Zenith Epigenetics Announces Start of Several National Cancer Institute (NCI)-Sponsored Oncology Clinical Trials

Seven NCI sponsored trials will evaluate safety and efficacy of its BET inhibitor (BETi) ZEN-3694 in combination with several targeted agents and/or chemotherapy in several solid tumor types with significant unmet need

CALGARY, Alberta, July 06, 2022 (GLOBE NEWSWIRE) -- Zenith Epigenetics Ltd. (“Zenith” or the “Company”) announced today that its leading BET inhibitor, ZEN-3694, is being evaluated in seven NCI sponsored clinical trials for safety and efficacy in multiple oncology indications with significant unmet need, through the NCI’s Cancer Therapy Evaluation Program (CTEP) under a collaboration between Zenith and NCI, part of the National Institutes of Health. These trials are being conducted by leading investigators and institutions funded by the NCI in the United States and are based on strong pre-clinical rationale for anti-cancer drug combination regimens incorporating ZEN-3694 in advanced and metastatic tumors that are resistant to other therapies. BETis, like ZEN-3694, have been shown in pre-clinical pharmacology studies to sensitize tumors resistant to targeted agents through epigenetic modulation, hence the significant interest in evaluating several such combination therapies. Three of the aforementioned trials are accruing patients, with the remaining five pending activation in the next few months. A rich translational program is embedded in each trial to validate the mechanism of action and identify markers of response and resistance.

Combination with immune-checkpoint inhibitors

NCT04840589 (enrolling) A Phase I/Ib Trial Evaluating the Safety and Efficacy of BET Inhibitor, ZEN003694 With PD-1 Inhibitor, Nivolumab With or Without CTLA-4 Inhibitor, Ipilimumab in Solid Tumors is evaluating the combination of ZEN-3694 + BMS’s immune-checkpoint inhibitors, Opdivo and Yervoy, in patients with advanced or metastatic solid tumors and wildtype BRCA, platinum resistant ovarian cancer. To date, checkpoint inhibitor trials have had limited success in ovarian cancer, and there are few options after patients progress on targeted therapies. ZEN-3694 has been shown preclinically to address several mechanisms of resistance to checkpoint inhibitors, and may sensitize tumors to the checkpoint combination. The trial is being led by Haider S. Mahdi, MD, Assistant Professor of Obstetrics, Gynecology & Reproductive Sciences at the University of Pittsburgh.

NCT05422794 A Phase 1b Trial of ZEN003694 (ZEN-3694) With Pembrolizumab and Nab-Paclitaxel in Patients With Metastatic Triple-Negative Breast Cancer will evaluate the combination of ZEN-3694 + Merck’s immune-checkpoint inhibitor, Keytruda, + Nab-paclitaxel in patients with advanced triple negative breast cancer whose tumors are PD-L1 negative. Keytruda is currently only approved in the PD-L1 positive TNBC population, leaving an unmet need in the PD-L1 negative population. The combination of BET inhibitors and paclitaxel are synergistic preclinically in TNBC. Preclinical rationale exists that combining immunotherapy with BETi and chemotherapy will increase the response rate in patients with PDL1 negative disease. The trial will be led by Ana Garrido-Castro, MD, Medical Oncologist at the Dana-Farber Cancer Institute.

Combination with PARP inhibitors

NCT05327010 A Phase 2 Trial of the Combination of the BET Inhibitor, ZEN003694 (ZEN-3694), and the PARP Inhibitor Talazoparib, in Patients With Molecularly-Selected Solid Tumors (ComBET) will evaluate the combination of ZEN-3694 plus talazoparib in additional indications such as PARPi resistant ovarian, prostate cancer, breast, and pancreatic cancers, and solid tumors with Ras alterations. This trial builds on the proof of concept shown in Zenith Epigenetics' mTNBC trial (NCT03901469) by expanding into additional indications where PARPi are utilized. BETi including ZEN-3694 has been shown to sensitize germline BRCA wild-type tumors to PARPi, by creating a “BRCAness” phenotype and reverse acquired resistance to PARPi in pre-clinical models. The trial will be led by Timothy A Yap, MBBS PhD FRCP, Associate Professor of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center.

