Darvadstrocel (1) – Alofisel®

Adult patients with inactive or minorly active luminal Crohn’s disease with complex perianal fistulas who have responded inadequately to at least one conventional or biologic therapy

• For darvadstrocel, there is a non-quantifiable additional benefit in the treatment of complex perianal fistulas in adult patients with non-active or minorly active luminal Crohn’s disease, where the fistulas have responded inadequately to at least one conventional or biological therapy.
• Due to the limitations in the collection and analysis of endpoints in the study, as well as the overall limited evidence base and the lack of long-term results, the G-BA classifies the extent of the additional benefit for darvadstrocel, based on the criteria in Section 5(7) of the AM-NutzenV, taking into account the severity of the condition, the written submissions and the oral hearing, as non-quantifiable.
• There is an additional benefit, but it is non-quantifiable because the scientific evidence base does not currently permit a quantifiable statement on the extent of the additional benefit for patient-relevant endpoints.
• mortality
  • In the ADMIRE-CD study, mortality was recorded as a safety endpoint as part of the adverse event monitoring. No deaths were reported up to week 52.
• Morbidity – Remission – Clinical remission and time to clinical remission
  • Clinical remission – defined as the closure of all treated external fistula openings, as assessed by clinical examination, which were secreting upon gentle finger compression at the start of the study – was assessed by the investigator during a clinical examination.
  • In the ADMIRE-CD trial, at week 24, more patients in the Darvadstrocel arm achieved clinical remission of the treated perianal fistulas than in the placebo arm; this difference is not statistically significant (53.3% vs. 41%; RR: 1.30 (95% CI [0.97; 1.74], p = 0.064).
  • At the data cut-off at week 52, however, there was a statistically significant advantage in favour of darvadstrocel for the endpoint of clinical remission (57% vs. 40%; RR: 1.43 (95% CI [1.07; 1.90], p = 0.014).
  • The median time to (first) achievement of clinical remission was 6.7 weeks in the darvadstrocel arm, compared with 14.6 weeks, and was shorter than in the placebo control arm at both the data cut-off at week 24 and at week 52.
  • By week 24, a total of 76.6% of patients in the intervention group and 59.0% of patients in the placebo group had achieved clinical remission at least once (HR = 0.57; 95% CI [0.41; 0.79]). This difference between the treatment arms persisted at week 52 (80.4% vs. 65.7%; HR = 0.58; 95% CI [0.42; 0.80]).
  • The results should be interpreted with caution due to existing limitations in the assessment of clinical remission (clinical examination using gentle finger compression: a subjective examination method lacking standardisation; potential for over- or under-assessment of fistula closure; internal branches and the more proximal sections of the fistula cannot be assessed) are subject to considerable uncertainty.
• Health-related quality of life – Inflammatory Bowel Disease Questionnaire (IBDQ)
  • Overall, the average total score improved by 3.81 points (SD: 25.53) in the darvadstrocel arm and by 4.01 points (SD: 25.56) in the placebo arm at week 24 compared with baseline. The differences between the groups are not statistically significant for either the total score or the four dimensions.
  • Due to the minor response rates resulting from the high dropout rates in both study arms, there are also significant methodological limitations regarding the quality of life results, which preclude a definitive assessment.
• Side effects
  • Neither the number of patients with AEs, nor the number of patients with severe AEs, severe SAEs or therapy discontinuations due to AEs differed statistically significantly between treatment with darvadstrocel and the comparator treatment up to week 52.
  • When interpreting the results on side effects, it should be noted that some endpoints in the ‘side effects’ category reflect the underlying symptoms of patients with perianal fistulas in Crohn’s disease and therefore overlap with the ‘morbidity’ category.
• Overall assessment
  • In summary, there were no statistically significant differences between the comparison arms in the endpoint categories of quality of life and side effects.
  • In the morbidity category, there are statistically significant advantages in favour of darvadstrocel for the endpoints relating to remission (clinical remission, time to clinical remission, recurrence-free period following prior clinical remission) and disease symptoms (PDAI).
  • The statistically significant advantages in favour of darvadstrocel demonstrated with regard to clinical remission and symptoms as measured by the PDAI cannot be assessed with sufficient certainty in the overall analysis due to significant limitations in their extent.
  • The available results in favour of Darvadstrocel suggest – despite consistent, statistically significant effect sizes – a time lag in the onset of efficacy, defined as closure of the external fistula opening or the cessation of secretion, between the patient-reported perspective (PDAI) and the clinical assessment by a blinded investigator (clinical remission).
  • Against this background, it is not possible to quantify the extent of the additional benefit.

Courtesy translation only, please refer to the German original.