J&J's new cancer drug leads a growing pipeline of dual-targeting antibodies

Monday, May 24, 2021

Source: Biopharma Dive

The Food and Drug Administration's approval of Johnson & Johnson's Rybrevant on Friday marked only the third time a drug of its type has won regulatory clearance in the U.S., and just the second time to treat cancer.

Behind Rybrevant, though, is a growing pipeline of so-called bispecific antibodies, offering hope that physicians may be better able to treat difficult conditions like lymphoma, multiple myeloma, leukemia and prostate cancer.

Antibody drugs like Avastin and Humira have been used for decades in cancer and autoimmune conditions, designed to block proteins that trigger or exacerbate disease. Bispecific antibodies, by contrast, bind to two proteins simultaneously. In oncology, drug developers often design the dual-targeting drugs to latch onto proteins on both tumor cells and immune cells, bringing the two together in a lethal marriage for the cancer.

The first bispecific antibody cleared in the U.S., Amgen's Blincyto, ties dysfunctional cells in patients with leukemia to immune defenders known as T cells. (The second FDA-approved bispecific antibody was Roche's Hemlibra, which binds to two proteins important in blood clotting to help stem bleeding in people with hemophilia.)

The FDA approved Rybrevant to treat a specific mutation in a cancer-linked protein that's thought to be present in about 2% of patients with non-small cell lung cancer. The drug blocks the action of two proteins that help tumors grow and spread.

A review of the pipeline of experimental bispecific cancer drugs reveals that many bind to the same T cell protein that Blincyto does, called CD3. Blood cancers such as lymphoma, leukemia and multiple myeloma are the most common target, although solid tumors such as lung and prostate cancers are also drawing attention from developers.

A selected list of the most advanced bispecific antibodies for cancer
DrugDeveloperTargetsLead indication(s)Phase of study
Blincyto Amgen CD19 x CD3 Leukemia Approved
Rybrevant J&J EGFR x cMET Lung cancer Approved
mosunetuzumab Roche CD20 x CD3 Lymphoma 3
glofitamab Roche CD20 x CD3 Lymphoma 3
epcoritamab AbbVie, Genmab CD20 x CD3 Lymphoma, leukemia 3
teclistamab J&J BCMA x CD3 Multiple myeloma 2
talquetamab J&J GPR5CD x CD3 Multiple myeloma 2
flotetuzumab Macrogenics CD123 x CD3 Leukemia 2
tebotelimab Macrogenics PD1 x LAG3 Solid tumors 2*
elranatamab Pfizer BCMA x CD3 Multiple myeloma 2**
odronextamab Regeneron CD20 x CD3 Lymphoma 2
REGN5458 Regeneron BCMA x CD3 Multiple myeloma 2
acapatamab Amgen PSMA x CD3 Prostate, lung cancer 1
pavurutamab Amgen BCMA x CD3 Multiple myeloma 1
AMG757 Amgen DLL3 x CD3 Lung cancer 1

*in combination with other drugs **enrollment paused SOURCE: Company disclosures, clinicaltrials.gov

In multiple myeloma, many companies are taking aim at a disease-specific protein called BCMA, following the same approach of the approved drugs Blenrep from GlaxoSmithKline and Abecma from Bristol Myers Squibb. In leukemia and lymphoma, the target protein on the tumor cells is called CD20, to which the aging Roche drug Rituxan also binds.

Roche is the most advanced using the CD20/CD3 approach, with two drugs called mosunetuzumab and glofitamab in Phase 3 trials. The former is being tested in combination with Bristol Myers' Revlimid against a Rituxan-Revlimid combination in follicular lymphoma, while the latter is being combined with a chemotherapy combination in a trial that compares it to Rituxan and chemo in diffuse large B cell lymphoma.

The Swiss company could face competition from AbbVie and Genmab, which have advanced epcoritamab into Phase 3 testing in the same indication as glofitamab.

Development looks equally competitive among the BCMA-targeting agents in multiple myeloma. J&J, Pfizer and Regeneron all have Phase 2 candidates and Amgen has one deep into Phase 1. J&J has a second multiple myeloma bispecific, called talquetamab, that targets a different protein on malignant cells.

Rybrevant's progress and approval also reflects pharma companies' eagerness to test bispecifics in solid tumors.

Macrogenics, for example, is advancing a candidate that targets two "checkpoints" — those T cell proteins that affect the immune system's response to cancer. One, called PD-1, is well-validated as it's the same targeted by Merck & Co.'s Keytruda and Bristol Myers' Opdivo, while the second, dubbed LAG3, has been under study for years. Bristol Myers experimental drug relatlimab, which recently succeeded in Phase 3 testing, also blocks LAG3.

While Rybrevant was approved in non-small cell lung cancer and Amgen's acapatamab is being tested in that condition, another of Amgen's candidates, AMG 757, is being developed for the less-common small cell lung cancer. In addition to CD3, the drug binds with a protein linked to small cell disease called DLL3, which AbbVie's failed experimental drug Rova-T also targeted.

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