Patients diagnosed with relapsed or refractory (r/r) multiple myeloma who were treated with the two highest doses of REGN5459*/**, a bispecific antibody targeting BCMA and CD3, experienced a 90.5% overall response rate. These results of a phase 1/2 clinical study were presented at the American Association for Cancer Research (AACR) 2023 Annual Meeting, being held April 14-19, 2023 at the Orange County Convention Center in Orlando, Florida.[1]

The study was supported by Regeneron Pharmaceuticals.

REGN5459 binds to the B-cell maturation antigen (BCMA), which is highly expressed on the surface of multiple myeloma cells and the CD3 receptor present on T-cells.

In October 2022, another drug, teclistimab-cqyv (Tecvayli™; Janssen Biotech), also a bispecific T-cell engager or BiTE* targeting BCMA and CD3, received accelerated approval from the U.S. Food and Drug Administration (FDA) to treat myeloma that persisted after four or more lines of prior therapy. Teclistamab was the first BCMA-directed BiTE to be approved.

Multiple myeloma, affects plasma cells, a type of blood cell derived from B lymphocytes that are responsible for producing antibodies. In patients with multiple myeloma, abnormal plasma cells accumulate in the bone marrow or soft tissues. According to National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) data, multiple myeloma is the second most common hematological neoplasm with more than 34,000 patients estimated to be diagnosed in the United States in 2022.

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Cytokine Release Syndrome
“A common side effect of bispecific antibody immunotherapy is cytokine release syndrome (CRS), a potentially life-threatening complication in which activated immune cells release a large number of cytokines into the bloodstream, resulting in an acute systemic inflammation,” explained Attaya Suvannasankha, MD, an associate professor of clinical medicine in the Division of Hematology and Oncology at Indiana University School of Medicine and a physician-scientist at the Indiana University Melvin and Bren Simon Comprehensive Cancer Center, who presented the study.

The clinical signs of CRS correlate with T-cell activation and high levels of cytokines, including interleukin 6 (IL-6) and interferon γ. CRS is characterized by symptoms including fever, low blood pressure and low oxygen levels, which often occur before the patient can receive the intended full dose. In order to mitigate these early events, patients receive progressive increments of the bispecific antibody therapy and are monitored to treat these adverse events. These challenges can create barriers to effective treatment.

Immunosuppression, using tocilizumab (Actemra®; Genentech/Roche), a recombinant humanized anti-interleukin-6 receptor (IL-6R) antibody, with or without corticosteroids, can reverse CRC. However, because early and aggressive immunosuppression may limit the efficacy of immunotherapy, treatment is generally designed to limit administration of immunosuppressive therapy to patients at risk for life-threatening consequences of the syndrome. In addition, researchers are developing new approaches designed to reduce CRC.

Loosely bound
“The advantage of REGN5459 is that it binds relatively loosely to CD3 on T-cells, which may mitigate CRS and decrease T-cell exhaustion,” Suvannasankha noted.

Attaya Suvannasankha, MD is an associate professor of clinical medicine in the Division of Hematology and Oncology at Indiana University School of Medicine and a physician-scientist at the Indiana University Melvin and Bren Simon Comprehensive Cancer Center.

“Dialing down the strength of binding to CD3 might sound contradictory. [Because] why would we not want the therapy to grab the T-cells very hard? [But] preclinical data suggested that decreasing the binding affinity to T-cells might reduce CRS, which may enable us to more safely deliver treatment to patients, particularly those who are older or more frail,” she explained.

In this study, Suvannasankha and colleagues recruited 43 patients with multiple myeloma that stopped responding to or relapsed following three or more prior lines of treatment.

In the phase I portion of the trial, patients were treated with full doses of REGN5459 ranging from 3 to 900 mg; 480 mg was selected as the recommended phase 2 dose.

Study results
The overall response rate in the study population was 65.1%. Among the 21 patients treated at the higher doses (480 mg and 900 mg), the response rate was 90.5%, of which 61.9% were complete responses or better, including 38.1% that were stringent complete responses, a deeper response category characterized by the absence of clonal myeloma cells in the bone marrow and a normal blood test result for free light chains.

