Pfizer Halts Patient Enrollment in Elranatamab MagnetisMM-3 Trial Due to Peripheral Neuropathy Cases

Pfizer Announces Suspension of Patient Enrollment in MagnetisMM-3 Clinical Trial of BCMA/CD3 Bispecific Antibody Elranatamab Due to Three Cases of Peripheral NeuropathyToday, Pfizer announced that patient enrollment in its MagnetisMM-3 clinical trial of the BCMA/CD3 bispecific antibody elranatamab has been suspended due to three cases of peripheral nerve injury. The trial enrolled approximately 150 patients with multiple myeloma who had received at least three prior major therapies, including some who had progressed after treatment with BCMA-targeted agents. The trial commenced in February of this year, and approximately 100 patients currently receiving elranatamab who are deriving benefit from the therapy may continue treatment. In Phase I clinical studies, the drug demonstrated a response rate as high as 83%, and this Phase II trial was originally intended to serve as the primary basis for accelerated approval and market authorization.

Drug Source Analysis

BCMA is one of the most important targets in multiple myeloma (MM) and the second target with approved products for CAR-T, a highly risky therapy. Recently, the FDA approved Abecma (generic name: cilta-cel, formerly known as BB2121), which was acquired by GSK from Celgene and co-developed with Bluebird Bio. A similar product developed by Chinese company Legend Biotech in collaboration with Johnson & Johnson is also expected to be launched soon. Allogene’s allogeneic BCMA CAR-T therapy ALLO-715 recently received RMAT (Regenerative Medicine Advanced Therapy) designation from the FDA, a new incentive mechanism that reportedly combines the advantages of both Fast Track and Breakthrough Therapy designations. In addition to CAR-T, major pharmaceutical companies such as GSK, Pfizer, AbbVie, Amgen, and Regeneron have various BCMA-related products in clinical development.

BCMA is expressed on 100% of B cells, making it a potential target for B-cell malignancies with more comprehensive efficacy. In addition to CD19, BCMA is the only other target that can withstand CAR-T cell therapy. However, even though B cells can tolerate large-scale elimination, CAR-T therapy still carries significant risks. Relatively milder approaches, such as antibody-drug conjugates (ADCs) and CD3 bispecific antibodies, are not only theoretically safer but also more convenient in terms of production and distribution. However, this safety advantage is largely theoretical, as ADCs and CD3 bispecific antibodies also have their own drawbacks. For instance, GSK’s Blenrep not only demonstrated slightly inferior efficacy, but also caused grade 3 or higher ocular toxicity in 40% of patients in clinical trials. Ocular toxicity associated with ADCs appears to be a unique adverse effect unrelated to the targeted antigen. AstraZeneca (AZN) recently terminated development of a similar drug, MEDI2228.

CD3 is one of the component receptors of the TCR complex on the surface of T cells. A CD3 engager binds to a tumor-specific antigen at one end and to the CD3 receptor at the other, theoretically altering the tissue distribution of T cells and promoting their enrichment within tumor tissues. This strategy is analogous to that of small-molecule PROTACs, as both utilize bifunctional molecules to modify the spatial relationships between biomolecules, thereby creating functions not found in nature or amplifying naturally weak functions. However, the emergence of such novel functions in inappropriate locations may pose risks even greater than those associated with cytotoxic agents entering unintended cells.

Although CD3 engagers constitute the majority of clinical bispecific antibody assets, to date, no products other than Blincyto (which lacks an Fc region) have been marketed. A primary reason is the scarcity of tumor-specific antigens, which also represents a major limitation for CAR-T and ADC therapies. Furthermore, while CD3 engagers recruit T cells to tumor tissues, they also participate in T cell activation. This activation is site-specific but not T cell-specific; tumor antigen-specific T cells are not preferentially activated, resulting in limited selectivity. Moreover, this non-physiological activation mechanism differs in coordination from the multi-faceted activation of T cells by antigen-presenting cells (APCs), lacking certain key signals and thereby leading to aberrant T cell responses.