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PIPELINE
A Highly Sought-After Target in Cardiovascular Medicine with Broad Potential
Pioneering Approach: We are the first company to discover and advance a therapeutic product candidate targeting CamKII into human clinical testing.
Clinical Advancement: As Cardurion leads the way with CaMKII inhibitors across a range of cardiovascular diseases, we are leveraging this mechanism to create novel therapeutics that can restore the calcium cycling process that is dysregulated in cardiovascular diseases.
CamKII Therapeutic Approach
CaMKII (Calcium–Calmodulin-Dependent Protein Kinase II) is an important regulator of calcium signaling in the heart and it has a causal role in multiple cardiovascular diseases. Despite advances in the understanding of the role dysregulated CaMKII plays in the pathogenesis of several cardiovascular diseases, translating this information into an effective therapeutic has so far proved elusive to multiple pharmaceutical companies due, in part, to the difficulty in developing molecules targeting CaMKII that have sufficient selectivity and potency and little or no brain penetration.
Cardurion is moving forward to evaluate our lead CaMKII inhibitor in multiple cardiovascular diseases, based on the important role that CaMKII plays in cardiovascular signaling and the influence of dysregulated CamKII on pathogenesis of several cardiovascular diseases. We currently have Phase 2 studies ongoing for our CamKII inhibitor in heart failure and in a rare cardiac arrhythmia, CPVT.
Heart Failure: We have initiated a Phase 2 study with our CaMKII inhibitor in heart failure, based on our promising preclinical studies in which our CaMKII inhibitors were validated in models of heart failure. Other preclinical studies have shown that pharmacologic and genetic inhibition of CaMKII has reversed cardiac dysfunction in heart failure.
CPVT, a rare genetic arrhythmia: We are currently evaluating the potential for CaMKII inhibition in a Phase 2 study in patients with polymorphic ventricular tachycardia (CPVT), a rare, genetic arrhythmia characterized by episodic cardiac arrhythmias that can lead to fainting or sudden cardiac death.
Other cardiac arrhythmias: With its role in calcium handling, CaMKII inhibition has the potential to treat a range of cardiac arrhythmias regardless of origin, including atrial fibrillation (AFib) which is the most common sustained cardiac arrhythmia driven by aging and its comorbidities.
CamKII Mechanism of Action
CaMKII is a protein kinase that modulates the cycling of calcium into and out of the cytoplasm of heart muscle cells (cardiomyocytes) with each heartbeat. When CaMKII becomes hyperactivated in the setting of heart disease, the calcium cycling process becomes dysregulated, leading to multiple cardiac disorders, including heart failure and common and rare arrythmias, such as atrial fibrillation and catecholaminergic polymorphic ventricular tachycardia (CPVT). Our goal is to prevent the hyperactivation of CaMKII, thereby correcting the calcium cycling abnormalities that can cause cardiovascular disease.
The figure below provides further detail on the process described above and the role of CaMKII.
Click the arrows to learn more about how CaMKII can become fixed in a hyperactivated state, and how inhibiting CaMKII can prevent its hyperactivation.
1. Calcium flows into the cell. With each heartbeat, the cardiomyocyte cell membrane depolarizes, which opens the L-type calcium channel, and leads to the flow of calcium ions into the cytoplasm of the cell.
2. CaMKII activation. CaMKII becomes activated by the binding of calcium/calmodulin and thereafter phosphorylates the L-type calcium channel, leading to more calcium flow into the cytoplasm.
3. Release of calcium ions. The calcium ions that enter the cell bind to and open ryanodine receptor 2 (RyR2), a membrane protein that forms a channel for calcium ion release from the sarcoplasmic reticulum, the main calcium-storage organelle within the cardiomyocyte, into the cytoplasm of the cardiomyocyte. The release of calcium ions from the sarcoplasmic reticulum is amplified by the phosphorylation of RyR2 by CaMKII.
4. Contraction. Entry of calcium ions into the cytoplasm of the cardiomyocyte allows them to activate the acto-myosin filaments, a collection of proteins that create heart muscle contraction, which ejects blood from the heart into the circulation.
5. Relaxation. Following contraction, the calcium ions are transported back into the sarcoplasmic reticulum or are extruded from the cell, which lowers calcium levels in the heart cells, leading to relaxation. In normal conditions, CaMKII returns to an inactive state.
6. Hyperactivation of CaMKII. In the setting of cardiovascular diseases, CaMKII can become hyperactivated, which means it phosphorylates its target proteins excessively. This causes the abnormal release of calcium ions from the sarcoplasmic reticulum into the cytoplasm at times when calcium release does not normally occur. This dysregulation of calcium ion cycling can lead to heart arrhythmias and heart failure.