- Cardiovascular disease (CVD), a leading cause of death and disability worldwide, involves structural and functional changes in the heart
- Local sterile inflammation by the innate immune system results in a signalling cascade, particularly activation of NLRP3
- NLRP3 activation, along with processing and release of downstream associated pro-inflammatory cytokines, IL-1β and IL-18, are now established as significant drivers in the development of heart failure
- The Journal of the American College of Cardiology (JACC): Basic to Translational Science, a leading CVD publication, recently published a review on the NLRP3 inflammasome as significant CVD target
- This seminal review publication cited the results of Olatec’s dapansutrile study in patients with stable heart failure (HF) with reduced ejection fraction (HFrEF) calling dapansutrile “the most interesting and promising study for patients with HF”
- The JACC review described dapansutrile’s results including its ability to improve heart health markers after a 2-week treatment
- New data from Olatec’s preclinical program in CVD published in Molecules, continue to support that dapansutrile, a selective NLRP3 inhibitor, targets the sterile inflammation pathway resulting in improved cardiac outcomes in a model of heart failure
NEW YORK–(BUSINESS WIRE)–Olatec Therapeutics LLC (Olatec) is honored to announce inclusion of their clinical heart failure (HF) study in a recent review manuscript authored by leading researchers and clinicians from Oslo University Hospital, Norway, within the high-impact publication, Journal of the American College of Cardiology (JACC): Basic to Translational Review. Titled “Targeting the Inflammasome in Cardiovascular Disease,” this JACC review demonstrates the cardiology community’s growing confidence in the life-prolonging potential of inhibiting NLRP3 activity to preserve heart function. Moreover, Olatec’s growing body of 1) clinical data in HF patients, which quantified cardiovascular improvements in both ejection fraction and exercise time after a 2-week treatment regimen, and 2) preclinical data in models of heart dysfunction, supports dapansutrile’s therapeutic potential to mitigate the progression of HF and treat its symptoms.
CVD is multifactorial in its development and its progression is associated with inflammation. Changes to heart architecture through age, genetics, and/or lifestyle factors gradually weaken the heart’s mechanical function and add stress to cardiac tissue. Acute cardiac damage caused by events such as myocardial infarction (i.e., heart attack) results in an intense inflammatory response and the development of fibrotic scar tissue. Within hours of the myocardial infarction, activation of endogenous damage-associated molecular patterns stimulates receptors in the innate immune system, which in turn activate NLRP3, leading to the assembly of inflammasome complexes and self-perpetuating processing of the pro-inflammatory cytokine IL-1β. Activation and upregulation of IL-1β-dependent inflammation drives additional structural changes that further compromise heart function and contribute to the development and exacerbation of CVD. When cardiac tissue loses structure and function, the ensuing stress results in patient disability.
As the role of inflammation in CVD has been elucidated over the past decade, IL-1β-neutralizing biologic therapies, e.g., anakinra and canakinumab, have already demonstrated to have marked benefits in improving clinical outcomes for patients with HF, as shown in the CANTOS trial (over 10,000 patients). This JACC review citing dapansutrile further establishes that selectively targeting NLRP3 offers promising advantages over the biologics. As Olatec’s Chief Scientific Officer, Dr. Charles Dinarello stated, “having an orally active and safe NLRP3 inhibitor such as dapansutrile could be a major breakthrough for treating CVD, particularly by inhibition of IL‑1β but also of IL-18. Advantages would include improved patient compliance and reduced unwanted side effects of biologics.”
Dr. Antonio Abbate, Professor of Medicine and Medical Director of the Clinical Research Unit at the Virginia Commonwealth University and Principal Investigator in Olatec’s heart failure study, for which results were previously published in the Journal of Cardiovascular Pharmacology, commented on the JACC review saying, “the manuscript provides an excellent review of all the preclinical and clinical data available related to the role of the NLRP3 inflammasome in heart disease and the results of the individual clinical trials; it was important to see the authors appraise the results of the dapansutrile phase 1b trial as the most interesting and promising study for patients with HF.”
Olatec is also pleased to report on another publication in CVD, covering dapansutrile’s new preclinical data demonstrating its cardio protective effects in this model. The data are published in the journal Molecules, titled, “Preservation of Contractile Reserve and Diastolic Function by Inhibiting the NLRP3 Inflammasome with OLT1177® (Dapansutrile) in a Mouse Model of Severe Ischemic Cardiomyopathy Due to Non-Reperfused Anterior Wall Myocardial Infarction.” The study shows that oral dosing with dapansutrile significantly prevents loss of heart function in a model of myocardial infarction in mice when compared to the control groups. The experiment modeled severe ischemic cardiomyopathy in mice through surgical ligation of the left coronary artery without reperfusion. Both contractile reserve and diastolic function, two important measures of heart function, were improved in the dapansutrile-treated groups of mice compared to control groups.
This investigation was led by Dr. Stefano Toldo, Associate Professor of Medicine, Virginia Commonwealth University. Dr. Toldo commented on the value of the new data: “oral dosing with the selective NLRP3 inhibitor, dapansutrile, presents a promising strategy for preserving heart function following myocardial infarction and restoring function in heart failure. Data in mice show significant preservation of contractile reserve and diastolic function in an experimental model of heart failure due to severe ischemic cardiomyopathy.”
About Heart Failure
It has been reported that heart failure affects approximately 64 million people worldwide and is increasing in prevalence. HF is a primary reason for hospital admission in individuals aged 65 or older. Global expenditures due to HF are known to be considerable, accounting for approximately US$ 346 billion according to Global Health Data Exchange registry.
About Dapansutrile
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 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), heart failure, contact dermatitis, multiple sclerosis, melanoma, pancreatic and breast cancers, spinal cord injury (SCI), Parkinson’s and Alzheimer’s disease.
About Olatec Therapeutics LLC
Olatec is a privately held, Phase 2 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.
Contacts
Damaris B. Skouras, Co-Founder and CEO, and
Olatec Investor Relations & Communications, ir@olatec.com
