FDA Warns about Risk of Death from Copiktra

The FDA is warning that Secura Bio’s Copiktra (duvelisib) in a clinical trial increased the increased risk of death compared with another medicine to treat leukemia and lymphoma. The study also found Copiktra was associated with a higher risk of serious side effects, including infections, diarrhea, inflammation of the intestines and lungs, skin reactions, and high liver enzyme levels in the blood.

Copiktra was approved in 2018 to treat adults with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who have received at least two prior therapies.

The FDA required Secura Bio to submit final five-year survival results from the phase 3 DUO clinical trial. It was conducted with 319 patients with CLL or SLL who received a previous therapy. The study compared Copiktra with Novartis’ Kesimpta (ofatumumab), and the primary endpoint was progression-free survival.

With a median of 63 months follow-up, the final overall survival results showed a possible increased risk of death with Copiktra, with a hazard ratio of 1.09. A hazard ratio above 1 indicates increased risk of harm.

Among the subpopulation of patients who had received at least two prior lines of therapy – the FDA approved use – the hazard ratio was 1.06. In addition to the risk of death, the incidence of deaths due to adverse events, serious adverse events, grade ≥3 adverse events, and treatment modifications due to adverse events were higher among patients receiving Copiktra.

The rate of serious side effects, dose modifications, and deaths resulting from these side effects were also higher among patients who received Copiktra. These included infections, diarrhea, inflammation of the intestine and lungs, skin reactions, and elevated liver enzyme levels in the blood.

These safety findings were similar for other medicines in the same PI3 kinase inhibitor class, which were discussed at an advisory committee meeting in April 2022. At that meeting, the FDA’s Oncologic Drugs Advisory Committee (ODAC) voted in support of basing future approvals for PI3K inhibitors on randomized data instead of single-arm clinical trials.

In briefing documents, the FDA indicated that a higher rate of death in trials for PI3K inhibitors may be due to toxicity. They said more robust dose exploration trials to clarify the relationship between overall response rate and toxicities are needed for this class of therapies, and the single-arm trials complicate dose exploration. Randomized trials, they said, are a more effective method to control for confounding factors and allow for assessment of important measurements such as profession-free survival, overall survival, and patient reported outcomes.

This isn’t the first challenge Secura Bio has faced. In December 2021, Secura Bio voluntarily withdrew the U.S. indication of Copikta for the treatment of patients with relapsed or refractory follicular lymphoma (FL) This indication had received accelerated approval in September 2018 with the requirement that an additional confirmatory trial be conducted in order for the product to be granted full approval.

The company indicated in a press release at that time that after discussions with the FDA, executives determined that the current treatment landscape for FL patients in the United States and the logistics, cost and timing of the post-marketing requirements in FL was no longer feasible.

Company executives stressed this was a business decision and is not related to any changes in either the efficacy or safety. This decision impacts only the relapsed or refractory FL indication in the United Statse and does not affect other approved indications in the United States and other countries.

Secura Bio is continuing with trials of Copiktra for the treatment of adult patients with relapsed or refractory (r/r) peripheral T-cell lymphoma (PTCL). The PRUNO study is an open-label, parallel cohort, phase 2 study that recently completed enrollment with a total of 157 patients.

In the dose optimization portion of the study, were randomized to receive Copiktra 25 mg or 75 mg twice daily until progressive disease or unacceptable toxicity. Based on the dose optimization results, an expansion group of 124 patients was added in which Copiktra is dosed at 75 mg twice daily for two cycles, followed by 25 mg twice daily.

An interim analysis of the first 78 patients in the expansion phase, with a minimum follow-up of six months, was reported in December 2021 at the 63rd Annual Meeting of the American Society of Hematology (ASH) in Atlanta, Georgia. Half of patients achieved overall complete response and 32.1% had a complete response, with a duration of response of 233 days.

The study is ongoing and is expected to have enough events for the primary endpoint analysis later in 2022.