PIPELINE
Potential to Address Unmet Medical Needs in People with Heart Failure
Pioneering Approach: We believe PDE9 inhibition presents an opportunity to make a meaningful impact in the lives of heart failure patients.
Clinical Advancement: With robust scientific rationale behind our work, Cardurion is confident we are on a strong path forward for our PDE9 inhibitor to become a new treatment for heart failure, with the potential for improved efficacy when added to standard of care.
PDE9 Therapeutic Approach
PDE9 (phosphodiesterase-9) is an enzyme that selectively degrades cyclic guanosine monophosphate (cGMP), an active signaling molecule in the natriuretic peptide signaling (NPS) pathway. The NPS pathway plays an important and protective role in cardiac function and its activation has been validated to confer outcomes benefit for patients with chronic heart failure. Inhibiting PDE9 represents a novel mechanism to activate the validated NPS pathway by increasing the levels of cGMP in the cardiomyocyte, one of the main cell types in the heart, thereby improving heart function.
Our PDE9 clinical development program is designed to establish PDE9 inhibition as additive to existing treatment regimens for heart failure, with the potential to improve upon the standard-of-care for patients and address unmet needs of patients with heart failure.
We recently concluded Phase 2a clinical trials of our PDE9 inhibitor in patients with heart failure who were already treated with guideline-directed medical therapies, with additional studies planned.
PDE9 Mechanism of Action
The figure below illustrates how the natriuretic peptide signaling pathway impacts activity within a heart cell and how PDE9 inhibition has the potential to provide benefit to patients suffering from heart failure.
Click the arrows to learn more about this pathway and why we believe PDE9 inhibition has the potential to provide transformational benefit to patients suffering from heart failure.
1. Role of natriuretic peptides. Natriuretic peptides (NPs) are hormones that are secreted from the myocardium in response to dilation or stress on the cardiac muscle. While the NPs play a role in a variety of tissues in the body, these secreted NPs also play an important role in cardiac function. The secreted NPs bind to the NP receptor on the surface of the cardiomyocyte. Heart failure patients commonly have elevated levels of NPs. When pressures inside the heart chambers are increased as a result of heart failure, heart muscle secretes more NPs in a manner that can feedback to the heart and help improve cardiac function.
2. Formation of cGMP. When these natriuretic peptides bind to the natriuretic peptide receptor, the intracellular enzymatic activity of the natriuretic peptide receptor catalyzes the formation of cyclic guanosine monophosphate (cGMP), an active signaling molecule, from guanosine triphosphate (GTP). For each natriuretic peptide molecule that binds to the natriuretic peptide receptor, multiple cGMP molecules are generated, and these second messenger molecules lead to downstream effects that improve cardiac functions.
3. Activation of PKG1. cGMP binds to and activates protein kinase G 1 (PKG1), a critical myocardial enzyme that mediates the effects of cGMP when it is generated by the natriuretic peptide receptor.
4. Beneficial downstream effects. Once activated by cGMP, PKG1 phosphorylates multiple proteins in the myocardium with direct, beneficial myocardial effects, including improved cardiac relaxation, decreased hypertrophy (thickness) of the heart muscle, and inhibition of fibrosis (buildup of excess fibrous tissue).
5. PDE9 degrades cGMP. The beneficial cGMP signaling and activation of PKG1 are limited by the activity of PDE9, which degrades cGMP and dampens this critical step in the signaling pathway. Importantly, it was discovered in the last several years that patients with heart failure have elevated levels of PDE9, limiting cGMP signaling when it is most needed.
6. Inhibiting PDE9. By inhibiting PDE9 (CRD-PDE9i), our goal is to increase the levels of cGMP and the natriuretic peptide signaling pathway at a step where it has been interrupted by the elevated levels and activity of PDE9.