BRCA2

Artios Pharma, a startup developing drugs that weaken a tumor’s ability to maintain its DNA, announced positive results in a subset of patients with advanced cancer. It’s the first big data reveal for the Cambridge, UK-based startup, which has been relatively quiet since 2021, when it struck a drug discovery partnership with Novartis and raised $153 million in Series C financing. The company’s drug, called ART0380, inhibits a DNA repair enzyme called ATR. When administered with a low dose of the chemotherapy irinotecan, the drug shrank tumors in 37% of patients whose cancer was considered “deficient” in another DNA damage response protein dubbed ATM, according to data from a Phase 1/2 study. In patients whose tumors lacked the ATM protein entirely, the response rate was 50%, with a median duration of response of 5.7 months so far. The response rate was 22% in patients with low levels of ATM. Patients with the ATM protein, however, did not respond to the therapy. “All those patients unfortunately progress quickly and unfortunately die very quickly,” Artios Chief Medical Officer Ian Smith told Endpoints News in an interview. The new data, presented Tuesday at the American Association for Cancer Research meeting, comes from 58 patients with advanced-stage and metastatic solid tumors who were treated at the dose the company plans to use in a Phase 2 study. Artios CEO Niall Martin told Endpoints that the company has funds “through 2026.” He said the startup is looking to raise another round of private funding to test its ATR inhibitor in pancreatic and colorectal cancers before pursuing bigger and broader tissue-agnostic studies. Martin said the company’s partnership with Novartis, which wasn’t focused on its ATR inhibitor, identified several targets that could potentially be paired with Novartis’ radioligand therapies, including its prostate cancer drug Pluvicto, and discussions are underway on next steps. Artios had struck a partnership with Merck KGaA in 2020 to search for drugs that target other DNA repair proteins, but Martin told Endpoints that partnership has ended. Artios was founded in 2016 to discover a new wave of drugs that target complex networks of proteins dedicated to the faithful replication and preservation of our genomes. While cancer can survive, and even thrive, with some DNA repair enzymes missing, too many missing pieces can cause the cancer to self-destruct. A class of drugs called PARP inhibitors exploit this vulnerability by blocking the eponymous DNA repair protein in tumors that have mutations in genes called BRCA1 and BRCA2, which are also important for DNA repair. Several companies have been searching for the next combination of targets that can deliver a similar double whammy to tumors, but progress has been slow. “The field hasn’t really evolved much since PARP inhibitors,” Martin said. “So we’ve been really thinking about what are the layers of DNA damage that are created in tumors that could be used as their sort of Achilles heel.” One of those layers, according to Artios, is a phenomenon called replication stress, which can occur when DNA replication, a key step for dividing cells, is blocked. ATR and ATM are two proteins that detect and clear up these blockages. Many forms of chemotherapy obstruct DNA replication. By first inducing a bit more of that stress with a low dose of chemo — but not enough to kill the cancer itself — and then blocking ATR in tumors with little to no ATM, Artios hoped to deliver a triple whammy to tumors. “There’s always been a push to get rid of chemotherapy and have targeted drugs,” Smith said.“But if you can’t get rid of chemotherapy, what you can do is really minimize it. And that’s what we’ve done here.” Smith said the company saw two complete responses, including one in a 62-year-old female who had pancreatic cancer but has been off treatment and cancer-free since August 2023. Neutropenia, a decline in white blood cells, was the most common side effect seen in 53% of patients, with grade 3 neutropenia in 45% of patients. Anemia occurred in 41% of patients. Fatigue, diarrhea, nausea and vomiting were also common side effects. Several other drugmakers have developed their own ATR inhibitors, but lackluster results have caused some pharma companies, including Bayer and Roche, to discontinue or pare back these efforts. “ATR inhibitors have been languishing,” Smith said. “The response rates are low relative to the toxicity that you tend to get.” Roche cut its partnership with Repare Therapeutics in 2024, which paused its ATR inhibitor program earlier this year after modest responses in only 19% and 17% of endometrial and ovarian cancer patients, respectively. Merck KGaA dropped its first ATR inhibitor, berzosertib, but is still testing a second one, called tuvusertib. And AstraZeneca is testing its ATR inhibitor ceralasertib in a Phase 3 study in lung cancer with its immunotherapy Imfinzi, which is expected to complete in August. Artios executives told Endpoints that other ATR inhibitors have faltered for three reasons: the drug’s half-life was too long, leading to intolerable toxicity; the drug was tested as a monotherapy, leading to low efficacy; or the drug was paired with the wrong therapies or tested in the wrong genetic subtypes of cancer. Martin said the company plans to develop a companion diagnostic to identify patients that are most likely to respond to its drug, with an initial focus on ATM. But Artios is looking for other biomarkers that may make tumors vulnerable to ATM inhibitors too. “This whole process of replication stress can be in up to 30% to 40% of tumors,” Martin said. “So there’s a huge area of biology which no one really has tapped into.”

