FDA spotlights eye safety in GSK anti-BCMA AdComm, but analysts expect approval anyway

The multiple myeloma field is teeming with BCMA-targeting agents, including bispecific antibodies and CAR-T therapies. GlaxoSmithKline’s antibody-drug conjugate (ADC) could beat the others to market, but first it has to convince an FDA panel that its benefits outweigh eye-related side effects.

In briefing documents released Friday, FDA staff “generally agrees with the Applicant’s assessments of efficacy in the DREAMM-2 trial,” which tested two doses of the ADC in nearly 200 patients with advanced multiple myeloma. But the FDA zeroed in on changes to the cornea called keratopathy that can result in dry eyes, blurry vision and, in some cases, severe vision loss. It’s a side effect that agency hasn’t seen in other myeloma drugs, and it affected nearly three-quarters (71%) of patients in a phase 2 study, according to the briefing documents. Of the 97 patients who received the lower dose of the treatment, 44% had at least one instance of severe keratopathy. No patients have lost their vision permanently.

The FDA’s focus was “no surprise given the safety data disclosed over the last 12-18 months,” wrote Jefferies analyst Biren Amin in an investor note. The Oncologic Drugs Advisory Committee will discuss and vote on the treatment Tuesday.

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For its part, GSK has stood by the risk-benefit profile of belantamab mafodotin. The company tested it in patients whose cancer had worsened despite trying 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 shrank tumors in about one-third of patients, helping them live a median of 15 months, according to data presented virtually at this year’s meeting of the American Society for Clinical Oncology.

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"It’s almost two times what we have with other compounds given as a monotherapy … That is important in the context of what you expect in this patient group, where the median survival is around six to nine months,” Axel Hoos, M.D., Ph.D., GlaxoSmithKline’s global senior vice president of oncology R&D, told Fierce Biotech in a previous interview.

The company is working to make sure doctors and patients can manage these side effects, Hoos added. 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 isn’t convinced these measures will 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.”

If the drug is approved, these side effects could limit its use to patients “that have no other options remaining,” Amin wrote.

And there’s another wrinkle—patients whose eye exams show they have keratopathy but who didn’t have any symptoms of the corneal changes. Of the 71% of patients on the low dose whose eye exams turned up keratopathy, only 44% had any symptoms.

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“It is notable that less than half of the patients in the 2.5 mg/kg [lower dose] cohort with keratopathy experienced any of these ocular symptoms during the course of their treatment,” the agency staff wrote.

“GSK mgmt. previously framed the keratopathy in many patients as laboratory/examination findings only and does not affect quality of life, since less than half the patients who developed keratopathy experienced any ocular symptoms,” wrote SVB Leerink analyst Geoffrey Porges.

But the FDA feels quite the opposite, Porges wrote: “The FDA suggests the absence of ocular symptoms in these patients indicates keratopathy could go undetected without close monitoring with frequent ophthalmic exams, which may lead to serious consequences including corneal ulcers and severe and permanent vision loss.”

Despite the safety concerns, analysts remain optimistic about belantamab’s chances. Porges expects the FDA panel to vote in favor of the treatment, even if it’s “almost certain” the drug will need a black box warning and a risk evaluation and mitigation strategy. Jefferies’ Peter Welford went so far as to predict peak sales of $1.5 billion for the drug, even as the FDA’s remarks “dented” his confidence on belantamab.