF and HFpEF, allowing us to assess the value of PDE9 inhibition in these patient populations, including important subgroups of patients who are on other heart failure medications. The data from this trial will be extensive and allow for robust decision-making for Phase 3.” The Executive Committee for the trial includes Dr. James Udelson, Principal Investigator and Chief of Cardiology at Tufts Medical Center; Dr. Scott Solomon, Professor of Medicine at Harvard Medical School; and Dr. John McMurray, Professor of Medical Cardiology and Deputy Director of the Institute of Cardiovascular and Medical Sciences at the University of Glasgow. Drs. Udelson, Solomon and McMurray, along with Dr. Eugene Braunwald, the Distinguished Hersey Professor of Medicine at Harvard Medical School, also lead Cardurion’s Clinical Advisory Board. The CARDINAL-HF Steering Committee is further comprised of leading international heart failure trialists. “CARDINAL-HF has been carefully designed to evaluate how a broad range of heart failure patients will respond to this novel drug candidate, which has the potential to address significant unmet medical need when added to the current standard of care,” said Dr. Jim Udelson, Principal Investigator for the CARDINAL-HF trial. “The design will also provide a rich data set to inform the structure of a Phase 3 program and help evaluate a potential patient selection biomarker.” About Chronic Heart Failure Heart failure is a prevalent and growing condition that is responsible for substantial morbidity and mortality. Approximately 6.5 million people in the U.S. suffer from heart failure, and 50 percent of these patients die from the condition within five years of diagnosis. One in five patients are hospitalized annually, and 25% of hospitalized heart failure patients will be admitted again within a month of discharge. Approximately half of heart failure patients have reduced ejection fraction and half have preserved ejection fraction. Despite the availability of drugs indicated to reduce morbidity and mortality in both types of heart failure, substantial unmet medical need remains. About Cardurion Pharmaceuticals Cardurion Pharmaceuticals is a clinical-stage biotechnology company focused on the discovery and development of novel, next-generation therapeutics for the treatment of heart failure and other cardiovascular diseases. Founded by physician-scientist Michael E. Mendelsohn, M.D., and built by a team of physician-scientists and industry leaders with extensive experience in cardiovascular science, drug development and business development, Cardurion Pharmaceuticals is pursuing unique drug discovery and development programs to target major unmet needs in cardiovascular medicine. Cardurion Pharmaceuticals has facilities in Boston and Burlington, Massachusetts and Shonan, Japan. For more information, please visit the company’s website at .

Primary endpoint to be changed to annualized rate of VOCs following written U.S. Food and Drug Administration recommendation No change to conduct or size of trial planned; Ardent trial remains on track for interim analysis of VOC rates in first quarter of 2022 BOSTON, Nov. 22, 2021 (GLOBE NEWSWIRE) -- Imara Inc. (Nasdaq: IMRA), a clinical-stage biopharmaceutical company dedicated to developing and commercializing novel therapeutics to treat patients suffering from rare inherited genetic disorders of hemoglobin and other serious diseases, today announced a change to the primary endpoint for the Ardent clinical trial, a Phase 2b study of tovinontrine (IMR-687) in patients with sickle cell disease (SCD), based on the recommendation of the U.S. Food and Drug Administration (FDA). Imara requested feedback from the FDA on the draft statistical analysis plan (SAP) for the Ardent trial in which fetal hemoglobin (HbF) response was the primary endpoint and annualized rate of vaso-occlusive crises (VOCs) was the key secondary endpoint. In reviewing the Ardent draft SAP and prior to any database lock for analysis, the FDA recommended that Imara change the primary endpoint to be annualized rate of VOCs. HbF response will continue to be evaluated as a key secondary endpoint. The endpoint revisions do not affect the conduct of the trial or operational aspects of the study. As part of its recommendation, the FDA suggested further interactions regarding the revised SAP and engagement on the potential of the current program for regulatory decision-making. “We welcome the FDA’s recommendations and are in the process of changing the primary endpoint of the Ardent trial to be annualized rate of VOCs and moving HbF response to be a key secondary endpoint,” said Rahul Ballal, Ph.D., President and Chief Executive Officer of Imara. “A reduction in VOC rate is an established approval endpoint, and we are engaging the FDA further on this and related topics, including possible streamlined paths to registration.” Dr. Ballal continued, “In light of this endpoint revision, the previously planned fourth quarter interim analysis will no longer occur. That interim analysis had been designed to have a focus on safety and pharmacodynamic biomarkers, including HbF, but did not include a review of VOCs. The first review of data from the Ardent trial, including annualized VOC rate, will be conducted when all subjects have completed assessment at Week 24 or terminated early, and is planned for the first quarter of 2022, subject to our upcoming discussions with the FDA. Final data analysis from the Ardent trial remains on track for the second half of 2022. In June 2021, we reported promising data from our Phase 2a and open label extension clinical trials in SCD that demonstrated reduced annualized rates of VOCs in patients treated with tovinontrine versus placebo. We expect to present updated 12-month VOC data from our ongoing Phase 2a open label extension clinical trial at the American Society of Hematology Annual Meeting in December 2021.” About the