- The Food and Drug Administration plans to ask an independent panel of experts to focus their attention on the safety profile of Novartis' experimental CAR-T therapy tisagenlecleucel when they meet to review the leukemia treatment at a public meeting scheduled for Wednesday.
- The advisory committee hearing marks the last major regulatory milestone before the agency decides whether to approve the treatment, which looks set to be the first CAR-T therapy to reach markets in the U.S.
- Briefing documents prepared by FDA staff ahead of Wednesday's meeting highlighted both the short-term and long-term safety concerns with tisagenlecleucel, as well as the challenges of reliably manufacturing the complex cell therapy.
Novartis hopes to first win approval for tisagenlecleucel for treatment of pediatric and young adult patients with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL), an aggressive blood cancer that affects just over 3,000 new patients each year.
Tisagenlecleucel, also known as CTL019, has demonstrated impressive efficacy in hard-to-treat ALL patients who have either relapsed or whose cancers have proven resistant to other treatment. In the ELIANA study, which formed the basis of Novartis' application of approval, treatment with tisagenlecleucel resulted in a best overall response rate of 83%, with 63% of successfully infused patients experiencing a complete response.
Beyond representing a step-change in the treatment of relapsed/refractory ALL, approval for tisagenlecleucel would be a landmark decision — ushering in CAR-T as a new class of personalized cancer treatments. A regulatory OK would also put Novartis at the head of that class, further than rivals like Kite Pharmaceuticals and Juno Therapeutics.
The briefing documents from FDA staff released Monday come two days ahead of Wednesday's planned meeting of the Oncologic Drugs Advisory Committee. While the FDA is not required to follow the advice of the independent experts, it usually does so, making Wednesday a key barometer of the issues likely to occupy FDA reviewers' attention.
And in the eyes of the FDA, tisagenlecleucel's efficacy appears largely proven. "The overall effectiveness of this product is not the primary issue for consideration by this committee," FDA staff wrote in the briefing documents.
Safety, and whether the therapy's benefits outweigh its risk, will be the main question surrounding the CAR-T treatment.
Cytokine release syndrome and higher levels of neurological toxicity are well-known side effects of CAR-T treatment, observed in studies of candidates developed by both Kite and Juno, as well as in Novartis' ELIANA and JULIET trials. Management of both events, which typically manifest shortly after infusion of the engineered T cells, has improved as medical teams at clinical sites have become more experienced with treatment.
In the briefing documents, however, the FDA also took care to highlight its concern over potential long-term safety issues with tisagenlecleucel, such as generation of replication-competent retrovirus or genotoxicity related to insertional mutagenesis.
"[M]ost study subjects have not been followed for very long, thus limiting the ability to assess the risk of delayed events," FDA staff wrote. "Therefore, post-marketing consideration for long-term safety monitoring may be necessary to address the potential safety concern."
Novartis has proposed a prospective registry to assess commercial tisagenlecleucel's long-term safety, as well as a long-term follow-up monitoring study.
Given the complexity of CAR-T, another issue will be whether Novartis can reliably ramp up manufacturing from clinical development to commercial sale.
The Swiss pharma produced tisagenlecleucel at two production sites in New Jersey and Germany for the ELIANA study, shipping the engineered cells to 25 study sites in North America, Europe and Asia. That experience, Novartis believes, will be scalable following a potential approval.