On December 8, 2019 Regeneron Pharmaceuticals, Inc. (NASDAQ: REGN) reported initial clinical data for REGN5458, a BCMAxCD3 bispecific antibody, in patients with relapsed or refractory (R/R) multiple myeloma (Press release, Regeneron, DEC 8, 2019, View Source [SID1234552066]). BCMA (B-cell maturation antigen) is a protein that is typically over-expressed on multiple myeloma cells. REGN5458 is designed to bind to BCMA on multiple myeloma cells and the CD3 receptor on T-cells, bridging them together and activating T-cell killing of the cancer cell.

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Results were presented today at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting from the first two dose groups (3 mg and 6 mg weekly doses). Patients had a median of seven lines of prior systemic therapy, and all had failed CD38 antibody treatment. Responses were observed in 4 of 7 (57%) patients, including 3 of 4 (75%) in the 6 mg dose group. In the 6 mg dose group, 2 patients (50%) were also minimal residual disease (MRD) negative, meaning that no cancer cells were detectable in their bone marrow.

"We are encouraged to see promising, rapid clinical activity even at the initial two doses of REGN5458 in heavily pretreated patients with multiple myeloma. Two patients achieved the high bar of MRD negativity, and another patient attained a very good partial response despite entering the trial with difficult-to-treat plasmacytomas outside of the bone marrow," said Israel Lowy, M.D., Ph.D., Senior Vice President and Head of Clinical and Translational Sciences for Oncology at Regeneron. "We are actively recruiting patients into higher dose groups in this trial and look forward to sharing further results in 2020. In addition, we have also initiated a clinical trial for our second BCMAxCD3 bispecific, REGN5459, which has different binding characteristics."

REGN5458 and REGN5459 were invented using Regeneron’s next generation VelocImmune "human antibody mouse" technology, together with its VelociBi platform. These allow for the creation of bispecific antibodies that closely resemble natural human antibodies with no linkers or artificial sequences. Additionally, Regeneron bispecifics are manufactured using similar approaches used for human antibody medicines, with similar pharmacokinetics.

As of data cutoff, there have been no neurotoxicity, dose-limiting toxicities or treatment discontinuations due to adverse events (AEs). The most common treatment-emergent AEs were lymphopenia (n=5), anemia (n=4) and thrombocytopenia and cytokine release syndrome (n=3 each). Grade 3 or higher treatment-emergent AEs were seen in 5 patients and included lymphopenia (n=3), hypertension (n=2) and anemia, atrial fibrillation, fatigue, febrile neutropenia, pain in extremity, septic shock and thrombocytopenia (n=1 each).

Multiple myeloma is the second most common blood cancer, with approximately 32,000 and 138,500 new diagnoses in the U.S. and world respectively. It is characterized by the proliferation of cancerous plasma cells (multiple myeloma cells) that crowd out healthy blood cells in the bone marrow, infiltrate other tissues and cause potentially life-threatening organ injury. Recent advances, such as CD38 antibody treatment, have increased life expectancy of patients from 3-4 years to 7-8 years. Despite this, multiple myeloma remains incurable, and most patients will experience relapse and require additional therapy.

The REGN5458 data follow other positive results from Regeneron’s growing bispecific pipeline, including updated REGN1979 data that will be presented at ASH (Free ASH Whitepaper). REGN1979 is an investigational CD3 bispecific that is being studied in R/R follicular lymphoma and diffuse large B-cell lymphoma, including in patients whose cancer did not respond to CAR-T therapy. Regeneron has also invented a second class of CD28 bispecifics, called co-stimulatory bispecifics, which have recently entered clinical trials.

About the REGN5458 Phase 1/2 Dose-escalation Trial
REGN5458 monotherapy is being investigated in an open-label, Phase 1/2 dose-escalation trial in patients with R/R multiple myeloma who have exhausted all therapeutic options, including proteasome inhibitors, immunomodulatory drugs and CD38 antibody treatments. The Phase 1 portion is assessing safety, tolerability and dose-limiting toxicities. Beyond the initial dose groups presented at ASH (Free ASH Whitepaper), additional dose groups are being evaluated to determine a recommended Phase 2 dose regimen. The Phase 2 portion will further assess REGN5458 anti-tumor activity and safety.

Among the patients being enrolled are those with heavily pre-treated multiple myeloma, including those with extra-medullary (outside of the bone marrow) and non-secretory disease (do not secrete detectable myeloma proteins).

In multiple myeloma clinical trials, treatment effectiveness is typically assessed by overall response rate (ORR; with response types categorized by the level of reduction in myeloma protein) and the rate of conversion to negative MRD (which measures the eradication of myeloma cells in bone marrow). For ORR, myeloma protein levels in the blood are reduced by more than 50% in partial responses (PR) and 90% in very good PR (VGPR), while complete responses are defined as no evidence of myeloma protein and ≤5% of plasma cells in the bone marrow. MRD is measured separately from ORR, and MRD negativity is defined as the absence of myeloma cells within 100,000 bone marrow cells.

About the Regeneron Bispecific Antibody Platform
All of Regeneron’s bispecific antibodies are designed to closely resemble natural human antibodies. They are derived from a next-generation version of Regeneron’s proprietary VelocImmune technology and created using the company’s VelociBi platform.

There are six Regeneron investigational bispecific antibodies currently in ongoing clinical trials for multiple blood cancers and solid tumors. These bispecifics fall into three categories:

— CD3 bispecifics are designed to bridge T-cells and tumor cells. At the tumor site, they activate T-cells via their CD3 receptors and promote T-cell killing of the cancer cells. Investigational candidates include:

CD20xCD3 (REGN1979) for non-Hodgkin B-cell lymphomas;
Two distinct BCMAxCD3s (REGN5458 and REGN5459) for multiple myeloma;
MUC16xCD3 (REGN4018) for ovarian cancer.
— CD28 costimulatory bispecifics are also designed to bridge T-cells and tumor cells. At the tumor site, they costimulate T-cells via their CD28 receptors and may synergize with PD-1 inhibitors and/or CD3 bispecifics. Investigational candidates include:

PSMAxCD28 (REGN5678) in combination with Libtayo (cemiplimab) for prostate cancer.
— Tumor-targeted bispecifics are designed to target proteins only on the cancer cell. In this way, they may affect various signaling pathways to hamper the cancer cells’ ability to survive and proliferate. Investigational candidates include:

METxMET (REGN5093) for non-small cell lung cancer that is driven by MET mutations and/or amplifications. REGN5093 targets two different parts of the MET receptor on cancer cells to degrade the receptor and block its ability to trigger cell proliferation.
Regulatory Status of Oncology Programs
REGN1979, REGN5458, REGN5459, REGN4018, REGN5678, REGN5093 and Libtayo are currently under clinical development for the diseases noted in this press release, and their safety and efficacy have not been evaluated by any regulatory authority for these diseases. As part of a global collaboration agreement, Regeneron and Sanofi are jointly developing Libtayo, as well as Regeneron’s BCMAxCD3 and MUC16xCD3 bispecific programs.

Libtayo is approved in the U.S. for the treatment of patients with metastatic cutaneous squamous cell carcinoma (CSCC) or locally advanced CSCC who are not candidates for curative surgery or curative radiation, and in other countries for similar indications. In the U.S., the generic name for Libtayo is cemiplimab-rwlc, with rwlc as the suffix designated in accordance with Nonproprietary Naming of Biological Products Guidance for Industry issued by the U.S. Food and Drug Administration.