Combination with MEK inhibitor

NCT05111561 (enrolling) A Phase 1 Study of ZEN003694 in Combination With Binimetinib in Solid Tumors With RAS Pathway Alterations and Triple Negative Breast Cancer is evaluating the safety and the activity of ZEN-3694 combined with Pfizer’s MEK inhibitor, Mektovi, in solid tumors with Ras alterations and mTNBC. ZEN-3694 + MEKi have shown synergistic activity in pre-clinical Ras activated tumor models. In Ras activated tumors, acquired resistance to MEKi prevent durable responses. This resistance has been shown to be driven by enhancer modeling and is BET-dependent. Pre-clinical has shown synergy between MEKi and ZEN-3694. The trial is being led by Sarina A. Piha-Paul, MD, Associate Professor at The University of Texas MD Anderson Cancer Center.

Combinations with chemotherapy or a CDK4/6 inhibitor for NUT carcinoma

NCT05019716 (enrolling) A Phase 1/2 Study of the Bromodomain Inhibitor ZEN003694 in Combination With Etoposide/Platinum in Patients With NUT Carcinoma is evaluating the combination of ZEN-3694 in combination with chemotherapy in the ultra orphan indication NUT carcinoma. NUT carcinoma is a BET-driven, ultra orphan indication with significant unmet need, and with strong pre-clinical and clinical proof of concept. BET inhibitors have been shown to disrupt the major oncogenic driver in NUT carcinoma. The trial is being led by Michael Cheng, MD, Medical Oncologist, at the Dana-Farber Cancer Institute.

NCT05372640 A Phase 1 Study of BET Bromodomain Inhibitor ZEN003694 in Combination With the CDK4/6 Inhibitor Abemaciclib in Patients With NUT Carcinoma and Other Solid Tumors will evaluate the combination of ZEN-3694 and Lilly’s CDK4/6 inhibitor, Verzenio, in NUT carcinoma as well. In a NUT carcinoma screen to identify resistance factors to BET inhibition, the CDK4/6 pathway was identified. Preclinically, ZEN-3694 and CDK4/6i are highly synergistic in NUT carcinoma models. The trial will be led by Geoffrey Shapiro, MD, PhD, Medical Oncologist, at the Dana-Farber Cancer Institute.

Combination with an HDAC inhibitor

NCT05053971 (enrolling) A Phase Ib/II Study of ZEN003694 and Entinostat in Advanced and Refractory Solid Tumors and Lymphomas will evaluate the combination of ZEN-3694 and Syndax’s HDAC inhibitor, entinostat, in solid tumors and lymphoma, with an expansion population in pancreatic cancer. HDACi have been shown pre-clinically in several systems to sensitize cancer cells to BETi, by hyperacetylating histones, the target of BET proteins. The trial will be led by Patricia M. LoRusso, DO, Professor at the Yale School of Medicine.

“We are very pleased with our collaboration with the NCI and that ZEN-3694 will be evaluated in additional oncology indications”, said Don McCaffrey, CEO of Zenith Epigenetics. “In addition to expanding the ZEN-3694 PARPi and the ZEN-3694 immune-checkpoint combination to reach additional patients, ZEN-3694’s potential as a combination agent in several different patient populations with a significant unmet need will also be evaluated. The level of interest by leading investigators and the NCI underscore the potential of ZEN-3694 in multiple oncology indications. We continue to advance ZEN-3694 toward registration and are committed to bring an important therapy to cancer patients”.

About Zenith and ZEN-3694

Zenith Epigenetics Ltd., a wholly-owned subsidiary of Zenith Capital Corp., is a clinical stage biotechnology company focused on the discovery and development of novel therapeutics for the treatment of cancer and other disorders with significant unmet medical need. Zenith Epigenetics is developing various novel combinations of BET inhibitors with other targeted agents. The lead compound, ZEN-3694, is in clinical development for various oncologic indications in addition to the clinical trials mentioned above, specifically:

  1. Phase 2b metastatic castration resistant prostate (mCRPC) cancer trial in combination with androgen receptor inhibitor, XTANDI (enzalutamide), conducted in collaboration with Astellas Pharma Inc and Newsoara Biopharma Co., Ltd. Zenith and Newsoara are the trial sponsors (NCT04986423).

