MUC16 x CD28

Regeneron's revised R&D road map includes the study of the bispecific as a monotherapy. Regeneron is rethinking development of its prostate cancer bispecific after two patients died in a clinical trial. The deaths prompted the Big Biotech to stop enrolling patients to receive REGN5678 and a full dose of its checkpoint inhibitor, but a reshaped bispecific development program is continuing.  REGN5678 is designed to bind to CD28 on cytotoxic T-lymphocytes (CTLs) and PSMA on tumor cells. By binding to the costimulatory T-cell-specific surface glycoprotein and tumor-associated antigen, the drug candidate could activate CTLs and direct them to attack cancer cells. Regeneron identified the targeting of CD28 on previously activated T cells as a way to reduce toxicity compared to CD3 bispecifics.  The candidate, which may synergize with anti-PD-1/L1 checkpoint inhibitors, came through the release of preliminary phase 1/2 data unscathed. But safety concerns have since come to light and prompted a shift in the R&D strategy. In its second-quarter results statement, Regeneron reported two immune-mediated deaths in a cohort of patients who received REGN5678 in combination with Libtayo, the company’s checkpoint inhibitor. The deaths drove Regeneron to stop enrolling patients to receive REGN5678 and a full dose of Libtayo. Regeneron is sticking with the candidate, though. The revised R&D road map includes the study of the bispecific as a monotherapy and in combination with lower doses of Libtayo and other immunotherapy modalities. Regeneron’s other costimulatory bispecific development programs, which include candidates against EGFR, MUC16 and CD22, are unaffected and are still making their way through dose escalation.  Even so, the removal of the option to pair REGN5678 with a full dose of Libtayo is a blow. Regeneron took the bispecific into the clinic in the belief the combination may be able to overcome the resistance of metastatic castration-resistant prostate cancer to PD-1 inhibition. Overcoming resistance could bring the benefits of checkpoint inhibitors to prostate cancer, a setting in which the drugs have had little impact. CD28 has a troubled history as a cancer target. The CD28 superagonist TGN1412 caused critical illnesses linked to cytokine storms in a phase 1 clinical trial in 2006. In recent years, companies including Johnson & Johnson and Sanofi have invested in candidates against the target, but fresh concerns emerged last year, when two deaths stopped trials of Alpine Immune Sciences’ conditional costimulator of CD28.

Lev Radin/Shutterstock Regeneron’s oncology strategy is to improve checkpoint inhibitor treatments with combination therapies – centered around Libtayo – according to a pipeline overview presented to investors Monday morning. In a webcast, David Weinreich, M.D., Regeneron’s EVP, global clinical development, noted four approaches: CD3 bispecifics, dubbed Signal 1; CD28 bispecifics, named Signal 2; tumor-targeted biparatopics; and modulating the immune response. The focus is to “enhance and expand” PD-1 treatment with Regeneron’s combinations to “mix and match best approaches to broadening and deepening anti-tumor activity,” Weinreich said. The company presently has three classes of investigational bispecifics being evaluated in ongoing Phase I/II studies. It is presenting data from two of these at EMSO. A mini-oral presentation will highlight ubamatamab, a bispecific designed to bridge MUC16 on cancer cells with CD3-expressing T cells to enhance local tumor-specific T-cell activation. “We hope to develop ubamatamab as a monotherapy or in combination with Libtayo or a costim [costimulatory] MUC16 for ovarian cancer and potentially for other MUC16-expressing tumors,” Israel Lowy, M.D., Ph.D., SVP, translational clinical Sciences, oncology, said during the webcast. Regeneron will present updated data from an expansion cohort combining Libtayo with fianlimab, a LAG-3 inhibitor, in advanced melanoma. In two independent patient cohorts, the duo demonstrated greater than 60% response rates. One cohort saw a 62.5% overall response rate (ORR), six complete responses (CS) and 19 partial responses (PR). The second cohort saw a 65% ORR with one CR and 25 PRs. The primary analysis of a Phase II trial of Libtayo alone in neoadjuvant cutaneous squamous cell carcinoma (CSCC) will also be shared. Lowy described an “almost plug-and-play” approach to mix and match therapies to treat cancers. To date, Regeneron has advanced 14 oncology drugs into the clinic, demonstrating preliminary therapeutic benefits in solid tumors and clinically meaningful benefits for hematological cancers with several bispecific antibodies. It has earned global regulatory approvals for Libtayo in multiple indications. When asked what, aside from Libtayo, investors should be interested in, Weinreich replied, “The two near-term oncology assets are going to be ubamatamab and fianlimab, where we have very strong Phase II data in hand.” The third area of individual focus, he said, is CD28 bispecifics. “For a while, this custom portfolio…has been restricted to positive animal data, which we know don’t always translate to clinical activity. We now have pretty convincing data that this costimulatory platform, our animal model, are predictive of what’s going to happen in the clinic.” Weinreich called this “a major change in our pipeline and for investors looking at our work.” Featured Jobs on BioSpace

