The FDA has upheld the accelerated approval of Jazz Pharmaceuticals’ Zepzelca (lurbinectedin), even though the drug failed to reach its primary endpoint in the confirmatory Phase III ATLANTIS trial.
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The FDA has upheld the accelerated approval of Jazz Pharmaceuticals’ Zepzelca (lurbinectedin), even though the drug failed to reach its primary endpoint in the confirmatory Phase III ATLANTIS trial.
This decision follows a citizen’s petition, filed by the law firm Foley Hoag in March, asking the regulatory body to pull its approval of Zepzelca for lack of established efficacy. The petition also asked, while proceedings to withdraw approval are ongoing, that the FDA require a label update for the drug to point out that it had failed its confirmatory assessment.
Zepzelca was first approved in June 2020 for adult patients with metastatic small-cell lung cancer (SCLC), who had already failed a previous line of platinum-based chemotherapy.
Citing a great unmet second-line need in this patient population, the FDA greenlit the injectable drug under the accelerated approval pathway. At the time, Zepzelca’s promising overall response rate and duration of response were enough to warrant a regulatory go-ahead—with the caveat that Jazz needed to perform a confirmatory study to ensure that its drug stays on the market.
The Phase III ATLANTIS trial, launched in 2015, was supposed to satisfy this requirement. However, whereas Zepzelca was approved as a 3.2-mg/m2 single-agent injection, ATLANTIS assessed the drug as a 2-mg/m2 dose in combination with another chemotherapy agent doxorubicin.
In December 2021, Jazz announced that ATLANTIS fell short of its primary endpoint. The drug combo did not statistically improve overall survival as compared with a physician’s choice chemotherapy. A Jazz spokesperson told BioSpace that ATLANTIS was “not designed to confirm treatment with Zepzelca” as it is currently approved.
In a response to the citizen petition, the FDA cited these dosing differences as the likely reason why ATLANTIS failed. Perhaps the lower dose, the agency argued, could have weakened the efficacy of Zepzelca and might be the reason the trial failed.
“When a confirmatory trial does not meet its endpoint, it does not necessarily mean that the drug is not effective for the indication approved through accelerated approval,” the FDA wrote. “When considering if withdrawal of an indication is appropriate or if additional confirmatory trials are warranted, FDA reassesses the medical need and available therapies to determine whether the conditions for accelerated approval still exist.”
Jazz, following an agreement with the FDA, is conducting two new confirmatory trials in place of ATLANTIS. The first, named LAGOON, is looking to enroll over 700 patients and will test Zepzelca in its approved dosing. LAGOON will also look at a 2.0-mg/m2 Zepzelca dose combined with irinotecan. LAGOON launched late last year.
The second trial, conducted in collaboration with Roche, is dubbed IMforte and will combine Zepzelca with Tecentriq (atezolizumab) as maintenance therapy for SCLC. The spokesperson said that while both trials have already initiated, it is still too early to identify which one will yield data first.
Will This Verdict Affect Other Accelerated Drugs?
It remains to be seen whether the FDA’s logic for Jazz will also hold for Covis Pharma. On Oct. 19, the Agency’s Obstetrics Reproductive and Urologic Drugs Advisory Committee voted 14-1 to pull Makena (hydroxyprogesterone caproate injection), the company’s preterm birth drug that was granted accelerated approval in 2011.
Like Zepzelca, Makena showed early promise and triggered significant benefits in surrogate markers, suggesting that it was reasonably likely that the drug could prevent infant death and illness. Similarly, Makena failed its confirmatory trial PROLONG, a result that Covis attributed to key differences in study populations.
Nevertheless, the company argued, there remain signals of Makena’s efficacy, particularly in high-risk patients. However, the advisory committee disagreed, noting that if they had access to both the initial and confirmatory trials in 2011, they would not have recommended Makena for accelerated approval in the first place.
The FDA is set to arrive at a final and official verdict of Makena in the coming months.
