Rosuvastatin Calcium/Telmisartan

Secura Bio says it has no plans to change the marketing status of its PI3K inhibitor Copiktra (duvelisib), which won full approval in September 2018 as a third-line treatment for relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma. Updated pivotal trial results raised fresh safety questions about that approval, and the FDA’s outside oncology experts last September voted 8-4 against the drug’s benefit-risk profile. But unlike other approvals that have gone before ODAC in recent memory that was for accelerated approvals with negative confirmatory trials, Copiktra’s third-line indication in r/r CLL and SLL doesn’t come with any confirmatory trials. In fact, the ODAC meeting was a result of the final data linked to the full approval. The company has an “obligation related to the original approval to report the follow-on overall survival (OS) data generated in the pivotal trial supporting approval that was not available at the time of original approval,” a spokesperson for Secura told Endpoints News via email . The trial in question, known as DUO, was a Phase III, open-label, randomized trial that began in 2014 and compared Copiktra with the mAb ofatumumab in 319 patients with relapsed or refractory CLL or SLL who received at least one prior line of therapy. The primary endpoint was progression-free survival. At the time of initial, full approval, OS data were limited, FDA said, noting that it required a final analysis of OS at five years to evaluate Copiktra’s longer-term efficacy and safety. While the study met its primary endpoint by significantly improving PFS when compared with ofatumumab for all patients (median, 13.3 months vs 9.9 months; hazard ratio [HR] = 0.52; P < .0001), Nicholas Richardson from FDA’s division of hematologic malignancies followed up at the September adcomm to explain that the final data show there was not only a higher number of deaths in the Copiktra arm of DUO when compared to ofatumumab, but a higher rate of deaths due to adverse events with duvelisib. Prior to that meeting, FDA last June sent a warning out explaining that Copiktra may increase the risk of death and severe side effects for this third-line indication. FDA’s ODAC met three months later and voted 8-4 against the benefit-risk profile of the drug, with the chair of the committee, Jorge Garcia of Cleveland’s University Hospitals Seidman Cancer Center, saying that ultimately the data did not support the notion that this drug prolongs life. FDA and company officials also got into heated arguments over whether the cancer or the side effects of the drug killed more people in the trial. Secura’s spokesperson said the drug’s benefit-risk profile has not changed since initial approval, “as the OS data were confounded by a high rate of crossover in the study. We are in favor of updating the COPIKTRA prescribing information to include the new OS data. Additionally, at the request of the FDA, we have sent a ‘Dear Doctor’ letter to all prescribers of COPIKTRA that reviews these data in detail.” That letter from last May explained the results of the trial as: Regarding Copiktra’s approval in r/r CLL and SLL moving forward, the company said it remains on the market, adding that “there are no additional requirements for clinical trials to support that indication.” And trying to pull a full approval is not common and can be difficult if the sponsor is unwilling. “I don’t know of any cases when the FDA has withdrawn a drug/indication for a full approval over a manufacturer’s objection,” Harvard Medical School professor Aaron Kesselheim told Endpoints.