NEW YORK, April 3, 2025 /PRNewswire/ -- A study led by NYU Langone Health researchers sheds light on how the major cancer gene BRCA2 determines which cancer cells can be killed by a class of precision cancer drugs called PARP inhibitors. Recently published in Nature, the work builds on the fact that, as human cells divide and grow, DNA damage occurs continuously and must be swiftly repaired to prevent cancer. BRCA2 is a key player in such a mechanism, homology-directed repair, but genetic changes, called mutations, occur and accumulate in cells, with some sabotaging the gene's DNA repair role to create cancer risk. Cancer cells also require DNA repair as their reckless growth causes a quick, lethal build-up of errors unless countered. When mutations hinder BRCA2 function, cancer cells are known to rely on the poly ADP-ribose polymerase 1 (PARP1) pathway for back-up DNA repair, and to continue abnormal growth. PARP inhibitors were designed to stop this. Now the new study, led by scientists at NYU Langone Health, reveals an unexpected role for BRCA2 in controlling the action of PARP1 at DNA damage sites, and explains why PARP inhibitors are effective in some patients but not in others. The effectiveness of PARP inhibitors in any cancer cell, the study authors found, depends on how well BRCA2 works there. While the percentage of cancer cells with functioning BRCA2 is hard to estimate accurately, it matters. As a proxy measure, past studies have shown that 15–20% of ovarian, 6–8% of breast, 8–10% of prostate, and 8–10% of pancreatic cancer cases feature either inherited BCRA2 mutations or those that arise for the first time as cells multiply in tumors. "This work is part of a larger effort across NYU Langone and Perlmutter Cancer Center to connect molecular discovery with clinical advances," said senior study author Eli Rothenberg, Ph.D., professor in the Department of Biochemistry & Molecular Pharmacology at NYU Grossman School of Medicine, and director of Single Molecule Biophotonics. "Through collaborations with clinical teams, we are set to translate insights about BRCA-related pathways into actionable diagnostics and new treatment strategies." Molecular Shield While many cancer patients see a temporary remission with PARP inhibitors, results vary greatly. To understand why, and to clarify the BRCA2-PARP1 interplay, the research team turned to proprietary imaging techniques developed at NYU Langone. "This finding would not have been possible without the specialized imaging tools pioneered by the Single Molecule Biophotonics program here," said Dr. Rothenberg. "They gave us a molecular window into how BRCA2 protects DNA repair complexes from disruption in living human cells in real time, bringing us closer to developing truly individualized cancer therapies." Single-molecule imaging revealed that BRCA2 functions as a molecular shield, physically preventing PARP1 from remaining stuck at DNA repair sites, the mechanism by which PARP inhibitors have their effect. Specifically, the researchers found that intact BRCA2 ensures that RAD51—a protein essential for accurate DNA repair—can access repair sites instead of PARP1, and carry out its function. This prevents the treatment-generated buildup of harmful DNA breaks in cancer cells that resist PARP inhibition. By contrast, in cells with defective BRCA2, PARP1 is free to bind to, and persist at, sites of DNA damage. This blocks RAD51 access and halts proper repair, causing fatal damage to cancer cells—a mechanism that explains the greater vulnerability of BRCA2-deficient tumor cells to PARP inhibitors. "Moving forward, our team is focused on how this mechanism can be used clinically," said first study author Sudipta Lahiri, Ph.D., the postdoctoral fellow at NYU Langone who led the experimental work. "The finding that variable BRCA2 activity dictates PARP inhibitor efficacy points to the need for patient-specific tumor profiling and may inform how clinicians select therapies. We are also looking at the structure of BRCA2 domains involved its ability to shield repair complexes from PARP1 with the goal of designing therapies that overcome resistance." Along with Drs. Rothenberg and Lahiri, study authors from the Department of Biochemistry and Molecular Pharmacology at NYU Grossman School of Medicine included Tony