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Heart failure is a serious condition in which the heart cannot pump blood sufficiently to meet the body’s needs. Approximately 6.5 million people in the United States have been diagnosed with heart failure and that number is growing. There are two major types of heart failure:
– Heart failure with reduced ejection fraction (HFrEF) occurs when the heart becomes enlarged, with decreased heart muscle function. As a consequence, there is a decrease in the amount of blood that is ejected from the heart with each heartbeat (reduced ejection fraction), causing insufficient flow of blood to the tissues of the body.
– Heart failure with preserved ejection fraction (HFpEF) occurs when the heart muscle becomes thickened and stiff. In this form of heart failure, though the ejection fraction remains normal (is preserved), the pressures in the heart are elevated, causing congestion in the lungs and the symptoms of heart failure.
Symptoms of heart failure include fatigue, shortness of breath, and swelling in the feet, ankles, and elsewhere. People with heart failure often require hospitalization and have a significantly increased risk of premature death. While certain existing therapies have been shown to reduce morbidity and mortality in both types of heart failure, a substantial unmet medical need remains.
WILL DIE WITHIN 5 YEARS
ARE ADMITTED TO HOSPITAL EVERY YEAR
25% will be readmitted within 30 days
When the heart is under stress, it activates the beneficial natriuretic peptide signaling pathway, which relaxes heart muscles, reduces hypertrophy (thickness) and reverses excess build-up of fibrous tissue (fibrosis). The beneficial effects of the natriuretic peptide signaling pathway in the heart muscle cell are mediated by cyclic guanosine monophosphate (cGMP), the critical second messenger in this pathway. PDE9 is an enzyme that selectively degrades cGMP, and it is now understood that PDE9 is elevated in all forms of heart failure, limiting the beneficial effects of the natriuretic peptide signaling pathway.
By inhibiting PDE9, our goal is to enhance the natriuretic peptide signaling within heart muscle cells by preserving the cGMP generated by activation of the natriuretic peptide receptor. We have validated this concept extensively in preclinical models, and Cardurion is the first company to test a PDE9 inhibitor in heart failure patients, where we have observed encouraging evidence of clinical activity that supports our preclinical studies. We recently concluded a Phase 2a clinical trial of our PDE9 inhibitor in HFrEF patients who are already treated with guideline-directed medical therapies. We are launching two Phase 2b trials in 500 patients with both forms of heart failure, HFrEF and HFpEF.
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 transformational 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.
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