FDA issues second CRL for tabelecleucel in EBV+ PTLD, a decision Atara calls a reversal on trial design

The FDA on January 9, 2026 issued a second Complete Response Letter for tabelecleucel (Ebvallo), an allogeneic, off-the-shelf EBV-specific T-cell immunotherapy developed by Atara Biotherapeutics and licensed to Pierre Fabre Pharmaceuticals. The agency concluded that the pivotal ALLELE study is "no longer considered to be adequate" to support accelerated approval for EBV-positive post-transplant lymphoproliferative disease (EBV+ PTLD)—a position Atara characterised as a complete reversal, given that the FDA had previously endorsed the single-arm design and accepted the accelerated approval pathway over roughly five years of alignment.

The first CRL, issued in January 2025, related solely to GMP compliance at a third-party manufacturing facility; no clinical concerns were raised, and the issues were subsequently resolved. This time, however, the FDA flagged the ALLELE trial's design, conduct and analysis as "confounding the trial's interpretability," while citing no new safety or manufacturing issues.

EBV+ PTLD is a life-threatening lymphoproliferative complication that affects 2–20 % of transplant recipients, with higher incidence in heart, lung and multi-organ transplants. Roughly 80 % of cases emerge within the first post-transplant year. Standard first-line treatment relies on reducing immunosuppression and administering rituximab, but roughly half of patients are refractory or relapse, leaving them with median survival of approximately six months. At the time of the decision there were no FDA-approved therapies for this indication.

Tabelecleucel works by harnessing donor-derived T cells that selectively recognise and destroy EBV-infected cells in an HLA-restricted manner, without genetic modification. In the global ALLELE Phase 3 trial (75 evaluable patients), the therapy achieved an overall response rate of 50.7 %, including a 28 % complete response rate, with a median duration of response of 23 months. One- and two-year overall survival for responders was 94.1 %, versus 0 % for non-responders, underscoring the clinical significance of achieving a response.

Tabelecleucel holds conditional marketing authorisation in the European Union, where it was approved in December 2022 as the first allogeneic T-cell immunotherapy cleared by any regulatory authority. It has also been approved in the UK and is available on a named-patient basis in additional markets.

Atara publicly disagreed with the FDA's position and said at the time that it was evaluating its options. Pierre Fabre holds US commercialisation rights. The rejection underscores a broader pattern of tightening FDA scrutiny of single-arm trials and external controls—a theme that has affected multiple programmes across rare-disease and cell-therapy development in 2025–26.

Sources: Atara Biotherapeutics and Pierre Fabre press release; FDA; ALLELE trial (NCT03394365).