NEW YORK–(BUSINESS WIRE)–Olatec Therapeutics LLC (Olatec) today announced the publication of the clinical data on its Phase 1b clinical study of patients with heart failure with reduced ejection fraction (HFrEF). Published in the Journal of Cardiovascular Pharmacology, the study met its primary objectives showing dapansutrile is safe and well tolerated in patients in all dose groups.
A total of 30 subjects were enrolled in 3 sequential cohorts by randomized, blinded allocation (8 active and 2 placebo within each cohort). Subjects were dosed dapansutrile capsules or placebo capsules for up to 14 consecutive days. No clinically significant differences were found with dapansutrile for systolic or diastolic blood pressure, heart rate, body weight, creatinine clearance, N-terminal pro B-type natriuretic peptide or peak oxygen uptake at Day 14 compared to baseline. There were no deaths or Significant Adverse Events, and any Adverse Events were mild and self-limiting.
Several indicators suggesting a potential positive effect of dapansutrile were observed in cohort 3, the high dose group of patients. In cohort 3, when compared to baseline, patients receiving dapansutrile 2000 mg daily experienced a significant increase in exercise time at cardiopulmonary exercise testing and in left ventricular ejection fraction (LVEF) measured by transthoracic Doppler echocardiography. Moreover, approximately 60% of all the patients had a concomitant diagnosis of diabetes mellitus, consistent with the strong link observed between diabetes and heart failure in the presence of metabolic stress-induced inflammation. The diabetic subjects treated with dapansutrile experienced a statistically significant decrease in fasting glucose.
Antonio Abbate MD PhD, with extensive expertise in the field of cardiac disease and the role of inflammation, was the Principal Investigator for the study, which was conducted at VCU Pauley Heart Center. Dr. Abbate and his team were involved in many of the early discoveries of the role of Interleukin-1 (IL-1) and the NLRP3 inflammasome in acute myocardial infarction and heart failure. In 2019, Dr. Abbate and Dr. Stefano Toldo reported on the efficacy of dapansutrile in an animal model of heart failure due to acute myocardial infarction in a publication entitled, The NLRP3 Inflammasome Inhibitor, OLT1177 (Dapansutrile), Reduces Infarct Size and Preserves Contractile Function After Ischemia Reperfusion Injury in the Mouse. The rationale for Olatec’s Phase 1b clinical study was largely based on dapansutrile’s preclinical data and the large body of external preclinical data supporting the NLRP3 inflammasome as a therapeutic target in heart disease.
Regarding the outcomes of the trial, Dr. Abbate said, “We believe the clinical data reinforces the hypothesis that an upstream signaling blockade through NLRP3 inflammasome inhibition avoids untoward effects on blood pressure or renal function and could be a promising therapeutic strategy to treat heart failure. The lack of adverse effects attributable to dapansutrile in this heart failure population in this trial is likely particularly relevant because it may also differentiate NLRP3 inhibition from other anti-inflammatory drug classes that are limited in the use in patients with heart failure.” Dr. Abbate continued, “These preliminary safety findings and evidence of NLRP3 inhibition further support research of dapansutrile as a therapeutic strategy in patients with HF in addition to other disease indications in which risk factors associated with the diseases do not recommend use of NSAIDs or glucocorticoids.”
In an accompanying commentary entitled, NLRP3 inflammasome: a new promising therapeutic target to treat heart failure, distinguished cardiologists congratulated the Olatec research team “for providing promising data on a new class of drug in HF patients, in this case for enabling hypothesis generation for possible future applications of selective NLRP3 inflammasome inhibitors for cardiovascular disease indications.” The commentary continued to state, “The future will likely include cytokine target therapies and possibly oral NLRP3 inflammasome inhibitors, to counteract the harmful sustained pro-inflammatory activation in patients with HF and hopefully improve HF-associated morbidity and mortality.”
About Heart Failure
It has been reported that heart failure affects around 26 million people worldwide and is increasing in prevalence. Furthermore, HF is caused by an abnormality in cardiac structure and/or function, but systemic inflammation plays a critical role in its development, progression, and outcomes. HF is a primary reason for hospital admission in individuals aged 65 or older. Expenditures due to HF are known to be considerable. The American Heart Association estimates that, at present, HF costs Americans approximately $30 billion annually with total costs expected to increase by approximately 130% by 2030 with the ageing population.
Dapansutrile (lab code: OLT1177®) is an investigational small molecule, new chemical entity that specifically binds to and blocks NLRP3 (nucleotide-binding and oligomerization domain [NOD]-, leucine rich repeat-, pyrin domain-containing 3), the sensor molecule integral in the formation of the NLRP3 inflammasome. Inflammasomes are multiprotein complexes involved in intracellular surveillance of danger signals that trigger an intense inflammatory response, via generation of bioactive IL-1β and IL-18 through caspase-1 activation. Dapansutrile has been shown to prevent the formation of the NLRP3 inflammasome, which in turn inhibits the production of IL-1β and IL-18. NLRP3 is one of the most characterized inflammasome sensors due to its involvement in a wide range of disorders, including sterile inflammation, infections, and rare genetic autoimmune syndromes. Dapansutrile is in Phase 2 clinical development and has been well tolerated and shown to improve clinical outcomes in patients with acute gout flare (see The Lancet Rheumatology) and heart failure (see Journal of Cardiovascular Pharmacology). Dapansutrile has also been observed to have anti-inflammatory properties and other promising activity in a broad spectrum of over 20 preclinical animal models including arthritis, asthma, acute myocardial infarction (AMI), contact dermatitis, multiple sclerosis, melanoma and breast cancers, spinal cord injury (SCI) and Alzheimer’s disease.
About Olatec Therapeutics LLC
Olatec is a privately held, clinical-stage biopharmaceutical company developing a platform of oral NLRP3 inhibitors to treat and prevent a broad spectrum of acute and chronic inflammatory diseases known to be mediated by IL-1. In addition to the lead compound, dapansutrile, Olatec’s platform of proprietary compounds includes approximately 60 analogues (OLT Analogues) being screened as viable drug candidates. An IP portfolio protecting Olatec’s compounds consists of over 130 patents granted, covering dapansutrile and OLT Analogues. Olatec’s drug development team is comprised of experienced management and international experts in translational medicine with unparalleled expertise in inflammation and immunology and has been involved in the discovery and development of first-line inflammation treatments in the market today. For more information, please visit http://www.olatec.com.
Disclaimer & Forward-looking Statement
The information contained herein is being provided for information purposes only. The Company makes no express or implied representation or warranty as to the completeness of this information. Any forward-looking statements contained in this release are based on assumptions made by Olatec at the time this Press Release was prepared. Any forward-looking statement contained in this Press Release is subject to known and unknown risks, uncertainties and other factors that may be materially different from those contemplated in such forward-looking statements. All information with respect to industry data has been obtained from sources believed to be reliable and current, but the accuracy thereof cannot be guaranteed by the Company. Olatec does not undertake any obligation to update or revise the forward-looking statements contained in this Press Release to reflect events or circumstances occurring after the date this Press Release was prepared, or to reflect the occurrence of unanticipated events.