After the FDA announced in November that multiple CAR T cell therapies were under review for potential safety concerns, shares of several relevant biopharma firms dropped. Giants like Gilead Sciences and Bristol Myers-Squibb, as well as smaller companies such as Cabaletta Bio were affected. Shares of the big companies have since climbed back but remain largely flat, perhaps reflecting some hesitation among investors.
The FDA clearly stated in its advisory that “the overall benefits of these products continue to outweigh their potential risks for their approved uses,” and pharmaceutical companies and analysts, recognizing the benefits of currently approved therapies, are largely optimistic about the status of the CAR-T market, which is expected to surpass $15 billion by 2030.
“For the currently approved indications, you are saving patients from dying of a disease. Often death is very rapid, and it’s hard to imagine any meaningful impact [of the FDA’s review] on the utilization of these drugs in those settings,” Jack Allen, a senior research analyst with Baird, told BioSpace.
Nevertheless, a cloud hangs over the CAR-T space as questions remain about what the FDA’s investigation will turn up.
There are currently six approved CAR T treatments for life-threatening blood cancers. All are included in the FDA notice:
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Does The FDA Know More Than It's Saying?
CAR therapy involves genetically engineering a patient’s T cells in the lab and then reinfusing them into the body to bind to and kill cancer cells. Even in advanced cancers, this approach can result in remission in a matter of weeks.
The expansion of CAR-T technology has been driven not only by the success of the approach but by increasing incidence of blood cancers such as myeloma and lymphoma, which these therapies have successfully treated. The treatment strategy is also being tested for less deadly or earlier-stage blood cancers, as well as autoimmune diseases.
But there is a low risk of off-target edits that could increase the risk of a second cancer. On November 28, the FDA announced it had received reports of 19 new, secondary blood cancers in patients who had undergone CAR-T treatment.
The biggest question on analysts’ minds is: Does the FDA have additional information it hasn’t yet shared? “The warning offered very little information, and it was that ambiguity that drew so much attention to the story,” Brian Skorney, a senior research analyst with Baird, told BioSpace. “We would all love to know if the FDA has already established some level of causality. Have they done genetic testing on any of these cases and seen a clear connection between the therapy and the secondary cancers?”
As of now, the FDA has not stated whether any of the 19 cancers carry the chimeric antigen receptor (CAR) that was engineered into the T cells.
Past FDA warnings have been more explicit, according to Rahul Banerjee, a physician and researcher specializing in myeloma at Fred Hutchinson Cancer Center. Banerjee recalled a 2019 FDA warning on the drug Venclexta, which offered a clear warning accompanied by data from a clinical trial. “In that case, we knew exactly what data the FDA had considered,” he told BioSpace, “and that the signal was real. Even though the drug worked it was potentially causing more deaths, and we completely changed how we used the drug based on that FDA warning. In that case, the FDA was the hero of the hour.”
Analysts from William Blair said the risk of a second cancer has been known all along. In their research note shared with BioSpace, they explain that because this therapy uses a viral vector, the “risk of insertional mutagenesis has been known, hence the FDA’s requirement for 15 years’ follow-up of all CAR-T treated patients.”
Analysts Expect Limited Impact on Existing CAR-T Therapy Market
In a research note shared with BioSpace, Skorney and Allen explained that “our initial read is that commercial CAR-T players will be unphased[sic], given the robust efficacy seen in controlled studies and the severity of NHL (non-Hodgkin lymphoma) and myeloma.” Allen added that the frequency of these potential side effects is also an important factor. “Malignancy rates seem to be extremely low,” he said.
Indeed, according to Bruce Levine, a specialist in cancer gene therapies at the University of Pennsylvania, “there have been around 35,000 patients treated worldwide with CAR T therapies.” Thus, 19 cases of secondary cancer is only 0.05% of treated patients. “If there is a very small percentage of cancers that have been induced by CAR, I don’t want to trivialize it, but we do have to put that risk in context with conventional chemotherapy,” which has also been linked to secondary cancers, Levine told BioSpace.
Expansion of Indications May Be Tougher
If there is to be an effect on the market, it’s likeliest to be in expanding the label to treat autoimmune diseases or slow-smoldering cancers such as chronic lymphocytic leukemia, Skorney and Allen said. In that case, other therapies work, and the risk of secondary cancer may be regarded as too high. In their research note, they write: “Less severe and more treatable indications likely warrant more caution.” More than 30 companies are pursuing CAR-T for autoimmune disorders, according to a December report by William Blair.
But time will tell if these predictions are accurate, as it largely depends on the outcome of the FDA inquiry. For example, the discovery that one particular CAR-T product presented more risk than others would potentially harm future sales of that particular therapy, Allen said. “If the FDA was to say, oh, drug A is causing 90% of these rare cancers, and drug B is only causing 10%, that would present a big risk to future sales of drug A,” he told BioSpace. “Right now the assumption is they all have equal risk. And in fact, it should not be hard to find out, by testing the malignant cells to see if they are CAR positive.”
But again, given the potential for these therapies to save lives that would otherwise be quickly lost, the sector remains optimistic that there is a bright future ahead for CAR T cells. A December 5 virtual panel held by William Blair led to a research note two days later that confidently announced: “Unanimously, the panelists shared the view that the overall enormous therapeutic benefits far outweigh the risks of such cell therapies in oncological applications and they do not see this information affecting cell therapies’ current market performance.”
https://www.biospace.com/article/market-for-car-ts-still-bright-despite-fda-cancer-safety-review/
