For a Second Time, FDA Denies Approval of Tab-Cel in EBV+ PTLD

The FDA has issued a complete response letter (CRL) for the biologics license application (BLA) of the T-cell immunotherapy tabelecleucel (tab-cel; Ebvallo) seeking accelerated approval for treatment of adult and pediatric patients aged 2 years and older with relapsed or refractory Epstein-Barr virus-positive posttransplant lymphoproliferative disease (EBV+ PTLD) who received at least 1 prior therapy, including an anti-CD20 containing regimen.¹ This marks the FDA’s second denial of the agent nearly 1 year after the first on January 15, 2025.

In July 2025, a class 2 resubmission of tab-cel’s BLA was initiated by Atara Biotherapeutics, developer and sponsor of tab-cel, after resolution of manufacturing issues cited in the first CRL. This BLA was again accepted and granted priority review by the FDA.

According to Atara, the latest CRL stated that the FDA is unable to approve the BLA in its present form given the design, conduct, and analysis of the phase 3 ALLELE study (NCT03394365), which formed the basis for BLA submission. The FDA deemed the study as no longer adequate to provide evidence of effectiveness for accelerated approval, specifically citing issues with confounding.

“We are surprised and disappointed by this FDA decision for [patients with] EBV+ PTLD who have a significant unmet need, highlighted by tabelecleucel’s [o]rphan [d]rug designation and by the granting of [b]reakthrough status at the time we submitted the ALLELE primary data,” said Cokey Nguyen, CEO of Atara Biotherapeutics, in a news release.¹ “The issues highlighted in the CRL were issues Atara and the FDA aligned on in previous reviews or communications. We had aligned with the agency to accept an [a]ccelerated [a]pproval and to perform a postmarketing confirmatory study to support full approval. We proceeded with the BLA submission on this basis and continued all remediation efforts after the resubmission in 2025, in full reliance of the confirmation provided by the FDA. We strongly believe that [tab-cel] can bring substantial benefit to patients [with PTLD] and look forward to addressing the concerns of the FDA clinical review team newly in place alongside our partners.”

Tab-Cel’s Regulatory Course

Having earned FDA orphan drug and breakthrough therapy designations for lymphoproliferative disorders (LPDs) early in its development course, tab-cel’s regulatory pathway has been marked by promising milestones; at the same time, it has encountered numerous setbacks.

In July 2024, the FDA accepted and granted priority review to the initial BLA of tab-cel seeking approval in this indication, setting a Prescription Drug User Fee Act (PDUFA) target action date of January 15, 2025.

On this date, the FDA issued a complete response letter (CRL) to the BLA, citing issues with a third-party manufacturing facility. No issues were identified regarding the clinical efficacy or safety data nor manufacturing process. As a result, the FDA placed a clinical hold on the investigational new drug (IND) application of tab-cel, eventually lifting the hold by May 2025 and enabling BLA resubmission in July 2025.

Shortly thereafter, Atara Biotherapeutics transferred tab-cel’s IND to partner Pierre Fabre Pharmaceuticals to assume global clinical development responsibility of tab-cel.

While tab-cel is approved in Europe, the FDA’s recent decision highlights ongoing hurdles in bringing a therapy for this rare, aggressive malignancy to US patients, who continue to face a significant unmet medical need.

Clinical Data and Further Development

Data from the phase 3 ALLELE study formed the basis for the BLA submission, which evaluated the efficacy and safety of tab-cel in patients with EBV+ PTLD who have relapsed or are refractory to rituximab (Rituxan) after allogeneic hematopoietic stem cell transplant (HSCT) or rituximab with or without chemotherapy after solid organ transplant (SOT).²

The pivotal data reported a statistically significant objective response rate (ORR) of 48.8% (P <.0001) at the time of BLA acceptance.³ In previous reports, an overall ORR of 50.7% (95% CI, 38.9%–62.4%) was achieved, with ORRs of 51% (95% CI, 36.3%–65.6%) in the SOT cohort and 50% (95% CI, 29.9%–70.1%) in the HSCT cohort.⁴

Tab-cel’s safety profile was also noted to be consistent with prior reports. Among observations in these earlier reports were the absence of cytokine release syndrome, infusion reactions, and graft-vs-host disease. Serious treatment-emergent events (TEAEs) occurred in 65.4% of the HSCT cohort and 61.2% of the SOT cohort, with fatal TEAEs seen in 19.2% and 18.4%, respectively.

The randomized, open-label, multicenter ALLELE study remains ongoing and is open for enrollment at various global sites, which will provide further confirmatory evidence about tab-cel’s long-term performance in this patient population.

Additionally, efforts are underway to expand tab-cel’s therapeutic potential across a broader spectrum of EBV-associated diseases, including EBV+ LPD, EBV+ acquired immunodeficiency LPD, EBV+ PTLD, and EBV+ sarcomas. A single-arm, multicenter, multicohort phase 2 study (NCT04554914), launched in 2021 and estimated to conclude by 2028, is recruiting a total of approximately 190 patients globally for efficacy and safety evaluations of tab-cel.

REFERENCES

1. Atara Biotherapeutics provides regulatory and business update on EBVALLO™ (tabelecleucel). News release. Atara Biotherapeutics. January 12, 2026. Accessed January 13, 2026. https://tinyurl.com/3t23dshm

2. A phase 3 study of tabelecleucel for participants with Epstein–Barr virus–associated post-transplant lymphoproliferative disease after failure with rituximab or rituximab and chemotherapy (ALLELE). ClinicalTrials.gov. Updated October 31, 2025. Accessed December 4, 2025. https://www.clinicaltrials.gov/study/NCT03394365

3. Atara Biotherapeutics announces U.S. FDA acceptance and priority review of the biologics license application for tabelecleucel (tab-cel®) for the treatment of Epstein-Barr virus positive post-transplant lymphoproliferative disease. News release. Atara Biotherapeutics. Published July 24, 2025. Accessed November 10, 2025. https://tinyurl.com/3m782yxb

4. Ghobadi A, Baiocchi R, Beitinjaneh AM, et al. Updated clinical results: A multicenter, open-label, phase 3 study of tabelecleucel for solid organ or allogeneic hematopoietic cell transplant recipients with Epstein–Barr virus-driven post-transplant lymphoproliferative disease after failure of rituximab or rituximab plus chemotherapy. Blood. 2024;144(Supplement 1):70-70. doi:10.1182/blood-2024-198159