Olatec Therapeutics Announces Publication of Preclinical Research on Oral NLRP3-Specific Inhibitor Dapansutrile in Pancreatic Ductal Adenocarcinoma

2023-10-03

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Olatec’s dapansutrile, an NLRP3 inhibitor NLRP3 inhibitor, was studied in a preclinical model of pancreatic ductal adenocarcinoma (PDAC) This study furthers our understanding of the role of NLRP3 in PDAC by showing how PDAC cells are able to induce NLRP3 activation and consequently promote tumor progression and immunosuppression Inhibition of NLRP3 with dapansutrile was shown to reduce tumor progression in mice by restoring an effective anti-tumor immunity Dapansutrile increased survival in mice in these PDAC studies Dapansutrile was also shown to increase the efficacy of standard chemotherapy in PDAC supporting its potential as therapeutic target The findings from Olatec’s PDAC research expands its preclinical data platform, generated previously in melanoma and breast cancer, showing tumor reduction by treating NLRP3 driven inflammation with dapansutrile Dapansutrile is being investigated at the Duke Cancer Institute Cancer Institute in an ongoing clinical trial as a combination therapy with pembrolizumab (Keytruda®) in treating patients with PD-1 refractory advanced melanoma PD-1 refractory advanced melanoma NEW YORK--(BUSINESS WIRE)-- Olatec Therapeutics LLC (Olatec), a leader in the developing class of oral selective NLRP3 inhibitors NLRP3 inhibitors, today announced a publication in Cancer Research Communications showing a reduction in tumor progression with dapansutrile as a monotherapy, resulting from inhibition of NLRP3/IL-1β pathway in mouse models of pancreatic ductal adenocarcinoma (PDAC). Additionally, the data show that dapansutrile, when administered in combination therapy with gemcitabine significantly increased efficacy of this chemotherapy. PDAC has been reported to constitute ninety percent of all pancreatic cancers and it is the third leading cause of cancer deaths in the US and seventh worldwide. Long-term survival among PDAC patients remains poor due to a lack of effective screening methods, nonspecific symptoms, and limited treatment options. While there has been improvement in systemic chemotherapy, an urgent need still exists for an effective treatment. Inflammation in the tumor microenvironment (TME) in PDAC models caused by activation of the IL-1β pathway has been shown to promote PDAC cell proliferation, metastasis and to limit response to chemotherapy. Olatec’s preclinical studies advance this understanding by demonstrating that NLRP3 participates in the IL‑1β-mediated PDAC progression. Dr. Carlo Marchetti, the investigator in these studies, shows NLRP3 to be highly expressed in the tissue of pancreatic tumors when compared to normal pancreatic tissue. Dr. Marchetti further demonstrates that PDAC-bearing wild type mice treated with dapansutrile significantly reduce tumor growth and mass, which was confirmatory in his studies using mice with the NLRP3 genetic deletion. Advancing Olatec’s understanding of dapansutrile’s immunologic effect in cancer, the studies also show that inhibition of NLRP3 with dapansutrile result in intra-tumoral increase in IL-2, a reduction in T-helper (Th)2 response, and an augmented activation of CD8 T cells which resulted in a favorable change in the T Cell phenotype of the TME. When asked about the implications of these findings, Charles Dinarello MD, Olatec SAB Chair, said: “the preclinical data we have generated using a well-established murine model of PDAC provide the rationale to advance dapansutrile into a PDAC clinical trial.” Olatec’s Founder and CEO, Damaris Skouras, commented: “There is an urgent unmet need for an effective treatment to extend patient survival with this pernicious form of pancreatic cancer. We believe patient outcomes could potentially be improved if the data from our preclinical studies translate in clinic trials.” About Pancreatic Ductal Adenocarcinoma Pancreatic ductal adenocarcinoma has been reported to constitute 90% of all pancreatic cancers and it is the third leading cause of cancer deaths in the US and seventh worldwide. The incidence rate for pancreatic cancer has increased by about 1% per year since the late 1990s in both men and women, according to American Cancer Society (Cancer Facts & Figures 2023). Lack of effective screening methods, nonspecific symptoms and limited treatment options are major limitations in the management of this disease that contribute to the extremely severe prognosis in pancreatic cancer patients. The 5-year survival reached approximately 11% for the first time in 2022. A combination of systemic therapy and surgery is needed to treat patients with PDAC in order to achieve the best chance at long-term outcomes. While there has been improvement in systemic chemotherapy, long-term survival among PDAC patients remains poor. Immunotherapy has increasingly become a treatment option of interest for many cancer types. The efficacy of immunotherapy to treat PDAC patients remains unclear, however, the PDAC tumor microenvironment may promote resistance to immunotherapy supporting the rationale for intervention with anti-inflammatory therapies. 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 inhibit 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. For a complete list of Olatec’s original publications on dapansutrile in various preclinical and clinical disease areas, please refer to Olatec’s publication page, here. About Dapansutrile’s Preclinical Cancer Research Dapansutrile is being studied in multiple murine models of cancer and immunomodulation, including melanoma, breast cancer, and pancreatic cancer. To date, Olatec has demonstrated that treatment with dapansutrile halts tumor progression by limiting the NLRP3/IL‑1ꞵ mediated immunosuppression which allows tumor cells to grow unabated. Dapansutrile, as a monotherapy, reduced tumor growth by up to 65% reduction in a mouse model of melanoma. Olatec’s team has confirmed that the concentration of dapansutrile in melanoma tumors was at levels sufficient to inhibit the NLRP3 inflammasome formation. Moreover, reduction in tumor volumes following dapansutrile treatment increased survival of the mice compared to untreated mice. Furthermore, data demonstrated that the combination of NLRP3 inhibition with dapansutrile and anti-PD-1 immunotherapy restores the host’s antitumor response and results in a greater reduction in the melanoma tumor volume than either treatment alone. Mice that received dapansutrile plus the checkpoint inhibitor showed a further reduction of 66% tumor volume when compared to mice treated with the control. When compared to each of the monotherapies, the combination therapy resulted in a further reduction in tumor volume of 51% compared to anti-PD-1 only. Overall, these findings support the concept that NLRP3 inhibition added to anti-PD-1 has greater efficacy in reducing tumor growth compared to either agent as a monotherapy (see publications in PNAS, Frontiers in Immunology). In models of metastatic breast cancer, dapansutrile showed reduced infiltration of myeloid-derived suppressor cells (MDSCs) and increased CD8+ T cells (see publication in Pharmaceuticals). In the same study, it was shown that, in combination with an anti-PD-1, dapansutrile increased efficacy of immunotherapy (see publication in Pharmaceuticals). About Olatec Therapeutics LLC Olatec is a privately held, Phase 2/3 clinical-stage biopharmaceutical company developing a platform of oral NLRP3 inhibitors NLRP3 inhibitors to treat and prevent a broad spectrum of acute and chronic inflammatory diseases known to be mediated by IL-1 (see list of clinical trials to-date, here). 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. A portfolio of intellectual property registrations protecting Olatec’s compounds consists of over 140 patents granted, covering dapansutrile and OLT Analogues. Olatec’s drug development team is comprised of experienced management and international experts in translational medicine with leading expertise in inflammation and immunology and has been involved in the discovery and development of first-line inflammation treatments in the market today. 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