Huang, Ph.D., professor of Biochemistry and Molecular Pharmacology; George Hamilton, Ph.D.; and M.D./Ph.D. student Liana Goehring. From the Department of Therapeutic Radiology at Yale University School of Medicine, co-authors included Gemma Moore and co-senior author Ryan Jensen, Ph.D. The study was supported by National Institutes of Health (and National Cancer Institute) grants GM134947, AI153040, CA247773 and CA288368, CA270788 and CA215990, GM139610, ES031658 and CA288368, as well as by the V Foundation, the Gray Foundation, the Laura Chang and Arnold Chavkin Charitable Donation, the Goldberg Family Foundation, and a Perlmutter Cancer Center support grant. About NYU Langone Health NYU Langone Health is a fully integrated health system that consistently achieves the best patient outcomes through a rigorous focus on quality that has resulted in some of the lowest mortality rates in the nation. Vizient Inc. has ranked NYU Langone No. 1 out of 115 comprehensive academic medical centers across the nation for three years in a row, and U.S. News & World Report recently placed nine of its clinical specialties among the top five in the nation. NYU Langone offers a comprehensive range of medical services with one high standard of care across seven inpatient locations, its Perlmutter Cancer Center, and more than 320 outpatient locations in the New York area and Florida. With $14.2 billion in revenue this year, the system also includes two tuition-free medical schools, in Manhattan and on Long Island, and a vast research enterprise. CONTACT: Gregory Williams, [email protected] SOURCE NYU Langone Health System WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

First and only immunotherapy to show meaningful overall survival benefit in a Phase 2 trial in patients with advanced ovarian cancer Initiation of trial sites underway for ground-breaking Phase 3 pivotal trial of DNA-mediated IL-12 therapeutic Company to hold conference call on Tuesday, March 25, 2025 , at 2:00 p.m. ET LAWRENCEVILLE, N.J. , March 24, 2025 (GLOBE NEWSWIRE) -- IMUNON , Inc. (NASDAQ: IMNN), a clinical-stage company in Phase 3 development with its DNA-mediated immunotherapy, today announced that the U.S. Food and Drug Administration (FDA) is aligned with the protocol for the Phase 3 pivotal trial, called OVATION 3, of its lead candidate IMNN-001 in development for the treatment of women with newly diagnosed advanced ovarian cancer. The company is currently initiating trial sites and working with trial investigators to begin enrolling study participants. “We are grateful for the ongoing guidance and support from the FDA and are very pleased that the agency is fully aligned on our plans related to the Phase 3 trial,” said Stacy Lindborg , Ph.D., president and chief executive officer of IMUNON . “The Phase 2 OVATION 2 study data are highly encouraging, demonstrating that IMNN-001 is the first immunotherapy to achieve a clinically effective response in ovarian cancer, including benefits in both progression-free and overall survival in frontline treatment, and we continue to observe strong improvements with additional monitoring and follow-up of patients. We look forward to potentially replicating these unprecedented results in the Phase 3 OVATION 3 study. We are currently initiating trial sites and are focused on enrolling study participants as quickly as possible as we work towards our goal of bringing thousands of women with advanced ovarian cancer a first-in-class and much-needed treatment option.” The Phase 3 OVATION 3 trial will assess the safety and efficacy of IMNN-001 (100 mg/m2 administered intraperitoneally weekly) plus neoadjuvant and adjuvant chemotherapy (NACT) of paclitaxel and carboplatin compared to standard of care (SoC) NACT alone. Study participants will be randomized 1:1 and include women with newly diagnosed advanced ovarian cancer (stage 3 or 4) who are eligible for neoadjuvant therapy, the intent-to-treat (ITT) population, with a sub-group of women positive for homologous recombination deficiency (HRD) including BRCA1 or BRCA2 mutations. Participants who are HRD positive will receive poly ADP-ribose polymerase (PARP) inhibitors as part of standard maintenance therapy. The primary endpoint of the study is overall survival (OS), and secondary endpoints are surgical response score, chemotherapy