On a quest to bring its multiple myeloma antibody-drug conjugate Blenrep back to the U.S. market, GSK has suffered a serious setback at the hands of the FDA’s Oncologic Drugs Advisory Committee (ODAC).
ODAC members on Thursday debated GSK's approval filing for Blenrep as part of combinations with Takeda's Velcade and dexamethasone and with Bristol Myers Squibb's Pomalyst and dexamethasone. For both combos, GSK is pursuing approval to treat patients with multiple myeloma who've received at least one prior line of therapy.
During Thursday's meeting, the committee members' main concerns surrounded the proposed dosages of the ADC treatment, potential safety issues and the demographics of those enrolled in GSK’s pivotal DREAMM-7 and -8 studies.
In a briefing document posted ahead of the July 17 meeting, the FDA pointed to "high rates of ocular toxicity" observed in those enrolled in GSK’s two phase 3 studies. Specifically, the majority of patients in both studies experienced keratopathy and visual acuity events, and treatment was further “associated with severe ocular toxicities” such as corneal ulcers.
The agency also highlighted concerns over the “high rates of dose modifications” seen in the studies, raising questions over whether the dosages evaluated in the DREAMM program were “adequately optimized.”
The FDA's oncology advisors were asked to decide whether the overall benefit-risk profile of Blenrep in combination with each of its proposed pairings were favorable “at the proposed dosage in the proposed patient population.” The votes shook out slightly differently for each combo but ended in a 5-3 negative vote for Blenrep when combined with Takeda’s Velcade and a 7-1 negative vote for the drug when paired with Bristol Myers Squibb’s Pomalyst.
During its discussion, the advisory committee focused on the toxicity and dosage issues previously raised by the FDA as well as the demographics of those enrolled in the DREAMM trials. A major point of contention was U.S. patient enrollment specifically, which totaled less than 5% in each study.
Many voters explained that voting was a difficult choice, with one going so far as to describe it as “the most difficult vote” he’s faced thus far as an ODAC committee member.
While GSK’s efficacy data were “strong,” the toxicity data were "also very strong,” another committee member noted, adding that the “proposed dosage” wording of the question influenced his negative vote.
The dosage concerns seemed to be the influencing factor for many voters, including one who said there “needs to be more work done” to land on an “optimal dose” for safety and efficacy.
The other aspect to the voting question, the “proposed population,” was the main voting rationale for others in the group. Considering that GSK enrolled “almost no” U.S. patients, the study effectively “precludes any assessment of the benefit/risk profile in the U.S.,” one voter pointed out.
The sole voter in favor of both Blenrep combos came from John DeFlice, M.D., a patient representative. DeFlice considered the voting questions the “wrong issues to be evaluated.”
“Based on the clinical experience of the researchers and the testimonies that we've heard, this is an amazing drug for an incurable disease,” he said.
DeFlice’s perspective was shared by many public speakers who spoke highly of the treatment's benefit during the meeting, pointing to the patient need for an off-the-shelf multiple myeloma treatment and the largely manageable nature of the ocular side effects.
Depending on whether the FDA sides with its oncology advisors, GSK’s dreams of bringing Blenrep back to the U.S. market may be stunted. The drug previously received the FDA’s blessing in 2020 as a monotherapy in the fifth-line treatment of multiple myeloma but was later pulled from worldwide markets in 2022 after it fell short in a confirmatory trial.
While it was marketed, Blenrep held a boxed warning from the FDA for its ocular toxicity risks.
GSK has already put its chips behind Blenrep’s return with a peak sales estimate of more than 3 billion pounds sterling (about $4 billion). The drug has so far been approved in the U.K. and Europe in the same proposed combinations.
With the ODAC vote, the British drugmaker's shares fell more than 5.5% on Thursday afternoon. The company said it "remains confident" in Blenrep's benefit/risk profile and pledged to continue to work with the FDA as the agency continues its review, the company said in an update on Thursday evening.
The FDA is not bound to the direction of the advisory committee and is expected to make the final call on the drug’s potential approval by July 23.