Responses occurred early and deepened with time, with a projected 78.1% of patients continuing to respond at a year.

“In comparison to the average lifespan of heavily pretreated patients at this stage, which is six to nine months, that the one-year progression-free survival may be more than 70% is very promising,” Suvannasankha said.

In terms of adverse events, across all dose levels, 53.5% of patients experienced CRS, of which none were grade 4 or 5 and 87% were grade 1. In all cases, Suvannasankha said, the condition did not lead to discontinuation and the patients were able to escalate treatment to the full planned dose.

Continuous T-cell activation can also cause T-cell exhaustion, in which T-cells stop functioning properly. This not only decreases the efficacy of the immune system against the cancer but can also leave the body vulnerable to infection, Suvannasankha said.

In this study, infections occurred in 62.8% of patients, 30.2% of which were grade 3 or higher, requiring hospitalization.

“While infections continue to occur with bispecific antibody treatments, we are excited about the data in this study. The severity of infection and the disruption to treatment were manageable,” she added.

According to Suvannasankha, the response rate demonstrates that binding affinity can be reduced without sacrificing clinical activity.

“Low-affinity T-cell engagers potentially result in T-cells that continue killing the cancer cells but with fewer side effects,” she concluded.

The authors of the study noted that limitations of this study included a relatively small number of patients treated at the recommended phase 2 dose and a population of patients who reside exclusively in the United States.

Note:* BiTEs are a type of fusion protein that is designed to harness the power of the immune system to treat cancer. They are created by linking the targeting regions of two antibodies. In this fusion protein, one arm of the molecule is engineered to bind with a protein found on the surface of cytotoxic T-cells, while the other arm is designed to bind to a specific protein found primarily on tumor cells. When engaged, the BiTE molecule forms a “bridge” between the cytotoxic T-cell and the tumor, enabling the T-cell to recognize the tumor. Upon administration, REGN5459 binds to both CD3 on cytotoxic T lymphocytes (CTLs) and BCMA on BCMA-expressing tumor cells. This activates and redirects CTLs to BCMA-expressing tumor cells, leading to CTL-mediated killing of BCMA-expressing tumor cells. [2]

** REGN5459 was developed by using Regeneron’s next generation VelocImmune® “human antibody mouse” technology, together with its VelociBi™ platform. This technology allows for the creation of bispecific antibodies that closely resemble natural human antibodies without linkers or artificial sequences. Additionally, Regeneron bispecifics are manufactured using similar approaches used for human antibody medicines, with similar pharmacokinetics.

Clinical trials
First In Human (FIH) Study of REGN5459 in Adult Patients With Relapsed or Refractory Multiple Myeloma (MM) – NCT04083534

Highlights of Prescribing Information
Teclistimab-cqyv (Tecvayli™; Janssen Biotech)[Prescribing Information]
Tocilizumab (Actemra®; Genentech/Roche)[Prescribing Information]

[1] Suvannasankha A, Kapoor P, Pianko MJ, Richter J, D’Souza A, Anderson Jr LD., Magyar A, Aina O, Boyapati O, Cronier D, Singh N, Rodriguez-Lorenc K, Kroog GS, Lee HC. Safety and efficacy from the phase 1/2 first-in-human study of REGN5459, a BCMA×CD3 bispecific antibody with low CD3 affinity, in patients with relapsed/refractory multiple myeloma. In: Proceedings of the 114th Annual Meeting of the American Association for Cancer Research; 2023 April 14-19; Orlando, FL. Philadelphia (PA): AACR; 2023. Abstract nr CT013
[2] Baeuerle PA, Kufer P, Bargou R. BiTE: Teaching antibodies to engage T-cells for cancer therapy. Curr Opin Mol Ther. 2009 Feb;11(1):22-30. PMID: 19169956.

Featured image: AACR 2016 Annual Meeting. Photo courtesy 2016 – 2023 © AACR/Scott Morgan. Used with permission.

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