- An advisory panel to the Food and Drug Administration unanimously supported approval of Novartis' CAR-T therapy tisagenlecleucel for an aggressive type of leukemia, likely signaling a clear path towards a regulatory OK later this year.
- Experts on the advisory committee concluded by a vote of 10 to 0 that the strong efficacy of tisagenlecleucel in pediatric and young adult patients with relapsed/refractory acute lymphoblastic leukemia outweighed the risks presented by the cell therapy's common side effects such as cytokine release syndrome.
- If approved, tisagenlecluecel would be the first CAR-T therapy cleared for commercial use anywhere in the world, putting Novartis ahead of rivals like Kite Pharmaceuticals and on track to meet its lofty expectations for the treatment. Shares in the Swiss pharma, higher throughout the meeting, closed roughly 1.5% above Wednesday's open.
While the panel's recommendation is not binding, the FDA usually follows the advice of its expert advisory committees. Novartis' therapy is the first CAR-T treatment to be reviewed by the FDA and, as such, is seen as a marker for the types of concerns the agency might have with other candidates such as Kite Pharma's axi-cel.
"Now that people see there is a path to approval at the FDA, that usually gets people off the sidelines," explained Brad Loncar, founder of a cancer immunotherapy exchange-traded fund. "I think you will see a rush of investment in the cellular therapy space, both from investors but also companies."
Aiman Shalabi, chief medical officer of the Cancer Research Institute, viewed the positive tone of the meeting and unanimous recommendation as a similarly momentum-generating event for CAR-T and immunotherapy more broadly.
Tisagenlecleucel's benefit for ALL patients who have relapsed from other treatments was clear before the meeting. Compared to existing treatments for the target population, treatment with tisagenlecleucel resulted in a substantially higher remission rate. Fifty two of the 63 patients (83%) included in the primary efficacy set experienced a complete response, all of whom tested negative for minimal residual disease.
In briefing documents released Monday, however, the FDA had largely set aside questions of tisagenlecleucel's efficacy, instead choosing to focus on the safety concerns surrounding CAR-T — which can be highly toxic for many patients.
Cytokine release syndrome (CRS), a potentially life threatening inflammatory response, and neurological toxicity are the two main safety concerns with CAR-T, seen across studies of different therapies.
In Novartis' pivotal ELIANA study, just over three quarters of patients experienced CRS, while 44% developed neurotoxicity. No deaths were reported due to refractory CRS, though, and Novartis detailed how better experience managing CRS at clinical sites helped to make most CRS and neurotoxicity reversible.
Notably for CAR-T, Novartis saw no cases of cerebral edema in its clinical program for tisagenlecleucel. Another company in the space, Juno Therapeutics, was forced to shut down its once-lead clinical candidate due to five deaths from cerebral edema — triggering concerns at the time about the class as a whole.
Long-term safety concerns
The advisory panel also delved into long-term safety concerns often raised in discussion of cell and gene therapies, namely worries of replication-competent retroviruses and insertional mutagenesis (i.e. the triggering of new malignancies due to oncogene activation).
To produce tisagenlecleucel, Novartis uses lentiviral vectors. As a retrovirus, lentiviral vectors theoretically could change the activity of host genes if the factors for replication aren't stripped out in the manufacturing process. While Novartis expressed confidence its production process mitigated the risk, the FDA maintained that a "slight risk" remained.
Novartis also proposed a risk evaluation and mitigation strategy to ready sites for using tisagenleleucel. Advisory panel experts appeared to view the company's plans as appropriate, especially when paired with the 15years of proposed long term follow up through Novartis' planned registry study.
More pressing will be the challenges that come with manufacturing a complex cell therapy from the necessarily varied T-cell material extracted from each patient. Panel members pushed Novartis on whether differences in the potency, CAR transduction or other product attributes led to any differences in efficacy. Novartis' answer, for the most part, was no, and the Swiss pharma came prepared with several charts mapping product attributes against complete responses.
Novartis believes it can turn around a finished CAR-T product 22 days from receipt of leukapheresed material to final packing and shipping. In the ELIANA study, tisagenlecleucel was produced mainly out of Novartis' production facility in Morris Plains, New Jersey and shipped to clinical trial sites in North America, Europe and the Asia/Pacific region.
Stephen Grupp of Children's Hospital of Philadelphia, who represented the clinical perspective for Novartis, highlighted the comparable safety and efficacy results seen in translating tisagenlecleucel from an earlier single-site study to the global ELIANA trial. The next step, if tisagenlecleucel is approved, will be ensuring similar production speed and reliability in commercialization.