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RWE Decision Alert

The Spanish AEMPS Approves EBVALLO®, Supported by Effectiveness and Safety Data from RWE


On February 8, 2024, the Spanish Agency for Medicines and Health Products/Agencia Española de Medicamentos y Productos Sanitarios (AEMPS) approved EBVALLO® (tabelecleucel) for the treatment of lymphoproliferative disorders, leveraging effectiveness and safety data from early access programs (EAPs) and an historical control arm supporting the single-arm pivotal study.

EBVALLO, manufactured by Pierre Fabre Medicament, received marketing authorization on December 16, 2022 from the European Medicines Agency (EMA) for the treatment of adult and pediatric patients two years of age and older with relapsed or refractory Epstein-Barr virus-positive post-transplant lymphoproliferative disease (EBV + PTLD) who have received at least one prior therapy.

EBV + PTLD is a rare disease and aggressive hematological malignancy that can occur after a solid organ transplant (SOT) or hematopoietic cell transplant (HCT) due to immunosuppression that is induced to prevent graft rejection. In 2023, the estimated incidence of EBV+PTLD in Spain was 1.8% of the HCT and 1.7% of the SOT (Sureda et al. 2023). The global prevalence of PTLD-HCT was 0.005 per 10,000 people, and that of patients with PTLD-SOT was 0.16 per 10,000 people.

The efficacy of EBVALLO monotherapy treatment is primarily based on the results of the pivotal ALLELE study, an open, multicenter, single-arm study in adult and pediatric patients estimated to be completed in 2027. The findings from this pivotal study were supplemented by data from three supporting single-arm studies, as well as real-world evidence (RWE) from patients treated with EBVALLO within the EAPs, compassionate use programs, and external comparison. After the ALLELE study concludes in 2027, further data on the effectiveness of EBVALLO in both adult and pediatric patients will be gathered through a planned post-authorization observational study that aims to characterize the real-world effectiveness of EBVALLO.

Clinical Effectiveness from RWE

A total of 66 patients were treated with EBVALLO across two EAPs (ATA129-EAP-901, ATA129-SPU).

  • In ATA129-EAP-901, a total of 46 patients were enrolled, 18 of whom had EBV+PTLD (10 post-HCT patients, 8 post-SOT). The objective response rate (ORR) was 72.2% in the population as a whole (n = 18), 70.0% in the post-HCT cohort (n = 10), and 75.0% in the post-SOT cohort (n = 8).
  • In ATA-129-SPU, 48 EBV+PTLD patients were enrolled (19 after HCT and 29 after SOT). In the population as a whole, the ORR was 43.8%, in particular, 26.3% in the HCT cohort, and 55.2% in the SOT cohort.

Additionally, the results of the single-arm ALLELE study were compared with a historical external control arm: Study ATA129-RS002. In Study ATA129-RS002, data was collected retrospectively over 20 years, however, only those diagnosed between 2010-2018 were included in the analyses for AEMPS. This analysis aimed at comparing, using a propensity score matching methodology, the overall survival (OS) of patients treated with EBVALLO in the pivotal ALLELE study with the control arm of subjects who received standard-of-care treatment for EBV + PTLD. EBVALLO demonstrated a significant OS benefit compared to the historical control with a risk ratio, HR unadjusted of 0.46, and an adjusted HR of 0.34 compared with the historical cohort.

The AEMPS considered that the efficacy results from all clinical studies and EAPs are favorable for treatment with EBVALLO, compared to historical data, for patients with EBV + PTLD. Nonetheless, these data were considered supportive evidence, reflecting the known limitations of retrospective studies compared to randomized controlled trials.

Clinical Safety from RWE

The evaluation of safety was based on data for all subjects ever treated with at least one dose of EBVALLO over more than 20 years. The pooled data was derived from ALLELE, three supporting studies, and two EAP studies including an overall population of 340 patients (adults, pediatric, and adolescent patients) of which 202 were recruited in clinical studies and 138 were exposed to EBVALLO through EAPs.

In the safety data collected through EAPs about treatment-emergent adverse events (AEs) leading to study treatment discontinuation and serious fatal AEs, none of the serious fatal AEs were considered related to treatment, except for one subject in the EAP (HCT cohort) who had two severe grade five AEs (enterococcal infection and bacteremia). The EAPs also collected data on infusion-related reactions, cytokine release syndrome, immunological events, and graft-versus-host disease.

Limitations and Future RWE Collection

Despite a positive outcome, the AEMPS considered that the interpretation of EBVALLO´s effectiveness and safety had a certain degree of uncertainty, due to limitations associated with the overall study design, namely a single-arm trial lacking an adequate control group. Additional limitations highlighted by AEMPS included the small sample size of the single-arm studies, the retrospective assignment of the groups (C-HCT, C-SOT), and inconsistency in dosing and in the duration of follow-up; these limitations contributed to a certain degree of bias. The design of the EAPs was criticized for its perceived simplified data collection approach and reduced assessment requirements, hindering the comparison with the single-arm trial. Despite the limitations, the AEMPS concluded that the efficacy results of the clinical trials and EAPs indicated a positive response for EBVALLO treatment when compared with the historical control. The AEMPS is expecting to receive additional evidence from the continuous recruitment to the pivotal trial and the post-authorization study planned to describe the safety and efficacy of EBVALLO in patients with ELPT-EBV+ in a real-world setting.

Author: Mrunmayee Godbole, Associate Consultant HEOR


  1. Informe De Posicionamiento Terapéutico – AEMPS EBVALLO (tabelecleucel) 
  2. EMA Assessment Report (EPAR) of EBVALLO (tabelecleucel)
  3. Expanded Access Protocol for EBVALLO (tabelecleucel)
  4. Sureda A, Simon Josè Antonio P, Cristina H. PB2421: EPSTEIN-BARR VIRUS-ASSOCIATED POST-TRANSPLANT LYMPHOPROLIFERATIVE DISEASE: RESULTS OF A DELPHI STUDY IN SPAIN. Hemasphere. 2023;7(Suppl):e69730b8. doi:10.1097/01.HS9.0000976392.69730.b8
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RWE Decision Alerts provide subscribers with timely analyses of published reports from HAS, AEMPS, NICE, EMA, and the FDA where RWE is used to support HTA and regulatory decision-making. We identify if a submission included RWE and assess the value of the RWE submitted.

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