GSK has been enjoying regulatory momentum in recent months as it works to bring its antibody-drug conjugate (ADC) Blenrep back to markets around the globe. But a new FDA briefing document indicates the company may need to address some of the agency's lingering concerns in order to reintroduce the drug in the key U.S. market.
In a document (PDF) posted ahead of the July 17 meeting of the Oncologic Drugs Advisory Committee (ODAC), FDA reviewers flagged "high rates of ocular toxicity" and "uncertainty regarding the proposed dosages" as key issues for Thursday's discussion.
On the ocular toxicity issue, FDA reviewers said the majority of patients in GSK's pivotal DREAMM-7 and DREAMM-8 trials experienced Keratopathy and Visual Acuity (KVA) events. KVA events at any grade occurred in 92% and 93% of patients in the trials, respectively, while grade 3-4 events happened in 77% and 78% of patients in the studies.
In addition, treatment with GSK's Blenrep was "associated with severe ocular toxicities, including corneal ulcers and clinically significant decline in visual acuity, including severe vision loss," the document reads.
In a particularly noteworthy comment from the agency, the reviewers said the corneal toxicity seen with the ADC drug is a "unique risk to this product and is not seen with currently available therapies" for multiple myeloma.
"There is potential for ocular toxicity to have a substantial impact on patient functioning and quality of life," FDA staffers added. "These toxicity concerns, coupled with the high rates of dose modifications, raise concerns about whether the dosages evaluated in DREAMM-7 and DREAMM-8 have been adequately optimized."
Eye toxicity has been a known concern for Blenrep and a major bear case for GSK’s 3 billion-pound ($4 billion) peak sales plan for the BCMA-targeted ADC. The British pharma has proposed a dose modification scheme, but the FDA apparently still has questions about that.
GSK is seeking FDA approval for Blenrep—in combination with Takeda's Velcade and dexamethaone—to treat adults with multiple myeloma who've received at least one prior line of therapy. In addition, the company is pursuing a nod for the drug in combination with Bristol Myers Squibb's Pomalyst and dexamethasone in patients who've tried at least one prior line of therapy, including BMS' Revlimid.
Blenrep won its original U.S. approval back in 2020 as a monotherapy for patients with multiple myeloma who've tried at least four therapies. But after the drug fell short in a confirmatory trial, GSK pulled Blenrep from markets worldwide in 2022.
Since then, the pivotal DREAMM studies have shown the ability of the Blenrep combinations to improve patients' progression-free survival—and overall survival in the case of DREAMM-7—compared with standard of care (SoC) regimens.
"Two independent, randomized Phase 3 studies consistently demonstrated clinically meaningful benefits of Blenrep arms over SoC arms across all endpoints, including statistically significant improvement in overall survival from the DREAMM-7 study," GSK said in its own briefing document (PDF) ahead of the advisory committee meeting.
"Overall, the efficacy data demonstrate the promise of Blenrep as an effective therapy in the evolving MM treatment landscape," GSK concluded.
ODAC is slated to discuss whether "appropriate dosages" of the drug have been identified in trials and vote on the benefit-risk profiles of the two proposed regimens, according to draft questions (PDF) posted by the agency. The FDA itself its expected to act on GSK's application by July 23.
As part of GSK's effort to bring the drug back to markets around the globe, regulators in the U.K. signed off on Blenrep combinations back in April, leveraging results from the DREAMM studies. The following month, Europe's Committee for Medicinal Products for Human Use endorsed the Blenrep regimens for use in that region.
Riding the comeback momentum, GSK has projected that the ADC can deliver peak sales of more than 3 billion pounds sterling (about $4 billion). In fact, Blenrep's return was one factor cited in the company's recent decision to raise its 2031 sales target to more than 40 billion pounds.