Regeneron Pharmaceuticals, Inc. (NASDAQ: REGN) today announced encouraging initial data from an ongoing Phase 1/2 trial investigating REGN5678, a novel PSMAxCD28 costimulatory bispecific antibody, in combination with the company's PD-1 inhibitor Libtayo® (cemiplimab) in advanced metastatic castration-resistant prostate cancer (mCRPC). REGN5678 is one of Regeneron's three clinical-stage costimulatory bispecifics, all of which are designed to bridge T cells to cancer cells and augment CD28 signaling to increase anti-tumor activity in combination with Libtayo or a CD3 bispecific.

"In past clinical trials, metastatic castration-resistant prostate cancer has been largely unresponsive to PD-1 inhibition and immunotherapy in general, leaving patients with inadequate treatment options, a poor prognosis and an expected survival of one to two years depending on the treatment history," said Mark Stein, M.D., a trial investigator and Associate Professor of Medical Oncology at Columbia University Vagelos College of Physicians and Surgeons. "These initial data provide the first clinical evidence indicating that a costimulatory bispecific antibody may synergistically combine with an anti-PD-1 agent such as Libtayo to enable activity against a tumor class previously resistant to anti-PD-1 immunotherapy. We look forward to further investigating the safety and efficacy of this combination."

The Phase 1/2, first-in-human, open label trial is currently enrolling patients with advanced mCRPC whose tumors have previously progressed on multiple anti-androgen therapies, with a majority also having received prior chemotherapy. In the Phase 1 dose-escalation portion, patients are initiated with weekly doses of REGN5678, for three weeks, to assess the safety and efficacy of this novel costimulatory antibody alone, which then continues in combination with standard dose Libtayo. The primary endpoints are safety, tolerability and pharmacokinetics. The key secondary endpoint is objective response rate defined as a ≥50% decline of prostate-specific antigen (PSA) from baseline and/or tumor shrinkage. PSA is a protein produced by the prostate gland and is commonly used as a biomarker to diagnose and follow prostate cancer, as many mCRPC patients have disease limited to bone lesions and cannot be assessed by conventional RECIST 1.1 criteria.

Preliminary data from the ongoing dose-escalation portion of the trial, across 8 dose level cohorts and a total of 33 patients, showed dose-dependent anti-tumor activity per centrally collected PSA values, as well as investigator reports. Not all patients have undergone or completed tumor assessments and the data are not yet final. At the lowest dose levels (cohorts 1-5), there was almost no evidence of anti-tumor activity, with only 1 of 17 patients showing a decrease (22%) in PSA; there were no ≥grade (Gr) 3 immune-related adverse events (irAE) at these doses. The lack of anti-tumor activity among these patients was consistent with the approximate 6% response rate reported in other trials with anti-PD1 monotherapy.

At the next three dose levels (cohorts 6-8), evidence of dose-dependent anti-tumor activity was generally seen within 6 weeks of starting combination treatment as follows:

• Cohort 6: 1 of 4 patients experienced a 100% decrease in PSA and a complete response (CR) in target lesions based on RECIST 1.1 criteria. The patient discontinued therapy due to a Gr3 irAE of the skin (that was considered to be a recurrence of a pre-existing condition, and has resolved with treatment per investigator report). The patient has maintained the 100% decrease in PSA and CR in target lesions for approximately 10 months to date per investigator report.
• Cohort 7: 3 of 8 patients experienced decreases in PSA of >99%, 44% and 22%. Two of these three patients had a Gr3 AE (aseptic encephalitis and seizure, respectively, both of which have resolved).
• Cohort 8: 3 of 4 patients experienced decreases in PSA of >99%, >99% and 82%. Of the two patients with >99% PSA reductions, one experienced a Gr3 case of mucositis (resolved) and the other experienced a Gr3 case of acute inflammatory demyelinating polyradiculopathy (ongoing).

In terms of safety, no ≥Gr3 irAEs were observed in patients without anti-tumor activity, and the occurrence of irAEs was correlated with anti-tumor activity; this is consistent with previous trials with anti-PD-1 immunotherapy, wherein irAEs have been reported to occur at a higher rate in responding patients. No Gr4 irAEs or ≥Gr2 cytokine release syndrome have been observed in the trial to date. There was one death that was considered unrelated to treatment. In this trial, irAEs are being treated according to standard management practices used for checkpoint inhibitors.

Additional data are planned for presentation at an upcoming medical meeting.

"Through extensive preclinical research, we hypothesized that augmenting T-cell costimulation alongside PD-1 inhibition could be a key to turning immunologically 'cold' tumors 'hot'," said George D. Yancopoulos, M.D., Ph.D., President and Chief Scientific Officer at Regeneron. "These preliminary data for our PSMAxCD28 costimulatory bispecific provide the first clinical evidence supporting the promise of our broader pipeline of costimulatory bispecifics in diverse solid tumors and hematological malignancies. By combining these costimulatory bispecifics with Libtayo or our CD3 bispecifics, we have the opportunity to create novel therapeutic synergies to address some of the most difficult-to-treat cancers. We look forward to partnering with the oncology community on this ambitious and potentially groundbreaking research."

The combination of REGN5678 and Libtayo is currently under clinical development for mCRPC, and its safety and efficacy have not been fully evaluated by any regulatory authority.