Tabelecleucel BLA Receives FDA CRL in Pretreated EBV+ Post-Transplant Lymphoproliferative Disease

The FDA has issued a complete response letter (CRL) to the biologics license application (BLA) seeking approval of tabelecleucel (Ebvallo) monotherapy in the treatment of adult and pediatric patients at least 2 years of age with Epstein-Barr virus (EBV)–positive post-transplant lymphoproliferative disease (PTLD), who have received at least 1 prior therapy, including an anti-CD20 containing regimen.¹

The CRL was related to observations that were reported as part of a standard prelicense inspection of a third-party manufacturing facility for tabelecleucel. No deficiencies related to manufacturing, clinical efficacy, or safety data in the BLA were identified. Additionally, the regulatory agency did not request any additional clinical studies to support the potential approval of the agent.

In July 2024, the FDA accepted the BLA seeking the approval of tabelecleucel monotherapy in this population.² The application, which was granted priority review and was given a Prescription Drug User Fee Act target action date of January 15, 2025, was supported by findings from the pivotal phase 3 ALLELE trial (NCT03394365), which examined tabelecleucel in patients with EBV-positive PTLD who were refractory to or relapsed following treatment with rituximab (Rituxan), with or without chemotherapy, following hematopoietic stem cell transplantation (HSCT) or solid organ transplant.³

“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 tabelecleucel,” Cokey Nguyen, PhD, president and CEO of Atara, stated in a news release.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 six months of resubmission. Atara and its partner Pierre Fabre remain confident in the potential of tabelecleucel and are committed to bringing this potential first-in-class medicine to US patients with EBV-positive PTLD who have limited treatment options and significant unmet need.”

ALLELE was a global, multicenter, open-label study that enrolled patients of any age with biopsy-proven EBV-positive post-transplant PTLD that was relapsed/refractory to rituximab after HSCT and rituximab with or without chemotherapy following solid organ transplant. Patients had an ECOG performance status of 3 or less. They received intravenous tabelecleucel at a dose of 2.0 x 10⁶ cells/kg on days 1, 8, and 15, and underwent clinical and radiographic assessment on approximately day 28.

After treatment, disease assessment occurred every 3 months for up to 24 months and survival status assessment occurred every 6 months for up to 5 years. The primary end point was overall response rate (ORR); key secondary end points included time to response (TTR) and time to best response, overall survival (OS) in responders vs nonresponders, progression-free survival (PFS) in responders, and rates of allograft loss/rejection episodes.

Updated data from ALLELE presented during the 2024 ASH Annual Meeting & Exposition demonstrated that patients who received tabelecleucel (n = 75) achieved an ORR of 50.7% (95% CI, 38.9%-62.4%), including a 28.0% complete response rate. The median TTR was 1.1 months (range, 0.6-9.0) and the estimated median duration of response was 23.0 months (95% CI, 12.1-not estimable [NE]). The median PFS was 23.9 months, with a 12-month PFS rate of 74.2%, and the median OS was 18.4 months (95% CI, 6.9-NE), with a 12-month OS rate of 55.7%.

Safety findings revealed that any-grade treatment-emergent adverse effects (TEAEs) were reported in 62.7% of patients, 8.0% of which were treatment related. There were no instances of tumor flare reaction, infusion-related reaction, cytokine release syndrome, bone marrow rejection, immune effector cell–associated neurotoxicity syndrome, immunogenicity, or infectious disease transmission. None of the fatal TEAEs that occurred were deemed to be related to tabelecleucel.

“We are disappointed by the delay and are willing to work with Atara on appropriate next steps to bring tabelecleucel to US patients that suffer from this deadly rare disease with no approved therapies,” Eric Ducournau, CEO of Pierre Fabre Laboratories, added in the news release.¹

The allogeneic, EBV-specific T-cell immunotherapy also received marketing authorization from the European Commission in December 2022. Another third-party manufacturer of tabelecleucel, FUJIFILM Diosynth Biotechnologies, was recently approved by the European Medicines Agency to manufacture tabelecleucel.

References

1. Atara Biotherapeutics provides regulatory and business update on EBVALLO (tabelecleucel). News release. Atara Biotherapeutics. January 16, 2025. Accessed January 16, 2025. https://investors.atarabio.com/news-events/press-releases/detail/367/atara-biotherapeutics-provides-regulatory-and-business
2. Atara Biotherapeutics announces US 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, Inc. July 17, 2024. Accessed January 16, 2025. https://investors.atarabio.com/news-events/press-releases/detail/356/atara-biotherapeutics-announces-u-s-fda-acceptance-and
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. Blood. 2024;144(suppl 1):70. doi:10.1182/blood-2024-198159