Ahead of the first-ever FDA AdComm for a CAR-T medication, the agency says experts should focus on the safety side of the new med, more than efficacy.
The briefing documents for Wednesday’s meeting were posted this morning as the agency gears up to pick through Novartis’ data for tisagenlecleucel, which is gunning to become the first-ever approved CAR-T drug.
The Swiss major is seeking a first license in children and young adults with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (ALL), although it is also testing the med in other blood cancers, along with rivals Kite, Juno, Bluebird Bio, and others.
“The overall effectiveness of this product is not the primary issue for consideration by this Committee,” the documents make clear, but rather the safety aspect of this new class.
As the committee points out, the medication has both short-term safety concerns and longer-term issues, including life-threatening cytokine release syndrome (CRS) and hemophagocytic lymphohistiocytosis (HLH), as well as potentially fatal infections.
In its phase 2 trial of the med, grades 3 or 4 CRS occurred in 32 subjects (47%) of the subjects. There were, however, no deaths from CRS.
The committee is also asked to look at long-term safety concerns with tisagenlecleucel, which include the potential for generation of replication-competent retrovirus (RCR) and the potential for insertional mutagenesis to cause new malignancies (genotoxicity).
It notes that “most study subjects have not been followed for very long, thus limiting the ability to assess the risk of delayed events.”
It says that the potential for genotoxicity from insertional mutagenesis is a concern with immunotherapy products that require gammaretroviral and lentiviral transduction. Given all this, “post-marketing considerations for long-term safety monitoring may be necessary to address the potential safety concern.”
The FDA says it wants two main points to be considered by the committee: post-marketing considerations for risk mitigation for short-term toxicities, particularly cytokine release syndrome; and long-term followup for anticipated safety concerns related to the potential for insertional mutagenesis and secondary malignancies.
As always, the balance between risk and efficacy will be the deciding factor, but the onus is squarely on risk. This comes around a year after rival Juno saw a series of deaths across its CAR-T program from cerebral edema, even though the FDA had checked one trial and given it a very quick turnaround to restart after the briefest of pauses.
Novartis was slightly down this morning, by around 0.4% premarket, while Kite, which should be second to market after Novartis with its CAR-T med, saw its shares unmoved either way.