response score, clinical response and time to second-line treatment. The study will also assess several exploratory endpoints. In December 2024 , IMNN-001 plus NACT boosted median overall survival to 46 months—outpacing standard-of-care NACT by 13 months—up 2 months from the prior 11-month mark after 7 additional months of follow-up, with an excellent safety profile showing no cytokine release syndrome or serious adverse events. In the same month, the company also announced a positive outcome from a Type C Chemistry, Manufacturing, and Controls (CMC) meeting with the FDA regarding current good manufacturing practice (cGMP) production of IMNN-001 for the Phase 3 trial and potential commercialization. Production of IMNN-001 is conducted at IMUNON’s in-house manufacturing facility located in Huntsville, Alabama . Conference Call and Webcast IMUNON is hosting a conference call to discuss the Phase 3 OVATION 3 pivotal trial of IMNN-001 on Tuesday, March 25, 2025 , at 2:00 p.m. ET . Company management will be joined by: Premal H. Thaker , M.D., Interim Chief of Gynecologic Oncology, David & Lynn Mutch Distinguished Professor of Obstetrics & Gynecology, Director of Gynecologic Oncology Clinical Research at Washington University School of Medicine , and the OVATION 2 Study Chair L.J. Wei , Ph.D., Professor of Biostatistics, Harvard T.H. Chan School of Public Health To participate in the call, please dial 833-816-1132 (Toll-Free/ North America ) or 412-317-0711 (International/Toll) and ask for the IMUNON Phase 3 protocol call. A live webcast of the call will also be available here. The call will be archived for replay until April 8, 2025. The replay can be accessed at 877-344-7529 ( U.S. Toll-Free), 855-669-9658 (Canada Toll-Free) or 412-317-0088 (International Toll), using the replay access code 9074731. An audio replay of the call will also be available here for 90 days. About the Phase 2 OVATION 2 Study OVATION 2 evaluated the dosing, safety, efficacy and biological activity of intraperitoneal administration of IMNN-001 in combination with neoadjuvant and adjuvant chemotherapy (NACT) of paclitaxel and carboplatin in patients newly diagnosed with advanced epithelial ovarian, fallopian tube or primary peritoneal cancer. Treatment in the neoadjuvant period is designed to shrink the tumors as much as possible for optimal surgical removal after three cycles of chemotherapy. Following NACT, patients undergo interval debulking surgery, followed by three additional cycles of adjuvant chemotherapy to treat any residual tumor. This open-label study enrolled 112 patients who were randomized 1:1 and evaluated for safety and efficacy to compare NACT plus IMNN-001 versus standard-of-care NACT. In accordance with the study protocol, patients randomized to the IMNN-001 treatment arm could receive up to 17 weekly doses of 100 mg/m2 in addition to NACT. As a Phase 2 study, OVATION 2 was not powered for statistical significance. Additional endpoints included objective response rate, chemotherapy response score and surgical response. About IMNN-001 Immunotherapy Designed using IMUNON's proprietary TheraPlas® platform technology, IMNN-001 is an IL-12 DNA plasmid vector encased in a nanoparticle delivery system that enables cell transfection followed by persistent, local secretion of the IL-12 protein. IL-12 is one of the most active cytokines for the induction of potent anticancer immunity acting through the induction of T-lymphocyte and natural killer cell proliferation. IMUNON previously reported positive safety and encouraging Phase 1 results with IMNN-001 administered as monotherapy or as combination therapy in patients with advanced peritoneally metastasized primary or recurrent ovarian cancer and completed a Phase 1b dose-escalation trial (the OVATION 1 Study) of IMNN-001 in combination with carboplatin and paclitaxel in patients with newly diagnosed ovarian cancer. IMUNON previously reported positive results from the recently completed Phase 2 OVATION 2 Study, which assessed IMNN-001 (100 mg/m2 administered intraperitoneally weekly) plus neoadjuvant and adjuvant chemotherapy (NACT) of paclitaxel and carboplatin compared to standard-of-care NACT alone in 112 patients with newly diagnosed advanced ovarian cancer. About Epithelial Ovarian Cancer Epithelial ovarian cancer is the sixth