The Friday Biotech Perspective #31
About All that Jazz
While many investors recognize Jazz Pharmaceuticals plc (NASDAQ:JAZZ) as a neuroscience company for its drugs to treat epilepsy, fibromyalgia and narcolepsy, the company quietly began assembling oncology drugs 12 years ago. Jazz typically sought out niche indications and cancer was no different. Early cancer drugs in development aimed to treat acute myeloid leukemia and acute lymphoblastic leukemia rather than, for example, breast cancer.
Always an active deal maker, Jazz partnered with Spain-based PharmaMar (MSE:PHM) in December 2019 to market Zepzelca (lurbinectedin) in the US to treat small cell lung cancer (SCLC). Zepzelca was on an accelerated approval pathway and Jazz paid $200 million up front with the potential for another $800 million in milestone and royalties for PharmaMar. SCLC was the ideal oncology submarket for Jazz, accounting for 10-15% of all lung cancer versus the 80-85% figure assigned to non-small cell lung cancer (NSCLC).
Zepzelca was approved to treat SCLC in June 2020 and Jazz started selling the drug. The approval, however, was conditional until a study named Atlantis demonstrated further results in confirmatory trial. In December 2020, Jazz and PharmaMar disclosed the Atlantis trial did not meet expectations. Among previously treated SCLC patients in Atlantis, the combination of Zepzelca and doxorubicin failed to extend patients’ lives over physician’s choice of doxorubicin-based chemotherapy or Hycamtin.
A review of the Atlantis trial by the FDA, Jazz and PharmaMar revealed SCLC patients dosed in Atlantis received a 2-mg/m2 dose of Zepzelca in combination with the chemotherapy agent doxorubicin. In contrast, Zepzelca initially was approved at a higher 3.2-mg/m2 single-agent injection. In spite of a citizen petition to pull Zepzelca from the market because of the failed Atlantis trial, the FDA held Jazz and PharmaMar could demonstrate the efficacy of Zepzelca by conducting two additional confirmatory trials. The FDA cited the lower dose as a likely reason for the unexpected failure in the confirmatory trial. The companies then began the trials in late 2021 and early 2022.
Why the lower dose in the confirmatory trial? Based on tumor response data, Zepzelca initially was indicated to treat adults with metastatic SCLC with disease progression on or after platinum-based chemotherapy. The Atlantis trial, begun in 2015, may have been designed to determine the tolerability of Zepzelca with a more potent or different chemotherapy. A Jazz spokesperson said at the time Atlantis was not designed to confirm treatment with Zepzelca, which already was approved. The FDA and PharmaMar were quick to point out in December 2020 Atlantis likely failed because of the lower dose.
Redemption arrived this week. In one of the two subsequent confirmatory trials, Zepzelca, in combination with Roche AG’s (OTCmarkets:RHHBY) Tecentriq, demonstrated superiority in treating extensive-stage SCLC patients following induction therapy with Tecentriq and chemotherapy, Jazz said on October 14, 2024. Notably, Investigators used the 3.2-mg/m2 dose in the trial.
With the positive data, Jazz expects to file for FDA approval of the Zepzelca-Tecentriq combination as a first-line maintenance treatment for extensive-stage SCLC in the first half of 2025. The approval would place Zepzelca back on the path it always intended to pursue in SCLC.
Though details of Atlantis trial design remain a bit sketchy, the FDA and the companies deserve praise for supporting continued use of the 3.2-mg/m2 dose in SCLC. The quality of treatment for SCLC, while always improving, naturally does not improve as fast as treatment for larger market cancers. Zepzelca was moved quickly to the market based on the evidence available at the time. A hiccup in the Atlantis trial ultimately did not result in pulling the drug from the market, resulting in a benefit for SCLC patients and their families.