Our pipeline is built on the differentiated therapeutic potential of our initial product candidate, IMR-687, which is an oral, once-a-day, potentially disease-modifying treatment for sickle cell disease (SCD) and β-thalassemia. IMR-687 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 IMR-687’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.
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
Posters & Publications
PDE9 Inhibition & Sickle Cell Disease
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 is currently conducting a Phase 2a randomized, double-blinded, placebo-controlled clinical trial of IMR-687 in adult patients with SCD. We have also initiated an open label extension trial, which allows patients from the Phase 2a clinical trial to continue into a long-term, four-year trial to evaluate safety and tolerability of IMR-687.