Two days before a panel of the FDA’s outside advisors grill Novartis about its groundbreaking cell therapy under review, agency staffers released their own assessment of the product, which now goes by the name tisagenlecleucel.
If approved for kids and young adults with acute lymphoblastic leukemia, or ALL, it would likely be the first so-called CAR-T medicine to reach the market. The field has faced years of intense scrutiny and questions about whether a patient’s own T cells can be genetically modified outside the body then reintroduced, alive, to fight cancer safely, without going into dangerous overdrive.
In the overview published this morning, FDA staffers have no qualms about the effectiveness of tisagenlecleucel, which for years was called CTL-019. According to Novartis’s data included in the FDA review, 40 of 63 patients under evaluation saw their cancer disappear; 29 of them were still in remission at the time Novartis submitted its data to the FDA. Nearly all of them had been followed for less than a year, according to Novartis data (click to enlarge):
However, the FDA raises questions about CAR-T’s short-term and long-term safety. The short-term risks, especially of the souped-up cells causing an immune overload called cytokine release syndrome (CRS), are no secret to the CAR-T field. Medical providers who have given the experimental treatments from Novartis and its rivals acknowledge the complexity of caring for CAR-T patients who suffer severe side effects.
CRS is often treated with anti-inflammatory drugs, but neurological complications, including seizures, confusion, and loss of balance, memory, even vision, are less understood and predictable. Severe brain swelling killed five adult ALL patients last year treated with an experimental Juno Therapeutics (NASDAQ: JUNO) product; Juno was forced to scrap the program. The same swelling, known as cerebral edema, also killed a lymphoma patient this year treated with a product from Kite Pharma (NASDAQ: KITE). Kite’s CAR-T product is currently under FDA review.
FDA is also worried about long-term risks that could stem from genetic alterations to the T cells. What if the modification process changes the cells’ DNA and makes them cancerous? Novartis did not provide those data, the report reads, but notes that the effects of cancer-causing mutations might not show up for a long time: “Most study subjects have not been followed for very long, thus limiting the ability to assess the risk of delayed events.”
The review cites cases of cancer showing up in patients years after they receive gene therapies to treat an immune system disease called SCID.
The FDA is asking its panel of outside advisors to weigh those risks against the potential benefits of the drug, which is meant for young people whose cancer has resisted other forms of treatment, all but dooming them. The FDA usually follows its advisory committees’ recommendations. But when it doesn’t, the results can be quite controversial, as the biomedical field saw last year with the approval of a treatment for Duchenne muscular dystrophy.
The report notes that Novartis already has in place a program to monitor patients for safety problems after approval of tisagenlecleucel. It does not say whether the proposed programs would be adequate. Such post-approval programs have become common for the FDA in its efforts to get new drugs quickly to patients who have bleak outlooks.
The FDA is expected to make a final approval decision by October 3.
T cell image courtesy of NIAID via a Creative Commons license.