FDA Lifts Clinical Hold on Tabelecleucel in EBV+ Lymphoproliferative Disease

The FDA originally placed a clinical hold on the program for tab-cel in January 2025 due to Good Manufacturing Practice (GMP) compliance issues associated with a pre-license inspection of a third-party manufacturing facility.

The FDA has lifted its clinical hold on the investigational new drug applications for tabelecleucel (tab-cel; Ebvallo) as a treatment for those with Epstein-Barr Virus (EBV)–positive post-transplant lymphoproliferative disease (PTLD), according to a news release from the developer, Atara Biotherapeutics, Inc.¹

The FDA originally placed a clinical hold on the program for tab-cel in January 2025 due to Good Manufacturing Practice (GMP) compliance issues associated with a pre-license inspection of a third-party manufacturing facility.² The agency highlighted these compliance issues in a complete response letter (CRL) for tab-cel issued earlier in January 2025.³ The CRL did not describe any deficiencies associated with the manufacturing process, clinical efficacy, or safety of tab-cel, and the agency did not request any additional clinical trials to support the agent’s approvability.

The FDA lifted the hold after reviewing additional data on the finished drug product. With the lifted hold, investigators may resume the phase 3 ALLELE trial (NCT03394365) evaluating tab-cel for patients with EBV-positive PTLD. Additionally, investigators can restart their assessment of the agent among patients with EBV-associated diseases as part of a multi-cohort phase 2 study (NCT04554914).

“We are very pleased to have addressed the FDA’s questions, and this has enabled the FDA to lift the clinical holds. We are working closely with our partner Pierre Fabre Laboratories and our clinical trial sites, and anticipate resuming enrollment and treatment of patients as soon as possible,” Cokey Nguyen, PhD, president and chief executive officer of Atara, stated in the press release.¹

The agency has also arranged a date with developers to discuss plans for addressing the issues associated with the CRL as part of a Type A meeting. Additionally, developers will speak with the agency about a path for resubmitting the biological license application (BLA) seeking tab-cel’s approval.

“We are pleased that the FDA has granted our request for a Type A meeting and hope to gain clarity on the timing for resubmitting the tab-cel BLA for review by the FDA,” Nguyen added.¹

Supporting data for the BLA came from the phase 3 ALLELE trial. Investigators presented updated findings from the ALLELE trial at the 2024 American Society of Hematology (ASH) Annual Meeting and Exposition.⁴

At the time of analysis, tab-cel produced an overall response rate (ORR) of 50.7% (95% CI, 38.9%-62.4%) across all patients (n = 38/75). The ORR was 51.0% (95% CI, 36.3%-65.6%) among patients (n = 25/49) who received prior solid organ transplant (SOT) and 50.0% (95% CI, 29.9%-70.1%) for those with prior hematopoietic stem cell transplant (n = 13/26; HCT).

Serious treatment-emergent adverse effects (TEAEs) affected 65.4% and 61.2% of patients with prior HCT and SOT, respectively. In each respective group, 19.2% and 18.4% of patients experienced fatal TEAEs. No fatal TEAEs were related to study treatment.

In the ALLELE trial, patients received 2 x 10⁶ cells/kg of tabelecleucel on days 1, 8, and 15 in each 35-day cycle for up to 5 years. The trial’s primary end point was ORR.⁵ Secondary end points included duration of response, time to response, time to best response, overall survival, and rates of allograft loss or rejection episodes.

Patients of any age with prior SOT of the kidney, liver, heart, lung, pancreas, small bowel, or any combination of these organs, or prior allogeneic HCT, as well as a diagnosis of locally assessed EBV-positive PTLD proven via biopsy, were eligible for enrollment on the study.

References

1. Atara Biotherapeutics provides regulatory updates on EBVALLO™ (tabelecleucel). News release. Atara Biotherapeutics, Inc. May 5, 2025. Accessed May 6, 2025. https://tinyurl.com/3cekvud5
2. Atara Biotherapeutics provides update on clinical programs related to EBVALLO™ (tabelecleucel) and ATA3219. News release. Atara Biotherapeutics, Inc. January 21, 2025. Accessed May 6, 2025. https://tinyurl.com/3yr7xpy2
3. Atara Biotherapeutics provides regulatory and business update on EBVALLO™ (tabelecleucel). News release. Atara Biotherapeutics, Inc. January 16, 2025. Accessed May 6, 2025. https://tinyurl.com/2sutywn9
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(suppl 1):70. doi:10.1182/blood-2024-198159
5. Tabelecleucel for solid organ or allogeneic hematopoietic cell transplant participants with Epstein-Barr Virus-associated post-transplant lymphoproliferative disease (EBV+ PTLD) after failure of rituximab or rituximab and chemotherapy (ALLELE). ClinicalTrials.gov. Updated April 18, 2025. Accessed May 6, 2025. https://tinyurl.com/4mhy57c2