Oren Gilad, Ph.D., President and CEO of Aprea, and Eric Brown, Ph.D., Aprea Scientific Consultant (SOURCE: Aprea)
Aprea Therapeutics: A Focus on New Targets and Biomarkers in Oncology
Aprea Therapeutics, based in Doylestown, PA, recently dosed the first patient in its Phase I/IIa study of ATRN-119 for advanced solid tumors. Specifically, ATRN-119 is an oral ATR inhibitor targeting cancers with DDR mutations.
Ahead of presentations at the 6th Annual DDR Inhibitors Summit in Boston this week, Oren Gilad, Ph.D., President and CEO of Aprea, and Eric Brown, Ph.D., Scientific Consultant to Aprea, member of the company’s Scientific Advisory Board, and Associate Professor of Cancer Biology at the University of Pennsylvania, took time out to speak with BioBuzz about the company and the significance of new target and biomarker identification in oncology research.
Gilad describes Aprea as a clinical-stage, precision oncology company focused on “developing novel synthetic lethality-based cancer drugs.” Their “multi-dimensional approach uses integrated proteomics and machine learning” to identify new biomarkers and targets that focus on the DNA damage response (DDR).
Synthetic lethality refers to when mutations in two genes together cause cell death, but a mutation in either gene by itself doesn’t. In cancer cells, a single mutated gene may depend on the normal partner gene for survival. Synthetic lethality is a way to interfere with the function of the normal partner gene to kill cancer cells.
Mutations in the DDR pathways are associated with many aggressive cancers. ATR inhibition is viewed as a promising therapeutic approach. ATR is a protein that plays several key roles in response to DNA damage.
Gilad noted that the value of their approach, precision oncology targeting biomarkers, “is more efficacy and more tolerability.”
In May 2022, Aprea completed the acquisition of Atrin Pharmaceuticals. Part of the acquisition was picking up ATRN-119 and ATRN-354. This expanded Aprea’s area of focus into DDR pathway inhibitors.
The company dosed the first patient with ATRN-119 as a monotherapy in patients with advanced solid tumors harboring specific mutations in DDR pathways. The focus of the study is dose escalation, tolerability, and pharmacokinetics. Aprea expects a data readout in the first quarter of 2024 with plans to initiate a Phase II trial based on the data. A Phase IIa expansion trial will follow to further evaluate the tolerability and efficacy of the drug alone.
Gilad says they also expect to initiate a trial of the drug in combination with other therapeutics.
The company is also developing ATRN-W1051, an oral selective small molecule inhibitor of WEE1. WEE1 is a key regulator of multiple cell cycle phases. Gilad indicated plans to file an Investigational New Drug (IND) of ATRN-W1051 by the end of the year.
“We are also enriching our pipeline,” Gilad said. The company has an undisclosed ATR inhibitor, ATRN-W1051 targeting WEE1, and another undisclosed novel DDR target.
Brown says, “focusing on specificity is key.” He also points out that there are only five of these specific types of kinases, compared to the broader kinase family. There are more than 500 sites in DNA that require an ATR checkpoint kinase so the DNA doesn’t break when replicated. ATR inhibitors cause DNA to break. This is important to the anti-cancer effects of ATRN-119.
ATR as well as PARP enzymes are part of the DNA Damage Response. Cancer cells use this response to survive replication stress and errors in DNA repair. By inhibiting this process, Aprea believes they can develop cancer therapies with “greater specificity and greater tolerability,” Gilad said.
Gilad added, “Precision is key to where oncology treatment is going. New target identification can help us with new combination therapeutics.”
Aprea’s approach is consistent with precision oncology, which involves developing genomic-based diagnostics and targeted therapeutics. The goal is to deliver the right cancer therapy to the right patient at the right dose and at the right time.
Brown believes they “are at the early stage, but it’s a great big adventure.”
At the DDR Inhibitors Summit, Brown is presenting “Repli-Biom: a Novel Proteo-Genomic Approach to Identify Predictive Biomarkers of DDR Inhibitor Efficacy” (Thursday, Jan. 26, 11:30 am ET).
Gilad is presenting “How are Newer Targets Being Validated to Move Towards Clinical Trials?” (Jan. 25, 5:30 pm ET), “Understanding DDRI’s in the Clinic: Why Is Toxicity Such a Big Issue?” (Jan. 26, 9:00 am ET), and “Adding On to Monotherapy: Combining DDR Inhibitors” (Jan. 26, 1:30 pm ET).
Gilad said, “There is a lot of knowledge that has been accumulated. We’re a very data-driven team. We really let the science lead us. We find this approach challenging, but do-able. And there’s more to come.”
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Mark Terry is a freelance writer, editor, novelist and ghostwriter. He holds a degree in microbiology & public health and spent 18 years in infectious disease research and clinical and research genetics prior to his transition to a writing career. His areas of expertise include biotechnology, pharma, clinical diagnostics, and medical practice management. He has written literally thousands of articles, as well as market research reports, white papers, more than 20 books, and many other written materials. He currently lives in Michigan with his family.
