FDA threatens to clamp down on another PI3K blood cancer drug—this time a full approval

Safety red flags have previously drawn the FDA’s attention to accelerated approvals given to a group of blood cancer drugs called PI3K inhibitors. But, through an upcoming expert panel discussion, the FDA is poised to get tough on a PI3K inhibitor that's marketed under a full approval.

In a briefing document prepared for an FDA oncology advisory committee meeting set to take place Sept. 23, the FDA laid bare its concerns over the toxicity of Secura Bio’s Copiktra and how the drug could detrimentally impact the life expectancy of patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

As the FDA sees it, Copiktra speaks to a PI3K classwide safety problem, which was already discussed during an FDA expert panel meeting in April. Feeling the pressure from that FDA scrutiny, Gilead Sciences, Bayer, Incyte and TG Therapeutics have either pulled their PI3K indications off the market or scrapped their application plans. But Secura doesn’t want to go down without a fight.

Secura has good reason to hold its ground. Unlike other problematic PI3K blood cancer drugs that are cleared under the accelerated approval pathway or are simply unapproved, Copiktra won a full approval in 2018 to treat CLL/SLL after at least two prior therapies based on showing it could slow disease progression or death over Novartis’ old CD20 drug Arzerra. Verastem, which was Copiktra’s owner at the time of the approval, handed over the drug to Secura in 2020 in a deal worth up to $311 million.

That 2018 go-ahead also included an accelerated approval in third-line follicular lymphoma. Secura did in late 2021 withdraw that small indication in the U.S. but decided to hold onto the larger CLL/SLL indication.

The FDA has other ideas for Copiktra. Despite an improvement in disease progression, CLL/SLL patients who got Copiktra appeared to live slightly shorter than their Arzerra peers did based on a longer follow-up of the phase 3 DUO trial. After a five-year look at the data, third-line patients on Copiktra lived a median 43.9 months, versus 46.8 months for Arzerra. The death risk was 6% higher for Copiktra, though the difference doesn’t bear statistical significance.

DUO actually enrolled a broader population that also included patients who had received just one previous CLL/SLL therapy. When those patients were counted, Copiktra’s death risk looked even greater.

Because Copiktra has shown a greater tumor response rate and a disease progression benefit, the FDA suggested the “potential detriment in [overall survival] is a primary safety concern,” according to the briefing document.

As the FDA reviewers noted, 23 patients (9%) in the Copiktra arm actually died from side effects, primarily fatal infections, versus just five patients (3%) for Arzerra. Besides, 31 patients (19.4%) had died before developing tumor progression, versus 12 patients (7.6%) for Arzerra.

The staffers labeled Copiktra as having “substantial toxicity and poor tolerability.” In fact, the FDA required the five-year patient survival analysis out of concerns of fatal and serious side effects, which weren’t clear back in 2018, the agency pointed out.

Based on the new data, “a re-evaluation of the overall benefit-risk of [Copiktra] … is warranted,” the FDA said.

But Secura disagrees. In its own briefing document, the Nevada biotech argued the FDA had already concluded its risk-benefit assessment of Copiktra for third-line CLL/SLL in 2018 in the form of a full approval, coupled with a boxed warning that recognizes the potential for many side effects including infections. The FDA “appropriately” limited the drug’s use to the third line instead of the second line as tested in the DUO trial while balancing the risks, the company said.

As for the five-year overall survival data, Secura noted the results were confounded by 57% of patients in the Arzerra arm crossing over to receive Copiktra upon progression. Even if the long-term data are usable, Secura said, the analysis doesn’t indicate any “significant change or detriment” to overall survival by Copiktra in the indicated third-line population. Instead, it “confirms that the safety experience in the longer term is consistent with the original” data at approval, the company said.

For Friday’s advisory committee meeting, the FDA is asking its external experts to weigh in on whether Copiktra’s risk-benefit profile is still favorable in third-line CLL/SLL.