Olatec Therapeutics Announces the Completion of First Dose Cohort in an Innovative Trial Investigating Olatec’s NLRP3 Inhibitor Dapansutrile and Merck’s Keytruda® in Patients with Advanced Refractory Melanoma at Duke Cancer Institute

  • Olatec’s dapansutrile - considered to be the first oral NLRP3 inhibitor tested in patients with advanced refractory melanoma - is addressing the inflammatory driven resistance to anti-PD-1 therapies, a large and growing unmet medical need
  • NLRP3 inhibition with dapansutrile reduces the pro-tumor inflammatory cytokine, IL‑1β, in human melanoma cells, and restores immune surveillance function leading to reduced tumor progression in mouse models
  • The DREAM (DapansutRile Plus PEmbrolizumab in Patients with PD-1 Refractory Advanced Melanoma) Trial is assessing dapansutrile in combination with pembrolizumab (Keytruda®), under Principal Investigator April Salama MD, Head of Duke Cancer Institute’s Melanoma Program
  • The first cohort of the DREAM Trial completed enrollment, showing no dose limiting toxicity allowing escalation to the second and highest dose cohort of the study

NEW YORK--()--Olatec Therapeutics LLC (Olatec), a leader in the developing class of selective NLRP3 inhibitors, today announced it has completed the lower dose cohort and entered the second, and highest, dose cohort of the DREAM Trial, a Phase 1/2 Investigator-initiated clinical study (NCT04971499). This trial is evaluating the combination treatment of Olatec’s dapansutrile, an NLRP3 inhibitor, and pembrolizumab (Keytruda®) in patients with PD-1 refractory advanced melanoma. The study is being led by Principal Investigator (PI), April Salama MD, Head of the Melanoma Program at The Duke Cancer Research Institute and supported by Olatec and Merck & Co., Inc. (Merck). The aim of the DREAM Trial is to address the unmet need in patients with PD-1 refractory advanced melanoma.

Immunotherapy with immune checkpoint inhibitors (e.g., anti-PD-1 therapies) has transformed the treatment of melanoma, significantly improving the outcome of patients with this disease. However, despite its significant benefit, reportedly only about 50% of patients experience lasting clinical improvement from this therapy. A significant proportion of patients have been known to develop PD-1 resistance, making this therapy incomplete for the large melanoma population. As PI, April Salama MD, commented: “While the initial responses to immunotherapy with immune checkpoint inhibitors have been impressive, only a subset of melanoma patients continue to benefit, and new combination approaches are needed.”

NLRP3 activation has been shown to induce proliferation of immunosuppressive cells and to suppress anti-tumor immunity leading to tumor progression. In its preclinical studies, Olatec has demonstrated that inhibition of NLRP3 with dapansutrile reduces the pro-tumor inflammatory cytokine, IL‑1β, in human melanoma cells and restores immune surveillance function in in vivo mouse models leading to reduced tumor progression (see publications in PNAS, Frontiers in Immunology and JCI). In mice, it was also demonstrated that the addition of dapansutrile to anti-PD-1 therapy increased the efficacy of the respective monotherapies. For more detailed explanation, see “About PD-1 Immunotherapies and the Rationale for NLRP3 to Mitigate Resistance” below.

Charles Dinarello MD, CSO of Olatec, remarked: “We are optimistic that our findings in animal studies in melanoma could now translate in humans. The DREAM Trial may likely show that co-administration of dapansutrile and pembrolizumab could re-sensitize human anti-tumor pathways in restoring targeted cancer cell eradication by the combination of these therapies.”

The DREAM Trial is designed in two parts: part 1 addresses the safety and tolerability of the escalating doses of dapansutrile in combination with pembrolizumab, and part 2 addresses the preliminary efficacy. Both parts 1 and 2 will initiate with a 14-day period of dapansutrile monotherapy to monitor for the safety profile of the novel medication in participants with melanoma and to assess the effects of dapansutrile monotherapy on the NLRP3-PD-1 immunological pathway. Subsequently, preliminary efficacy of the treatment in restoring pembrolizumab sensitivity will be measured and quantified by the ORR (objective response rate) and PFS (progression free survival).

Alberto Mantovani MD, Olatec SAB member commented, “I believe the results from the DREAM study could identify NLRP3 inhibition as a key target in the design of future clinical studies in multiple treatment-resistant cancers beyond melanoma.”

