Last week, FDA staff raised concerns about eye-related side effects that may come with GlaxoSmithKline’s BCMA cancer treatment. Despite questions about whether those problems, which include loss of vision, so severe patients stopped reading or driving, could be effectively identified and managed, the drug came out of an advisory committee meeting with a 12-0 vote in favor of approval.
GSK is seeking an authorization 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 application of the drug is based on a phase 2 study that tested two doses of the treatment in almost 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 Darzalex
The lowest dose of the drug shrunk tumors in about a 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 almost twice as long as patients take other self-administered compounds, Axel Hoos, MD, Ph.D., senior vice president of global oncology R&D at GlaxoSmithKline, told Fierce Biotech in a previous interview.
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In addition to the expected side effects of blood cancer treatments, such as low platelet levels, some patients experienced changes to the cornea called keratopathy, a side effect that the FDA has not seen with other medications for multiple myeloma. . These changes can cause dry eyes, blurred vision, and, in some cases, severe vision loss. Of the 97 patients who received the lowest dose of treatment, 44% had at least one instance of severe keratopathy. Although Glaxo has said that no patients have permanently lost their vision, FDA staff did not buy it: “The FDA disagrees with the applicant’s statement that permanent changes in vision have been avoided to date or damage to the cornea, “employees wrote in information documents. released before the meeting.
GlaxoSmithKline is working to ensure that doctors and patients can control these side effects, Hoos said. This strategy includes giving patients an eye exam before each cycle of belantamab mafodotine and reducing or delaying the next dose appropriately, according to the information documents. But the FDA was not convinced that these measures would suffice.
“There are no identified therapeutic strategies to mitigate ocular toxicity with belantamab mafodotine,” wrote the FDA staff, adding, “Despite implementing dose modifications, the ocular toxicities were recurrent and persistent.”
The Oncology Drug Advisory Committee felt differently. Of the 14 committee members, 12 voted that the benefits of belantamab mafodotine outweighed its risks. Two panelists were unable to vote because technical difficulties and delays during the virtual meeting lengthened the day’s agenda.
While the FDA does not always follow an advisory committee’s recommendation in terms of approval, it generally does.
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Several panelists felt that the drug should be available to any patient who wants it, and that patients can make the decision to risk losing their sight for cancer treatment.
“I voted yes for reasons we’ve heard. I think it seems clear that this is an active agent. Toxicity is certainly not life threatening, “said Philip Hoffman, MD, committee chair and professor of medicine at the University of Chicago.
“I think patients are probably willing to take this risk and I think the mitigation strategy that the company has outlined to [eye] examinations before each dosage … are reasonable and address concerns, “he added.
“The discussion was about a drug-antibody conjugate, which I found to be well tolerated aside from this unique ocular toxicity, which we recognize may be severe in some cases and may not be mitigable or reversible in all patients,” said Gita Thanarajasingam, MD, assistant professor of medicine at the Mayo Clinic. “But the drug is effective and may be more tolerable in some patients than in others. I think it is reasonable to open up the decision-making option 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 is a new drug. “A new class of drug for refractory recurrent multiple myeloma with a positive risk-benefit profile and a drug that can be removed from the shelf,” said John DeFlice, MD, patient representative for the committee. “So I sincerely voted yes.”
“We need a BCMA drug in multiple myeloma, and patients with recurrent or refractory multiple myeloma could make the decision here,” said David Mitchell, founder of the Patients for Affordable Drugs organization and the consumer representative on the panel. “It would be important for many people to have that option and have this drug on the market with REMS [risk evaluation and mitigation strategy] to which everyone has referred. “
There are a multitude of agents targeting BCMA in the pipeline behind mafodotine belantamab, including a bispecific antibody from Johnson & Johnson and CAR-T therapies from J&J and Bristol Myers Squibb. But Glaxo believes that an antibody-drug conjugate could have an advantage over other types of treatments, thanks to a shorter infusion period than bispecific ones and faster and less complicated manufacturing than CAR-Ts.
Jefferies analysts say they see a worldwide sales spike of around $ 1.5 billion, but based on a relapse / refractory environment. “We remain skeptical about the expanded use of belantamab in the first lines of therapy,” the firm said in a note to clients.
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