Biotech drugmaker Amgen presented its first-in-human data on its bispecific monoclonal antibody drug for multiple myeloma Tuesday at the American Society of Hematology’s annual meeting. But with the data still early, it remains uncertain where in the blood cancer’s treatment paradigm the drug will fit.

“It really is the million-dollar question,” vice president and therapeutic area for global development Greg Friberg said in a phone interview. The Thousand Oaks, California-based company presented data from a Phase I dose-escalation study of the drug, AMG 420, at the ASH conference in San Diego, which concluded Tuesday.

The question, in this case, is whether physicians will reach for AMG 420 or a CAR-T therapy first, and whether the two therapeutic modalities will overlap or be used in sequence, Friberg said.

AMG 420 was developed using BiTE, the same drug-development platform that the company used to develop its marketed BiTE antibody, Blincyto (blinatumomab), which initially won Food and Drug Administration approval for acute lymphoblastic leukemia in December 2014. The drugs are called bispecific because they bind to both the antigen CD3 on T cells and also to antigens specific to the cancer cells, enabling T cell-mediated killing of the cancer cells. Blincyto’s cancer-specific antigen is CD19 – one highly expressed in ALL – and AMG 420’s is BCMA, one commonly seen in multiple myeloma.

AMG 420’s antigen target is what makes its placement in therapy the million-dollar question it is.

In an oral presentation of the data, it was shown that among 42 patients with relapsed/refractory disease receiving doses ranging from 0.2 to 800 micrograms per day, 13 had clinical responses, including seven complete responses. Four patients treated at 400 micrograms achieved minimal residual disease-negative complete responses, meaning no cancer cells were detected in the bone marrow. Of the seven patients responding to that dose, six remained in response at 7.5 months. Meanwhile, 20 patients experienced serious side effects, including 17 who had to be hospitalized. Serious side effects deemed related to treatment included polyneuropathy and edema, while cytokine release syndrome was seen in 16 patients. The 400-microgram dose is what the company is targeting for the drug’s further development, Friberg noted.

BCMA is also the favored target of CAR-T cell therapies in multiple myeloma, most notably bluebird bio’s bb2121, which is currently in a Phase II trial whose data the company hopes to use to apply for FDA approval next year. This has led to news media speculation that the two modalities would be in competition with each other. But as the experience with Blincyto illustrates, that may not be the case.

One potential risk from both the bispecifics and the CAR-Ts is that the cancer will use an escape mechanism known as antigen-negative relapse, whereby the disease returns, but no longer expressing the targeted antigen and thus rendering therapies that depend on it ineffective. But Friberg said that only about 10-15 percent of patients on Blincyto experience CD19-negative relapse, meaning the rest who do relapse remain candidates for CAR-T therapy that also targets CD19, particularly Novartis’s Kymriah (tisagenlecleucel).

Friberg said the company has not reported what the percentage of patients on AMG 420 who have experienced antigen-negative relapse. Moreover, whether the underlying biology of antigen-negative relapse differs between therapies targeting CD19 or BCMA is unclear.

But another difference – one that potentially works in AMG 420’s favor – is that the populations in the CAR-T studies are more selected, for patients with sufficient T cells for manufacturing and expansion and also who can survive long enough before infusion of the therapy, Friberg said. By contrast, bispecific antibodies are much more flexible, as off-the-shelf therapies.

Photo: royaltystockphoto, Getty Images



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