We are proud to announce that the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (NIH) has awarded a $2 million Small Business Innovation Research (SBIR) Phase II grant to Numerate, following successful completion of our work funded by a Phase I Award[i]. We, collaborating with members of the UCLA Cardiovascular Research Laboratory (CVRL), will use the funds to support the discovery of novel, small molecule drug candidates that address the need for a well-tolerated anti-arrhythmic therapy for the treatment and prevention of ventricular tachycardias and fibrillation (VT/VF).
Under Phase I funding, the research team applied Numerate’s AI-driven small molecule drug discovery platform to identify two lead compounds and demonstrate feasibility of the program. Following screening of a library of about 10 million compounds in silico against computational models for key compound characteristics, 63 molecules were acquired or synthesized and tested in the laboratory, with 18 molecules meeting the in vitro criteria for activity and biodistribution. From this research, two lead candidates met all of the established program milestones for the Phase I grant:
- Potent binding to a subunit of the CaV2 voltage-dependent calcium channel complex;
- Peripheral restriction (lack of penetration of compounds into the brain) in a mouse model;
- Suppression of early afterdepolarizations in isolated ventricular myocytes from rabbit hearts in vitro;
- Reversion of induced ventricular arrhythmias to sinus rhythm in intact isolated rat heart preparations.
“In just a few months, we were able to leverage Phase I funding and demonstrate how our AI-driven drug discovery platform can be used to efficiently generate novel small molecule leads against a challenging set of goals,” said John Griffin, Ph.D., Chief Scientific Officer of Numerate, “Following the success of our initial research, Phase II will allow us to continue our discovery efforts, with the goal of identifying a new medicine that is safe and effective in preventing and treating serious cardiac arrhythmias.”
“We are encouraged by the Phase I findings and expect to build on our success to, ultimately, develop a new class of therapy for cardiac arrhythmias (class VI antiarrhythmics) that are more effective and better tolerated than current treatment options. Specifically, we believe this mechanism of action will be able to resolve VT/VF without negatively impacting cardiac contractility, making them a better therapeutic class for patients with heart failure, among others, ” said Uwe Klein, Ph.D., Vice President of Biology at Numerate, and Principal Investigator. “We are thankful for the support from the NIH and are looking forward to continuing our successful partnership with Drs. Karagueuzian and Olcese at the UCLA Cardiovascular Research Laboratory.”
About the Research Team
Uwe Klein, Ph.D., Vice President of Biology at Numerate, will continue to serve as Principal Investigator and will lead discovery efforts for the program titled, “Peripherally restricted α2/δ-1 subunit ligands that modulate CaV channel gating as novel antiarrhythmic drugs.” The project is funded under Grant Number 2R44HL139143-02.
Co-Investigators from the UCLA CVRL include Dr. Hrayr S. Karagueuzian, Professor Emeritus of Medicine at the David Geffen School of Medicine at UCLA, Director of Translational Arrhythmias Research Section, and Dr. Riccardo Olcese, Professor of Anesthesiology and Physiology at UCLA, Division of Molecular Medicine.
About Cardiac Arrhythmias and Treatment Options
According to the Mayo Clinic, more than 4 million Americans, most over age 60, experience heart arrhythmias (abnormal heart rhythms)[ii]. Arrhythmias are caused by problems with the electrical system that regulates the steady heartbeat. The heart rate may be too slow or too fast; it may stay steady or become irregular and disorganized[iii]. The most serious and life-threatening arrhythmia is ventricular fibrillation (VF), which is an erratic disorganized firing of impulses in the lower chambers of the heart, called the ventricles. VF result in the heart being unable to pump blood, and is the most common cause of sudden cardiac death, claiming the lives of over 300,000 adults in the United States each year[iv].
Current treatment options remain highly empirical and are poorly tolerated. A new class of VI antiarrhythmics (cardiac channel gating modifiers) has been postulated to provide the next generation of therapeutics, by targeting solely arrhythmogenic currents and avoiding effects on cardiac contractility[v].
[i] Research was supported by the National Heart, Lung, And Blood Institute of the National Institutes of Health under Award Number R43HL139143, NIH RePORT Project Information. Accessed August 5, 2019.
[v] Journal of Heart Health, Wanted: Class VI Antiarrhythmic Drug Action; New Start for a Rational Drug Therapy. Accessed August 5, 2019.