Securo Bio’s Copiktra looks on track to follow other PI3K inhibitors in bowing out of certain blood cancer markets after an FDA expert panel backed a negative review by the agency’s internal team.
An FDA panel of external cancer experts voted 8-4 against Copiktra’s currently FDA-approved use in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).
The panel reiterated the FDA’s concerns that the drug hasn’t demonstrated a favorable benefit-risk profile. Because of serious side effects, Copiktra could have a potential detrimental effect on patient survival despite it's ability to stave off disease progression, the FDA found.
During heated discussions at Friday’s meeting, Securo and the FDA argued about whether Copiktra’s side effects indeed killed more patients than the cancer would have otherwise.
The data that triggered the FDA scrutiny came from a longer follow-up of the phase 3 DUO trial. After a five-year follow-up, patients who received Copiktra after failing at least two prior therapies experienced a 6% higher risk of death compared with Novartis' Arzerra, though the difference wasn’t statistically significant.
Still, the debate isn’t about Copiktra’s efficacy—the drug showed strong tumor response and disease progression data—but rather safety. Among patients who enrolled in DUO for third or later-line treatment, 13 patients (14%) in the Copiktra arm died from side effects, versus four (4%) for Arzerra.
DUO’s trial design also allowed patient crossover between the study groups upon disease progression. By the FDA’s analysis, among nine patients in the Copiktra arm that later got Arzerra, none died because of side effects. In contrast, among 90 Arzerra patients that went on to receive Copiktra, nine (10%) died from side effects.
Secura, the FDA and the expert panel all acknowledged that patient crossovers have made an exact interpretation of Copiktra’s patient survival profile impossible. But the FDA figured the safety signals are alarming enough.
For its part, Secura argued that the longer-term analysis at least didn’t show any detrimental effect of Copiktra on patient survival. After all, the death risks were similar between the two trial arms, the company said.
But as an FDA official pointed out during the meeting, it’s not a qualification for approval if a drug doesn’t show patient detriment. Rather, showing a benefit is. And several panelists agreed.
“It’s incumbent upon the sponsor to establish that there was a favorable risk-benefit profile. I think, given the current context, that data about this class, extended follow up on this study, I don’t think they’ve established that.” David Harrington, Ph.D., from the Dana-Farber Cancer Institute noted in his no vote.
“I thought this data was extremely difficult to interpret, but […] I do have concerns about this class of medication,” Christopher Lieu, M.D., from the University of Colorado Cancer Center, explained for his vote against Copiktra. “If we’re not clearly improving overall survival in our patients, but we’re increasing toxicity and treatment-associated death, I’m not sure that we are truly helping patients.”
Before Copiktra, the FDA studied safety problems with multiple PI3K inhibitors during a separate advisory committee meeting in April. As the FDA’s scrutiny mounted, Gilead Sciences, Bayer, Incyte and TG Therapeutics either pulled their PI3K indications off the market or scrapped their application plans.
Secura has also pulled a Copiktra accelerated approval in follicular lymphoma in December but decided to keep fighting for the full approval in CLL/SLL, which is currently the drug’s only commercial indication. The company has recently also withdrawn Farydak as a treatment alongside Takeda’s Velcade and the corticosteroid dexamethasone in multiple myeloma after two prior regimens, citing difficulty to complete the required confirmatory clinical trial.
Four panelists during Friday’s meeting sided with Secura, arguing the tumor shrinkage and disease progression benefits support Copiktra’s use at least in some heavily pretreated CLL/SLL patients.
“I think the drug reduces the burden of CLL in many patients,” Jorge Nieva, M.D., from the University of Southern California said of his yes vote. “Ultimately, I trust the decision making of physicians and patients to make informed decisions and would like to see this drug available.”