As the first CAR-T treatment for an autoimmune disease draws ever closer, officials at the FDA have signaled a willingness to support the development of these novel cell therapies with a flexible regulatory approach.
While interested in CAR-T therapies’ potential to achieve durable, drug-free remission in serious autoimmune conditions, the FDA is equally wary of their “unpredictable long-term toxicity,” according to an article published Monday in the Annals of Internal Medicine.
In the article, Vinay Prasad, M.D., director of the FDA’s Center for Biologics Evaluation and Research, and two other regulators said that, recognizing the complexity of autoimmune conditions in terms of seriousness and type, the agency will work with CAR-T makers “on a case-by-case basis to encourage appropriate study populations in rheumatologic autoimmune disease.”
Simultaneously, citing a need to monitor a drug’s effect on fertility, the FDA officials recommended that industry conduct long-term follow-up studies for CAR-T products in the autoimmune setting, “as is standard for genetic therapies and CAR T-cells for oncologic indications.”
While the FDA “shares enthusiasm for this class of products,” it will “carefully shepherd” the advancement of clinical studies “focused on the development, durability, and long-term safety of CAR T-cell therapies,” the regulators wrote.
Publication of the FDA’s perspective comes as the first CAR-T therapy for an autoimmune disease could arrive soon in the form of Kyverna Therapeutics’ mivocabtagene autoleucel (miv-cel). After reporting positive pivotal clinical trial results in December, the California biotech is targeting an FDA application for the CD19-directed CAR-T cell therapy for the treatment of stiff person syndrome (SPS) in the first half of 2026. Kyverna has said it is aligned with the FDA on its registrational trial design.
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The new article “does not change our strategy or impact our clinical development plans,” a Kyverna spokesperson told Fierce, adding that the company already has long-term patient monitoring in place. The December readout from the registrational KYSA-8 trial evaluated miv-cel’s treatment effect after 16 weeks of treatment, with patients planned to be followed for a year.
Kyverna’s KYSA-8 study enrolled SPS patients who had had an inadequate response to prior immunomodulatory therapies. Because of potential long-term toxicity, the FDA has generally encouraged drugmakers to develop CAR-T meds for patients with refractory disease who have failed at least two previous immunosuppressants, Prasad and colleagues noted in the article.
However, this restriction may be inappropriate for patients with severe disease, given the high risk for irreversible organ damage, the FDA officials acknowledged. Therefore, the regulators suggested a case-by-case development plan.
CAR-T therapies were initially developed for blood cancers. While highly efficacious at staving off diseases such as large B-cell lymphoma and multiple myeloma, these one-time treatments may carry the risk of late-onset side effects such as Parkinson’s disease and secondary T-cell cancer. These products were approved with the FDA’s requirement to conduct observational studies for 15 years to assess their secondary cancer risks over the long term.
In the Feb. 3 article, Prasad and colleagues didn’t specify how long the FDA is asking autoimmune CAR-T trials to be followed. Based on precedents with cancer CAR-T meds, having long-term data is a post-market commitment rather than a condition for approval.
“We don’t think the views in this paper are substantively different than current practice,” Stephen Majors, VP of global communications and investor relations at Alliance for Regenerative Medicines, said in a statement to Fierce. “However, we would encourage the FDA to periodically review the requirement for 15 years of follow-up on all CAR-T products in light of new evidence emerging over time.”
Enthusiasm for turning CAR-T therapies against autoimmune diseases was ignited in 2021 after researchers in Germany reported a patient with severe systemic lupus erythematosus who achieved rapid, drug-free remission after receiving anti-CD19 CAR-T cells. The idea is that these immunotherapies may eradicate autoreactive B cells that drive autoimmune diseases.
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In September, the same German team, led by Georg Schett, M.D., from the University of Erlangen-Nuremberg, reported long-term data for 11 patients with refractory SLE who had been followed up by a median of two and a half years or up to four years. All patients remained in a sustained, drug-free remission despite one SLE flare. The team also pointed to a better safety profile of the CAR-T therapy compared with the lymphoma setting.
Of the limited number of patients treated with autoimmune CAR-T drugs to date, no secondary malignancies have been publicly reported.
In an email to Fierce, Schett argued that T-cell lymphoma risk in autoimmune disease is “not an issue.”
Unlike B-cell lymphoma, autoimmune disease does not come with an increased underlying risk for secondary T-cell cancer, he noted. In blood cancer treatment, recipients of CAR-T cells typically have received extensive, toxic prior therapies, which are major drivers of secondary cancers. In contrast, patients with autoimmune disease are often treated with immunosuppressants and generally have not been exposed to the same volume of highly genotoxic agents as oncology patients.
The possibility of the genetic material of the CAR receptor being integrated into the human genome gives rise to concerns of secondary malignancies. But in autoimmune patients, the CAR-T cells do not live long, Schett noted.
Unlike in oncology, where CAR-T cells often must persist to keep cancer at bay, the therapeutic goal in autoimmune diseases like SLE is often to quickly deplete the problematic B cells and therefore reset the immune system.
