Unlocking pathways that drive cardiovascular disease

Heart failure affects an estimated 6.7 million Americans, a number projected to exceed 8.5 million by the end of the decade, and more than 64 million adults globally.

Heart failure is a serious condition in which the heart muscle doesn’t pump blood as efficiently as it should, causing shortness of breath, fatigue, and swelling of the feet, ankles, legs, abdomen, or neck veins, and has a 50% mortality rate within five years of diagnosis.

There are two major types of heart failure that differ in their underlying biology and existing treatment options. Patients across both types of heart failure have unmet medical needs, and there is an opportunity to develop novel therapies for heart failure to improve outcomes and have a better tolerability profile.

Patients with heart failure with reduced ejection fraction (HFrEF) have a weakened heart pump and are treated with a well-established four-drug combination that meaningfully reduces hospitalizations and death. The priority here is building on that already-effective foundation with new, highly tolerable mechanisms that can be layered on top to further reduce residual risk.

Patients with heart failure with preserved ejection fraction (HFpEF) have hearts that don’t relax and fill properly. Because mechanisms effective in HFrEF have largely failed in this population, treatment options remain very limited, and there’s a pressing need for genuinely new mechanisms that address the underlying biology of HFpEF.

One of Cardurion’s drug programs targets PDE9, an enzyme that is elevated in the heart in both major types of heart failure, limiting the beneficial effects of the natriuretic peptide signaling pathway on cardiac function. Our PDE9 inhibitor drug candidate is advancing in later-stage clinical trials.

Our second drug program targets CaMKII, an enzyme that regulates calcium handling and whose dysregulation in the setting of disease is a long-recognized driver of heart failure and arrhythmias. Until recently, no drug specifically targeting CaMKII had ever reached human testing.

Both mechanisms are designed to be additive to existing treatment regimens for heart failure, and they have the potential to improve upon the standard of care and address unmet needs of patients with heart failure.

Arrhythmias, or abnormal heart rhythms, arise from disruptions to the heart’s electrical activity. They range widely in origin, from arrhythmias acquired over a lifetime through aging and disease, to those inherited through a genetic mutation present from birth.

The most common sustained cardiac arrhythmia is atrial fibrillation (AFib) which is primarily driven by aging and comorbidities such as hypertension, diabetes, obesity and heart failure.

Inherited arrythmias are rare, but can result in sudden and severe cardiac events.

AFib is characterized by chaotic, uncoordinated electrical activity in the atria that impairs the heart’s pumping efficiency. It increases risks of stroke, systemic embolism, heart failure, dementia, and cardiovascular mortality. It also recurs and progresses over time. Current medication treatment options are severely limited by side effects and are contraindicated for many patients with AFib. Catheter ablation is a standard-of-care procedure available to some patients but has a failure rate of about 33% in the first year.

Genetic arrhythmias are a group of rare, inherited conditions, that include catecholaminergic polymorphic ventricular tachycardia (CPVT). These conditions are caused by mutations that affect the heart’s electrical or calcium-handling machinery, and vary widely in prevalence, presentation, and age of onset. CPVT, in particular, is estimated to affect roughly 1 in 10,000 individuals and generally presents in children and young adults, most often triggered by exercise or acute emotional stress. There are no therapies currently approved for CPVT.

With its role in calcium handling, Cardurion’s CaMKII inhibitor has the potential to treat multiple types of cardiac arrhythmias. Cardurion is currently conducting a clinical trial with its CaMKII inhibitor in the treatment of CPVT.