Pictured: Regeneron logo on a light brown building Shutterstock/Lev Radin Regeneron’s oncology strategy is centered around improving checkpoint inhibitor treatments with combination therapies, according to a pipeline overview presented Monday morning. Lev Radin/Shutterstock Regeneron ’s oncology strategy is to improve checkpoint inhibitor treatments with combination therapies – centered around Libtayo – according to a pipeline overview presented to investors Monday morning. In a webcast, David Weinreich, M.D., Regeneron’s EVP, global clinical development, noted four approaches: CD3 bispecifics, dubbed Signal 1; CD28 bispecifics, named Signal 2; tumor-targeted biparatopics; and modulating the immune response. The focus is to “enhance and expand” PD-1 treatment with Regeneron’s combinations to “mix and match best approaches to broadening and deepening anti-tumor activity,” Weinreich said. The company presently has three classes of investigational bispecifics being evaluated in ongoing Phase I/II studies. It is presenting data from two of these at EMSO. A mini-oral presentation will highlight ubamatamab, a bispecific designed to bridge MUC16 on cancer cells with CD3-expressing T cells to enhance local tumor-specific T-cell activation. “We hope to develop ubamatamab as a monotherapy or in combination with Libtayo or a costim [costimulatory] MUC16 for ovarian cancer and potentially for other MUC16-expressing tumors,” Israel Lowy, M.D., Ph.D., SVP, translational clinical Sciences, oncology, said during the webcast. Regeneron will present updated data from an expansion cohort combining Libtayo with fianlimab, a LAG-3 inhibitor, in advanced melanoma. In two independent patient cohorts, the duo demonstrated greater than 60% response rates . One cohort saw a 62.5% overall response rate (ORR), six complete responses (CS) and 19 partial responses (PR). The second cohort saw a 65% ORR with one CR and 25 PRs. The primary analysis of a Phase II trial of Libtayo alone in neoadjuvant cutaneous squamous cell carcinoma (CSCC) will also be shared. Lowy described an “almost plug-and-play” approach to mix and match therapies to treat cancers. To date, Regeneron has advanced 14 oncology drugs into the clinic, demonstrating preliminary therapeutic benefits in solid tumors and clinically meaningful benefits for hematological cancers with several bispecific antibodies. It has earned global regulatory approvals for Libtayo in multiple indications. When asked what, aside from Libtayo, investors should be interested in, Weinreich replied, “The two near-term oncology assets are going to be ubamatamab and fianlimab, where we have very strong Phase II data in hand.” The third area of individual focus, he said, is CD28 bispecifics. “For a while, this custom portfolio…has been restricted to positive animal data, which we know don’t always translate to clinical activity. We now have pretty convincing data that this costimulatory platform, our animal model, are predictive of what’s going to happen in the clinic.” Weinreich called this “a major change in our pipeline and for investors looking at our work.” Featured Jobs on BioSpace