Ardent Phase 2b Clinical Trial The Ardent Phase 2b clinical trial is a fully-enrolled, global, randomized, double-blind, placebo-controlled, multicenter study with approximately 115 adult patients with sickle cell disease (SCD) enrolled. The planned primary efficacy objective will be to evaluate the annualized rate of vaso-occlusive crises (VOCs) in patients dosed with tovinontrine (IMR-687) as compared to placebo. A key secondary endpoint will be to evaluate the proportion of all patients with fetal hemoglobin (HbF) response, defined as an absolute increase from baseline of at least 3% in HbF, as compared to placebo. Additional endpoints include the evaluation of the effect of tovinontrine versus placebo on other VOC-related outcome measures, HbF-associated biomarkers, markers of red blood cell hemolysis, white blood cell adhesion markers and quality of life measures over the course of a one-year treatment period. For more information about the Ardent trial visit ClinicalTrials.gov here. The FDA has granted Orphan Drug, Fast Track and Rare Pediatric Disease designations and the European Commission has granted Orphan Drug designation for tovinontrine for the treatment of SCD. About Tovinontrine (IMR-687) Tovinontrine is a highly selective and potent small molecule inhibitor of phosphodiesterase-9 (PDE9). PDE9 selectively degrades cyclic guanosine monophosphate (cGMP), an active signaling molecule that plays a role in vascular biology and hemoglobin production in red blood cells. Lower levels of cGMP are found in people with sickle cell disease (SCD) and beta-thalassemia and are associated with reduced blood flow, increased inflammation, greater cell adhesion and reduced nitric oxide mediated vasodilation. Blocking PDE9 acts to increase cGMP levels, which is associated with several benefits including the potential reactivation of fetal hemoglobin (HbF), a natural hemoglobin produced during fetal development. Increased levels of HbF in RBCs have been demonstrated to improve symptomology and substantially lower disease burden in both patients with SCD and patients with beta-thalassemia. About Sickle Cell Disease Sickle cell disease (SCD), a hemoglobinopathy, is a rare inherited red blood cell disorder. The disease causes structural abnormalities in hemoglobin that cause red blood cells to become inflexible and elongated, ultimately blocking blood flow to organs, which can lead to vaso-occlusive crises (VOCs). SCD is characterized by debilitating pain, progressive multi-organ damage and early death. The global prevalence of SCD is estimated to be approximately 4.4 million patients, including an estimated 100,000 patients in the United States and 134,000 patients in the European Union. About Imara Imara Inc. is a clinical-stage biotechnology company dedicated to developing and commercializing novel therapeutics to treat patients suffering from rare inherited genetic disorders of hemoglobin and other serious diseases. Imara is advancing tovinontrine (IMR-687), a highly selective, potent small molecule inhibitor of PDE9 that is an oral, potentially disease-modifying treatment currently in clinical development for sickle cell disease and beta-thalassemia and preclinical development for heart failure with preserved ejection fraction, or HFpEF. Imara is also advancing IMR-261, an oral activator of nuclear factor erythroid 2–related factor 2, or Nrf2. For more information, please visit . Cautionary Note Regarding Forward-Looking Statements Statements in this press release about future expectations, plans and prospects, as well as any other statements regarding matters that are not historical facts, may constitute “forward-looking statements” within the meaning of The Private Securities Litigation Reform Act of 1995. These statements include, but are not limited to, statements relating to (i) the Company’s plans to change the primary and secondary endpoints for the Ardent Phase 2b clinical trial of tovinontrine (IMR-687), (ii) the timing for reporting of additional data from the Ardent Phase 2b and open label extension clinical trials of tovinontrine in patients with sickle cell disease and (iii) the Company’s planned discussions with the FDA regarding the regulatory pathway for tovinontrine. The words “anticipate,” “believe,” “continue,” “could,” “estimate,” “expect,” “intend,” “may,” “plan,” “potential,” “predict,” “project,” “should,” “target,” “will,” “would” and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Actual results may differ materially from those indicated by such forward-looking statements as a result of various important factors, including: the impact of extraordinary external events, such as the risks and uncertainties resulting from the impact of the COVID-19 pandemic on the Company’s business, operations, strategy, goals and anticipated milestones, including its ongoing and planned research activities and ability to readout data from the Ardent Phase 2b and open label extension clinical trials of tovinontrine in sickle cell disease; the Company’s ability to advance the development of tovinontrine under the timelines it projects in current and future clinical trials, demonstrate in any current and future clinical trials the requisite safety and efficacy of tovinontrine; and other factors discussed in the “Risk Factors” section of the Company’s most recent Quarterly Report on Form 10-Q, which is on the Securities and Exchange Commission and in other filings that the Company makes with the Securities and Exchange Commission in the future. Any forward-looking statements contained in this press release speak only as of the date hereof, and the Company expressly disclaims any obligation to update any forward-looking statement, whether as a result of new information, future events or otherwise. Media Contact: Marin Bergman Ten Bridge Communications 818-516-2746 marin@tenbridgecommunications.com Investor Contact: Michael Gray 617-835-4061 mgray@imaratx.com