FDA Issues CRL for Atara Biotherapeutics’ BLA for T-Cell Immunotherapy Tabelecleucel for EBV+ PTLD
The CRL was related inspection of a third-party manufacturer rather than any efficacy or safety concerns regarding the product itself.
This is a developing story and will be updated with new information as it becomes available.
The FDA has issued a complete response letter (CRL) to Atara Biotherapeutics regarding its biologics license application (BLA) for tabelecleucel (tab-cel, also known as Ebvallo), an allogeneic Epstein-Barr virus (EBV)-specific T-cell immunotherapy, which is under evaluation for the treatment of patients with relapsed/refractory EBV-positive post-transplant lymphoproliferative disease (EBV+ PTLD).1
Notably, the CRL was related to issues with a standard prelicense inspection of a third-party manufacturer for tab-cel rather than to any concerns regarding the efficacy and safety data contained within the BLA. The manufacturing process itself was not implicated, and the FDA has not requested additional clinical trials for tab-cel.
“We are working closely with our partner Pierre Fabre Laboratories, the FDA, and the third-party manufacturer to address the feedback to support marketing approval for EBVALLO,” Cokey Nguyen, PhD, the president and chief executive officer of Atara, said in a statement.1 “Once the third-party manufacturer GMP compliance issues have been adequately addressed, we will file for a resubmission, which we would expect to be potentially approved within 6 months of resubmission. Atara and its partner Pierre Fabre remain confident in the potential of Ebvallo and are committed to bringing this potential first-in-class medicine to United States patients with EBV+ PTLD who have limited treatment options and significant unmet need.”
The BLA was submitted by Atara to the agency in May 2024.2 The submission was supported by data from the phase 3 ALLELE clinical trial (NCT03394365), updated results from which were recently presented at the 66th American Society of Hematology (ASH) Annual Meeting, held December 7-10, 2024, in San Diego, California.2,3 In the open-label study, the overall response rate (ORR) with tab-cel was 50.7%, which included a complete response (CR) rate of 28.0%. The median time to response was 1.1 months and the estimated duration of response was 23.0 months. Median progression-free survival (PFS) was 23.9 months among patients who responded, with a 12-month PFS rate of 74.2%. The median overall survival (OS) for all patients treated was 18.4 months, with a 55.7% 12-month OS rate.
"For treatment-emergent adverse events of special interest, there was no tumor flare, no cytokine release syndrome, no immune effector cell-associated neurotoxicity syndrome," ALLELE lead investigator Armin Ghobadi, MD, Division of Oncology, Washington University School of Medicine, said during his presentation of the results at ASH.2 "Graft-versus-host disease happened in 2 patients, both in patients who received prior transplant. Bone marrow/organ rejection was seen in 3 patients, all were treated and it was resolved in these patients."
Over the past few years, tab-cel has previously been approved in the Europe Union, the United Kingdom, and Switzerland for the treatment of relapsed/refractory EBV+ PTLD in patients who have received at least 1 prior therapy.2 In these jurisdictions, it is approved for patients aged 2 years and older under the name Ebvallo. Atara has noted that a manufacturing facility located in Thousand Oaks, California, operated by FUJIFILM Diosynth Biotechnologies, a separate third-party manufacturer from the one identified in the CRL, recently received approval from the European Medicines Agency to manufacture tab-cel.1
“We are disappointed by the delay and are willing to work with Atara on appropriate next steps to bring Ebvallo to US patients that suffer from this deadly rare disease with no approved therapies,” Eric Ducournau, the CEO of Pierre Fabre Laboratories, added to Nguyen's statement.1
REFERENCES
1. Atara Biotherapeutics provides regulatory and business update on EBVALLO (tabelecleucel). News release. Atara Biotherapeutics, Inc. January 16, 2024. Accessed January 16, 2024. https://investors.atarabio.com/news-events/press-releases/detail/367/atara-biotherapeutics-provides-regulatory-and-business
2. Atara Biotherapeutics Submits Tabelecleucel (Tab-cel®) Biologics License Application for Treatment of Epstein-Barr Virus Positive Post-Transplant Lymphoproliferative Disease with U.S. FDA. News release. Atara Biotherapeutics. May 20, 2024. Accessed January 15, 2024. https://www.businesswire.com/news/home/20240520985176/en/Atara-Biotherapeutics-Submits-Tabelecleucel-Tab-cel%C2%AE-Biologics-License-Application-for-Treatment-of-Epstein-Barr-Virus-Positive-Post-Transplant-Lymphoproliferative-Disease-with-U.S.-FDA
3. 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. Presented at: ASH 2024 Annual Meeting & Exposition. December 7-10; San Diego, CA. Abstract #70.
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