GSK's anti-BCMA safety issues? FDA panel turns a blind eye

GlaxoSmithKline GSK House in Brentford, UK
Of the 14 committee members, 12 voted that the benefits of belantamab mafodotin outweighed its risks. Two members did not vote because they had to leave the meeting early. (GlaxoSmithKline)

Last week, FDA staffers laid out their concerns about eye-related side effects that can come with GlaxoSmithKline’s anti-BCMA cancer treatment. Despite questions about whether those issues—which include vision loss so severe patients gave up reading or driving—could be identified and managed effectively, the drug emerged from an advisory committee meeting with a 12-0 vote in favor of approval.

GSK is seeking an OK for belantamab mafodotin, an antibody-drug conjugate (ADC), for patients with multiple myeloma whose disease has worsened or returned after trying at least four other treatments. The drug’s application is based on a phase 2 study that tested two doses of the treatment in nearly 200 patients who had tried a median of seven other treatments, including an immunomodulatory drug, a proteasome inhibitor and an anti-CD38 antibody such as Johnson & Johnson’s Darzalex.

The lower dose of the drug shrank tumors in about one-third of patients and helped them live a median of 15 months, according to data presented virtually at this year’s meeting of the American Society for Clinical Oncology. That’s nearly twice as long as patients get on other compounds given on their own, Axel Hoos, M.D., Ph.D., GlaxoSmithKline’s global senior vice president of oncology R&D, told Fierce Biotech in a previous interview.

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In addition to side effects that are expected with blood cancer treatments, such as low levels of platelets, some patients experienced changes to the cornea called keratopathy, a side effect the FDA has not seen with other multiple myeloma drugs. These changes can cause dry eyes, blurry vision and, in some cases, severe vision loss. Of the 97 patients who received the lower dose of the treatment, 44% had at least one instance of severe keratopathy. Although Glaxo has said no patients have lost their vision permanently, the FDA staff didn’t buy it: “FDA disagrees with the Applicant’s statement that permanent changes in vision or damage to the cornea have been avoided to date,” staffers wrote in briefing documents released ahead of the meeting.

GlaxoSmithKline is working to make sure doctors and patients can manage these side effects, Hoos said. This strategy includes giving patients an eye exam before each cycle of belantamab mafodotin and reducing or delaying the next dose appropriately, according to the briefing documents. But the FDA was not convinced these measures would be enough.

“There are no therapeutic strategies identified to mitigate the ocular toxicity with belantamab mafodotin,” FDA staff wrote, adding, “Despite implementing dose modifications, ocular toxicities were recurrent and persistent.”

The Oncologic Drugs Advisory Committee felt differently. Of the 14 committee members, 12 voted that the benefits of belantamab mafodotin outweighed its risks. Two panelists were unable to vote as technical difficulties and delays during the virtual meeting stretched out the day’s agenda.

While the FDA does not always follow an advisory committee's recommendation in terms of approval, it usually does.

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Multiple panelists felt that the drug should be available to any patient who wants it, and patients can make the decision to risk losing their sight for cancer treatment.

“I voted yes for reasons we’ve pretty much heard. I think that it seems clear that this is an active agent. The toxicity is certainly not life-threatening,” Philip Hoffman, M.D., chairperson of the committee and a professor of medicine at the University of Chicago, said.

“I do think patients are probably willing to take this risk and I think the mitigation strategy the company has outlined for [eye] exams before each dosing … is reasonable and addresses the concerns,” he added.

“The discussion was of an off-the-shelf antibody-drug conjugate, which to me seemed well-tolerated other than this unique ocular toxicity, which we acknowledge may be severe in some cases and may not be mitigatable or reversible in all patients,” said Gita Thanarajasingam, M.D., an assistant professor of medicine at the Mayo Clinic. “But the drug is efficacious and may be more tolerable in some patients than others. I think it’s reasonable to open the option of decision-making to patients, who can express their values and preferences.”

Other panelists focused on BCMA as a new target in the treatment of multiple myeloma.

“It’s a new drug. A new class of drug for refractory, relapsed multiple myeloma with a positive benefit-risk profile, and a drug that can be taken off the shelf,” John DeFlice, M.D., the committee’s patient representative, said. “So, I wholeheartedly voted yes.”

“We need a BCMA drug in multiple myeloma and relapsed or refractory multiple myeloma patients could make the choice here,” said David Mitchell, founder of Patients for Affordable Drugs and the consumer representative on the panel. “It would be important for a whole lot of people to have that choice and have this drug out there with the REMS [risk evaluation and mitigation strategy] that everyone has referred to.”

There is a crowd of BCMA-targeting agents in the pipeline behind belantamab mafodotin, including a bispecific antibody from Johnson & Johnson and CAR-T therapies from J&J and Bristol Myers Squibb. But Glaxo thinks an ADC could have a leg up over other types of treatments thanks to a shorter infusion period than bispecifics and quicker, less complicated manufacturing than CAR-Ts.

Analysts at Jefferies say they see worldwide peak sales of around $1.5 billion, but based on a relapsed/refractory setting. "We remain skeptical on expanded use of belantamab into earlier lines of therapy," the firm said in a note to clients.

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