Our pipeline is built principally on the differentiated therapeutic potential of our initial product candidate, tovinontrine (IMR-687), which is an oral, once-a-day, potentially disease-modifying treatment for sickle cell disease (SCD) and β-thalassemia. Tovinontrine is a highly selective, potent small molecule inhibitor of PDE9 that has a multimodal mechanism of action that acts primarily on red blood cells (RBCs) and has the potential to act on white blood cells (WBCs), adhesion mediators and other cell types that are implicated in sickle cell disease. We aim to leverage tovinontrine’s differentiated mechanism of action, its ease of administration and stable drug properties to potentially serve a broad range of patients suffering from hemoglobinopathies around the world, including those in underserved regions.
We are also evaluating the potential of tovinontrine in other conditions in which the inhibition of PDE9 could serve as an attractive target, including the prevention and treatment of vascular diseases such as heart failure with preserved ejection fraction (HFpEF).
In November 2021 we announced the addition to our pipeline of IMR-261, an activator of nuclear factor erythroid 2–related factor 2, or Nrf2. IMR-261 was previously evaluated by Complexa, Inc. as CXA-10 in Phase 2 clinical trials in focal segmental glomerulosclerosis (FSGS) and pulmonary arterial hypertension (PAH). Independent medical literature suggests potential promise in a broad array of red blood cell diseases, including disorders of hemoglobin. We have initiated work on drug product manufacturing for IMR-261 as we explore potential clinical development paths.
Hemoglobinopathies are a diverse range of rare inherited genetic disorders in which there is abnormal production or absence of hemoglobin, the iron-containing protein in RBCs responsible for transporting oxygen in the blood. The first group of hemoglobinopathies, which includes sickle cell disease (SCD), results from structural abnormalities that cause the RBC to become inflexible and elongated, ultimately blocking blood flow to organs, which can lead to vaso-occlusive crises, or VOCs.
The second group of hemoglobinopathies, which includes β-thalassemia, results from decreased or absent production of hemoglobin, thereby producing smaller, paler RBCs that do not deliver adequate oxygen to vital tissues.
The Unmet Need: Limited Treatment Options
Managing hemoglobinopathies and their various clinical manifestations is complex, and patients have few accessible treatment options. Currently approved therapies for SCD have significant limitations, including safety concerns, complex dosing regimens, variable response rates and potential adverse effects from long term use. There are no currently approved oral therapies for β-thalassemia. Blood transfusions are used to treat both SCD and β-thalassemia, but are suboptimal due to limited patient access and serious potential complications that include iron overload, adverse immune response and transmission of transfusion-associated infections.
Allogeneic hematopoietic stem cell transplant, or HSCT, is also available as a potentially curative treatment for both disorders, but it is rarely used due to the difficulty in finding a matched donor and an approximately 5% mortality rate. More recent approaches to treating both disorders are emerging, such as gene therapy and gene editing, however, these are complex, costly, difficult to administer and potentially only suitable for a limited subset of patients.
IMR-687 & PDE9
IMR-687 is a highly selective and potent small molecule inhibitor of PDE9. PDE9 selectively degrades cyclic guanosine monophosphate (cGMP), an active signaling molecule that plays a role in vascular biology. Lower levels of cGMP are found in people with 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 cyclic GMP levels, which is associated with reactivation of fetal hemoglobin, or 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 β-thalassemia.
- Highly potent PDE9 inhibitor
- Differentiated selectivity and tolerability profile
- Minimal brain penetration
- Drug product stability
Presentations & Publications
PDE9 Inhibition & Sickle Cell Disease
The Safety, Pharmacokinetics & Pharmacodynami Effects of IMR-687, a Highly-Selective PDE9 Inhibtor, in Adults with Sickle Cell Disease: Phase 2a Placebo-Controlled & Open Label Extension Studies
26th Congress of the European Hematology Association, June 11, 2021
Benefits and Safety of Long-Term Use of IMR-687 as Monotherapy or in Combination with a Stable Dose of Hydroxyurea (HU) in 2 Adult Sickle Cell Patients
62nd ASH Annual Meeting and Exposition, December 6, 2020
Phosphodiesterase-9 inhibition with IMR-687 and natriuretic peptide levels in adult patients with sickle cell disease
Annual Academy for Sickle Cell and Thalassemia Conference, October 2020
IMR-687, A Highly Selective Phosphodiesterase 9 Inhibitor (PDE9I), Increases F-Cells and Fetal Hemoglobin in a Ph-2A Interim Analysis
25th Congress of the European Hematology Association, June 12, 2020
IMR-687, a Highly Selective Phosphodiesterase 9 Inhibitor (PDE9I), Demonstrates Preliminary Evidence of Activity on Red and White Cell Biomarkers in a Ph-2a Interim Analysis
24th Congress of The European Hematology Association, June 15, 2019
cGMP modulation therapeutics for sickle cell disease
Experimental Biology and Medicine, February 2019
A Novel, Highly Potent and Selective PDE9 Inhibitor for the Treatment of Sickle Cell Disease
The Blood Journal, December 2016
Hydroxyurea and a cGMP-amplifying agent have immediate benefits on acute vaso-occlusive events in sickle cell disease mice
The Blood Journal, October 2012
Inhibition of phosphodiesterase 9A reduces cytokine-stimulated in vitro adhesion of neutrophils from sickle cell anemia individuals
Inflammation Research, July 2011
High expression of the cGMP-specific phosphodiesterase, PDE9A, in sickle cell disease (SCD) and the effects of its inhibition in erythroid cells and SCD neutrophils
British Journal of Haematology, September 2008
Role of hydroxyurea in thalassemia intermedia
Journal of Fatima Jinnah Medical University, April – June 2018
Hydroxyurea Treatment in Transfusion-Dependent β-Thalassemia Patients
Iranian Red Crescent Medical Journal, June 2014
Imara is developing IMR-687, an oral, once-a-day, potentially disease-modifying treatment for sickle cell disease (SCD) and beta-thalassemia. IMR-687 is a highly selective, potent small molecule inhibitor of PDE9.
IMR-687 for the treatment of sickle cell disease
Imara has completed enrollment in its Phase 2a randomized, double-blinded, placebo-controlled clinical trial of IMR-687 in adult patients with SCD. Patients from the Phase 2a trial may enroll in a related open-label extension trial, which enables eligible patients to continue into a long-term, four-year trial to evaluate the safety and tolerability of IMR-687.
In addition, Imara has initiated enrollment in the Ardent Phase 2b clinical trial for patients with sickle cell disease. This randomized, double-blind, placebo-controlled, multicenter study will enroll approximately 99 patients, aged 18 to 65 years with SCD.
Going forward Imara intends to expand clinical development of IMR-687 into developing world regions and other SCD patient populations, including adolescent and pediatric patients and those with milder forms of the disease.
IMR-687 for the treatment of beta-thalassemia
Based on the similar pathophysiology and symptomology shared between SCD and b-thalassemia, Imara believes there is a compelling rationale to expand clinical development of IMR-687 into beta-thalassemia. Various preclinical studies, as well as favorable safety data from Imara’s Phase 1 trial, further support the development of IMR-687 in this indication.
Beta-thalassemia patients are classified as either TDT (having a well-established and lifelong transfusion regimen) or NTDT (a clinically diverse group, with intermittent transfusion needs).
Imara has initiated enrollment in the Forte Phase 2b clinical trial for patients with beta-thalassemia. This randomized, double-blind, placebo-controlled trial will enroll approximately 60 TDT patients and approximately 60 NTDT patients.