ATR

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.”

Boehringer Ingelheim is paying an upfront fee, of publicly undisclosed size, for global rights to the ALT program.\n Boehringer Ingelheim has slipped another piece of its oncology R&D strategy into place, partnering with Tessellate Bio on a synthetic lethal program in a deal worth more than 500 million euros ($570 million) in biobucks. European biotech Tessellate exited stealth in 2023 with a focus on novel synthetic lethality approaches. PARP inhibitors have shown the potential to shrink tumors by targeting pairs of genes that are essential for the survival of cancer cells. Companies including AstraZeneca and Merck KGaA are studying forms of synthetic lethality beyond the homologous recombination deficiency pathway targeted by PARP drugs. Tessellate has found a largely unclaimed piece of territory, namely tumors that depend on alternative lengthening of telomeres (ALT) for their growth. About 10% to 15% of cancers rely on ALT, according to the biotech. ALT-positive tumors are associated with poor prognosis and a lack of targeted therapies. Boehringer is paying an upfront fee, of publicly undisclosed size, for global rights to the ALT program. Once milestones and other fees are factored in, the value of the agreement could swell to more than 500 million euros.  Telomeres, the caps at the ends of chromosomes, shorten with each cell division and limit the life span of cells. Some cancers, including many sarcomas, gliomas and neuroepithelial tumors, use ALT to maintain telomere length. Tumors’ reliance on ALT creates opportunities to selectively kill cancer cells by targeting the mechanism. Tessellate said it has developed inhibitors of an undisclosed target that helps enable uncontrolled growth of ALT-positive cancer cells. Blocking the target drives DNA damage, replication stress and cell death, the biotech said. When it exited stealth, Tessellate said its lead ALT program targeted the FANCM protein complex. Studies have shown FANCM suppresses DNA replication stress at ALT telomeres. Artios Pharma, another European biotech, has a discovery-stage ALT program, but the industry’s efforts to expand synthetic lethality have largely focused on other pathways to date. AstraZeneca, which helped put PARP inhibitors on the map, is running trials of drug candidates that hit targets including ATR. Other targets include WEE1, USP1 and POLθ.    

ACESOT-1051 Trial Expanded to Include HPV+ Head and Neck Squamous Cell Carcinoma (HNSCC) Patients, Targeting Populations Most Likely to Benefit for WEEI Inhibition DOYLESTOWN, Pa., March 31, 2025 (GLOBE NEWSWIRE) -- Aprea Therapeutics, Inc. (Nasdaq: APRE) (“Aprea”, or the “Company”), a clinical-stage biopharmaceutical company developing innovative treatments that exploit specific cancer cell vulnerabilities while minimizing damage to healthy cells, today announced that a patient with HPV+ head and neck squamous cell carcinoma (HNSCC) has been dosed in the ongoing ACESOT-1051 clinical trial evaluating APR-1051. This is the first patient to be dosed in Cohort 5 (70 mg once daily) of the study. Open label data from the study are expected in the second half of 2025. WEE1 inhibition has emerged as a promising strategy for targeting tumor cells with high replication stress and DNA damage accumulation. HPV driven cancers, including HPV+ HNSCC, are characterized by defects in the DDR pathway, making them potentially susceptible to WEE1 inhibition. HPV+ cancers are those where the underlying cause is persistent infection with human papillomavirus, a group of viruses that infect the skin and mucous membranes. A high proportion of HNSCC cases are attributable to HPV. An estimated 70% of the 20,000 cases of oropharyngeal squamous cell carcinoma (HNSCC that occurs in the oropharynx) seen annually in the US are attributable to HPV. APR-1051 is a potent and selective small molecule that has been designed to potentially solve tolerability challenges of the WEE1 class. The ongoing ACESOT-1051 (A Multi-Center Evaluation of WEE1 Inhibitor in Patients with Advanced Solid Tumors, APR-1051) clinical trial is a Phase 1 trial evaluating single-agent APR-1051 in patients with advanced solid tumors harboring cancer-associated specific gene alterations. “Enrollment of the first patient with HPV+ head and neck cancer in the Phase 1 ACESOT-1051 trial is an important step and is in line with our goal of identifying patient populations most likely to benefit from WEE1 inhibition,” said Philippe Pultar MD., Senior Medical Advisor and Lead WEE1 Clinical Development of Aprea. “We are pleased with the progress of the trial and encouraged by the safety profile of APR-1051 to date. We look forward to continuing the study as we work toward identifying the optimal dose for future studies. We continue to believe that APR-1051 has best in class potential.” The latest patient in ACESOT-1051 was enrolled at MD Anderson Cancer Center. Aprea recently entered into a Material Transfer Agreement (MTA) with MD Anderson to support preclinical research aimed at exploring the potential of APR-1051 in treating HPV+ and HPV- head and neck squamous cell carcinoma (HNSCC) expressing genomic markers of replication stress. ACESOT-1051 Study Design ACESOT-1051 (A Multi-Center Evaluation of WEE1 Inhibitor in Patients with Advanced Solid Tumors, APR-1051) is designed to assess the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of single-agent APR-1051 in advanced solid tumors harboring cancer-associated gene alterations. Oral APR-1051 will be administered once daily for 28-day cycles. The study consists of two parts. Part 1 is dose escalation and is expected to enroll up to 39 patients with advanced solid tumors. The first three dose levels (10mg, 20mg and 30mg) used accelerated titration. Bayesian Optimal Interval (BOIN) design is now being employed for the remaining dose levels (50mg and above). Part 2 (up to 40 patients) is designed for dose optimization, with the goal of selecting the Recommended Phase 2 Dose (RP2D). The primary objectives of the study are to measure safety, dose-limiting toxicities (DLTs), maximum tolerated dose or maximum administered dose (MTD/MAD), and RP2D; secondary objectives are to evaluate pharmacokinetics, preliminary efficacy according to RECIST or PCWG3 criteria; pharmacodynamics is an exploratory objective. The University of Texas MD Anderson Cancer Center is the lead site, and the study will be performed at between 3 and 10 sites in the U.S. For more information refer to clinicaltrials.gov NCT06260514. About Aprea Aprea is pioneering a new approach to treat cancer by exploiting vulnerabilities associated with cancer cell mutations. This approach was developed to kill tumors but to minimize the effect on normal, healthy cells, decreasing the risk of toxicity that is frequently associated with chemotherapy and other treatments. Aprea’s technology has potential applications across multiple cancer types, enabling it to target a range of tumors, including ovarian, colorectal, prostate, and breast cancers. The company’s lead programs are APR-1051, an oral, small-molecule inhibitor of WEE1 kinase, and ATRN-119, a small molecule ATR inhibitor, both in clinical development for solid tumor indications. For more information, please visit the company website at www.aprea.com. The Company may use, and intends to use, its investor relations website at https://ir.aprea.com/ as a means of disclosing material nonpublic information and for complying with its disclosure obligations under Regulation FD. 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