Regeneron’s early stage bispecific shows promise

The potentially revolutionary nature of CAR-Ts has made them the hottest properties in haemato-oncology in recent years, but a wave of bispecific antibody therapies look set to challenge them.

Representing an evolution of the well-established monoclonal antibody platform, bispecifics can hit two or more cell surface targets. This approach could see them match the clinical performance of CAR-Ts, but with a far easier and lower cost manufacturing process, and without the risk of serious side effects including cytokine-release syndrome (CRS).

Regeneron is one many companies developing bispecifics, and on Saturday at the ASH 2018 congress in San Diego, unveiled phase 1 proof of concept data for its REGN1979 in relapsed or refractory (R/R) follicular lymphoma and diffuse large B-cell lymphoma (DLBCL), the two most common types of Non-Hodgkins Lymphoma (NHL).

The company says REGN1979 demonstrated an acceptable safety and tolerability profile with no observed dose-limiting toxicities (DLTs), and no clinically-significant neurotoxicities, including no occurence of seizures or encephalopathy.

The drug binds to CD3 on immune system T-cells and CD20 on B-cell malignancies.

The clinical response from patients was very encouraging: heavily pre-treated patients with R/R FL grades 1 to 3a who received REGN1979 doses of 5 mg to 40 mg, experienced a 100% overall response rate (ORR) (8 complete responses [CR] and 2 partial responses, with 90% of responders maintained a response during treatment.

Regeneron says it will now initiate in 2019 a phase 2 trial of the drug, which could be sufficient to file with regulators, and says it could be a future first line therapy.

"While a high response rate is frequently observed in the first-line treatment of follicular lymphoma, it is remarkable to see a 100% response rate in heavily pre-treated relapsed or refractory follicular lymphoma patients," said Israel Lowy, M.D., Ph.D., Head of Clinical and Translational Sciences, Oncology at Regeneron.

Dose escalation will continue in the more difficult-to-treat DLBCL setting to see if efficacy can be improved further in these patients.

REGN1979 is being investigated in combination with Regeneron’s newly FDA-approved checkpoint inhibitor Libtayo (cemiplimab-rwlc) in an ongoing phase 1 study.

While Libtayo is far behind the immunotherapy leaders of Merck & Co’s Keytruda and BMS’ Opdivo, the firm is hoping to gain an edge by testing a combination of the two therapies, making it the first to investigate the combination of  of a CD20xCD3 bispecific antibody with a PD-1 or PD-L1 inhibitor.

Regeneron's George Yancopoulos

"There have been tremendous recent advances in the field of immuno-oncology, with new breakthrough therapies including checkpoint inhibitors and personalised cell-based therapies," said George D. Yancopoulos, M.D., Ph.D., President and Chief Scientific Officer at Regeneron.

Yancopoulos said its bispecific pipeline could offer off-the-shelf alternatives to cell-based therapies for both solid tumours and haematologic malignancies.

Its bispecific antibody pipeline includes REGN1979 and a MUC16xCD3 antibody for ovarian cancer in early development, with a BCMAxCD3 antibody for multiple myeloma expected to enter human studies before the end of this year.

“In 2019, we expect to start clinical trials of a new class of bispecific antibodies that engage cellular immunity in novel ways,” he added. “We believe that cancer treatment in the future will require precision medicine-based combinations of these and other approaches and that Regeneron is well positioned to be a future leader in this exciting area."

Also presenting bispecific antibodies at ASH are Amgen (AMG 420) and Pfizer (PF-06863135).

Another alternative platform is antibody-drug conjugates (ADCs). GlaxoSmithKline is presenting early data from its anti-BCMA GSK2857916 at the congress.