deadliest malignancy among women in the U.S. There are approximately 20,000 new cases of ovarian cancer every year and approximately 70% are diagnosed in advanced Stage III/IV. Epithelial ovarian cancer is characterized by dissemination of tumors in the peritoneal cavity with a high risk of recurrence (75%, Stage III/IV) after surgery and chemotherapy. Since the five-year survival rates of patients with Stage III/IV disease at diagnosis are poor (41% and 20%, respectively), there remains a need for a therapy that not only reduces the recurrence rate, but also improves overall survival. The peritoneal cavity of advanced ovarian cancer patients contains the primary tumor environment and is an attractive target for a regional approach to immune modulation. About IMUNON IMUNON is a clinical-stage biotechnology company focused on advancing a portfolio of innovative treatments that harness the body’s natural mechanisms to generate safe, effective and durable responses across a broad array of human diseases, constituting a differentiating approach from conventional therapies. IMUNON is developing its non-viral DNA technology across its modalities. The first modality, TheraPlas®, is developed for the gene-based delivery of cytokines and other therapeutic proteins in the treatment of solid tumors where an immunological approach is deemed promising. The second modality, PlaCCine®, is developed for the gene delivery of viral antigens that can elicit a strong immunological response. The Company’s lead clinical program, IMNN-001, is a DNA-based immunotherapy for the localized treatment of advanced ovarian cancer that has completed Phase 2 development. IMNN-001 works by instructing the body to produce safe and durable levels of powerful cancer-fighting molecules, such as interleukin-12 and interferon gamma, at the tumor site. The Company has completed enrollment for a first-in-human study of its COVID-19 booster vaccine (IMNN-101) which remains ongoing. IMUNON will continue to leverage these modalities and to advance the technological frontier of plasmid DNA to better serve patients with difficult-to-treat conditions, and to further strengthen IMUNON’s balance sheet through attractive business development opportunities. For more information, please visit www.imunon.com. Forward-Looking Statements IMUNON wishes to inform readers that forward-looking statements in this news release are made pursuant to the “safe harbor” provisions of the Private Securities Litigation Reform Act of 1995. All statements, other than statements of historical fact, including, but not limited to, statements regarding the timing for commencement and potential outcome of a Phase 3 trial of IMNN-001, the timing and enrollment of the Company’s clinical trials, the potential of any therapies developed by the Company to fulfill unmet medical needs, the market potential for the Company’s products, if approved, the potential efficacy and safety profile of our product candidates, and the Company’s plans and expectations with respect to its development programs more generally, are forward-looking statements. We generally identify forward-looking statements by using words such as “may,” “will,” “expect,” “plan,” “anticipate,” “estimate,” “intend” and similar expressions (as well as other words or expressions referencing future events, conditions or circumstances). Readers are cautioned that such forward-looking statements involve risks and uncertainties including, without limitation, uncertainties relating to unforeseen changes in the course of research and development activities and in clinical trials, including the fact that interim results are not necessarily indicative of final results; the uncertainties of and difficulties in analyzing interim clinical data; the significant expense, time and risk of failure in conducting clinical trials; the need for IMUNON to evaluate its future development plans; possible actions by customers, suppliers, competitors or regulatory authorities; and other risks detailed from time to time in IMUNON’s filings with the Securities and Exchange Commission . IMUNON assumes no obligation, except to the extent required by law, to update or supplement forward-looking statements that become untrue because of subsequent events, new information or otherwise. Contacts: Source: Imunon, Inc.