“By reducing NLRP3 inflammasome activation, dapansutrile has the potential to become an important therapeutic in combination therapy improving patient outcomes in treatment-resistant melanoma as well as other cancers,” stated Damaris Skouras, CEO of Olatec.


About PD-1 Immunotherapies and the Rationale for NLRP3 to Mitigate Resistance
PD-1 immunotherapies are considered one of the more novel approaches to metastatic cancer treatment that is able to target disease, reducing tumor progression by activating CD8+ T cells of the immune system to selectively target aberrant cells. PD-1, short for programmed cell death protein 1, is a receptor expressed on the surfaces of T cells. Upon engagement of PD-1 with its ligand, program cell death ligand 1 (PD-L1), T cell-mediated immune responses are shut off. PD-L1 is normally expressed on innate immune cells, such as macrophages, and is an important mechanism in promoting self-tolerance through regulation of T cell activity. However, tumor cells expressing PD-L1 have been shown to use the PD-1/PD-L1 axis to evade the immune system. Administration of the monoclonal antibody, pembrolizumab, binds PD-1, thereby preventing engagement with PD-L1 and freeing CD8+ T cells to mobilize and kill the tumor cells.

Changes in the tumor microenvironment, shown to be facilitated by activation of the NLRP3 inflammasome, induce proliferation of immunosuppressive cells that suppress anti-tumor immunity. This immunosuppressive outcome of aberrant NLRP3 activation have been corroborated by preclinical studies showing that inhibition of NLRP3 with dapansutrile reduces the pro-tumor inflammatory cytokine, IL‑1β, in human melanoma cells and restores immune surveillance function in in vivo mouse models leading to reduced tumor progression (see publications in PNAS, Frontiers in Immunology and JCI). Therefore, Olatec’s preclinical work supports the hypothesis that co-administration of dapansutrile and pembrolizumab could restore an efficient immune response toward targeted cancer cell eradication.

About Melanoma
Skin cancer is the most common form of cancer in the United States, and melanoma accounts for the vast majority of skin cancer deaths. Among young adults, it is the second most common invasive cancer and, according to the American Academy of Dermatology Association, 1 in every 5 people in the United States suffers from skin cancer. In 2023, according to the American Cancer Society about 97,000 people in the US are expected to develop melanoma requiring systemic therapy. The most common form of systemic treatment is immunotherapy.

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‑1 mediated immunosuppression which allows melanoma tumor cells to grow unabated. Dapansutrile, as a monotherapy, was shown to reduce tumor growth by up to 65% in a melanoma mouse model. Olatec’s team has demonstrated that the concentration of dapansutrile in the tumors was at levels sufficient to inhibit the NLRP3 inflammasome formation. Moreover, reduction in tumor volumes in dapansutrile treated mice had increased survival when 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 than either treatment alone. Specifically, mice that received dapansutrile plus the checkpoint inhibitor/anti-PD-1 antibody showed a further reduction in tumor growth of 66% when compared to the control group. The combination therapy (dapansutrile + anti-PD-1) further reduced tumor volume by 51% compared to anti-PD-1 immunotherapy only. Overall, these findings support the concept that the NLRP3 inhibition added to anti-PD-1 immunotherapy may have greater efficacy in reducing tumor growth compared to either agent as a monotherapy (see publications in PNAS and Frontiers in Immunology).

In Olatec’s studies of metastatic breast cancer in mice, dapansutrile showed reduced infiltration of myeloid-derived suppressor cells (MDSCs) and increased CD8+ T cells. Specifically, it was shown that, in combination with an anti-PD-1 immunotherapy, dapansutrile increased efficacy of immunotherapy (see publication in Pharmaceuticals).

In 2022, Carlo Marchetti, PhD, Olatec senior scientist and assistant research professor at University of Colorado, secured grant funding to investigate the role of NLRP3 in Pancreatic Ductal Adenocarcinoma (PDAC).

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. 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 Olatec Therapeutics LLC
Olatec is a privately held, Phase 2/3 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 (see list of clinical trials to-date, here). In addition to the lead compound, dapansutrile, Olatec’s platform of proprietary compounds includes OLT Analogues being screened as viable drug candidates. A portfolio of intellectual property registrations 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
This press release is not an offer to sell and is not soliciting an offer to buy any equity interests in the Company. 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.


For more information, please contact: ir@olatec.com