  2. Phase 2b Triple Negative Breast Cancer (TNBC) trial in combination with the PARP inhibitor TALZENNA (talazoparib), conducted in collaboration with Pfizer and Newsoara Biopharma Co, Ltd. Zenith and Newsoara are the trial sponsors (NCT03901469).

  3. Phase 2 androgen receptor independent mCRPC trial in combination with immune checkpoint inhibitor KEYTRUDA (pembrolizumab) and XTANDI (enzalutamide), conducted by the University of California, San Francisco in collaboration with Merck Sharp & Dohme LLC, the U.S. Army Medical Research and Development Command, and the University of Michigan (NCT04471974).

About Triple Negative Breast Cancer (“TNBC”)

TNBC is an aggressive form of breast cancer with low survival rates. TNBC accounts for about 10-15% of all breast cancers and it differs from other types of invasive breast cancer in that it tends to grow and spread faster, has fewer treatment options, and tends to have a worse prognosis. The term triple-negative breast cancer refers to the fact that the cancer cells have only low or no amount of the receptors ER, PR, and HER2. Approximately 75,000 women in the US, Japan and the major EU countries are diagnosed with TNBC each year.

About Prostate Cancer

Prostate cancer is the second-most commonly diagnosed cancer among men and the fifth most common cause of male cancer death worldwide. Adenocarcinoma of the prostate is dependent on androgen for tumor progression and depleting or blocking androgen action has been a mainstay for over six decades. Although tumors are often initially sensitive to medical or surgical therapies that decrease levels of testosterone and to ARSIs that block AR signaling, disease progression ultimately occurs leading to mCRPC. The treatment of prostate cancer patients has evolved rapidly over the past ten years with second generation ARSIs. Despite these advances, many patients with mCRPC fail or develop resistance to existing treatments, leading to continued disease progression and limited survival rates

About NUT Carcinoma

NUT carcinoma (NC) is a rare, aggressive cancer defined by rearrangements of the NUTM1 gene, most often fusing NUTM1 to a BET protein family member. NC is underdiagnosed, and lacks effective treatments. BET inhibitors have been shown to inhibit NC growth, both preclinically and clinically.

About Ovarian Cancer

In the US epithelial ovarian cancer is the fifth most common cause of cancer death in women and the most common gynecologic malignancy with about half of women being diagnosed over 65 years of age often with advanced disease. Although primary treatment is effective, most women will relapse and develop resistance to conventional agents.

About Ras activated tumors

Approximately 40% of colorectal cancer, 30% on non-small cell lung cancer, and 95% of pancreatic cancer carry mutations in the oncogene RAS. Ras-mutant cancers are aggressive and poor prognosis, and Ras small molecule inhibitors only target a small percentage of the total Ras-mutant population.

For further information, please contact:

Investor Relations & Communications

Zenith Epigenetics
Phone: 587-390-7865
Email: info@zenithepigenetics.com
Website: www.zenithepigenetics.com

This news release may contain certain forward-looking information as defined under applicable Canadian securities legislation, that are not based on historical fact, including without limitation statements containing the words "believes", "anticipates", "plans", "intends", "will", "should", "expects", "continue", "estimate", "forecasts" and other similar expressions. In particular, this news release includes forward looking information relating to the potential role of ZEN-3694 in the treatment of cancer and other disorders, and the Company’s development of ZEN-3694 including its current and planned clinical studies. Our actual results, events or developments could be materially different from those expressed or implied by these forward-looking statements. We can give no assurance that any of the events or expectations will occur or be realized. By their nature, forward-looking statements are subject to numerous assumptions and risk factors including those discussed in our most recent MD&A which are incorporated herein by reference and are available through SEDAR at www.sedar.com. The forward-looking statements contained in this news release are expressly qualified by this cautionary statement and are made as of the date hereof. Zenith disclaims any intention and has no obligation or responsibility, except as required by law, to update or revise any forward-looking statements, whether as a result of new information, future events or otherwise.