Caplacizumab (1) – Cablivi®

• Clinical trials
  • The benefit assessment is based on the Phase III HERCULES (ALX0681-C301) study, which was used to support marketing authorisation and investigated the efficacy and safety of caplacizumab in patients with acquired thrombotic thrombocytopenic purpura compared with placebo.
  • The TITAN study (ALX-0681-2.1/10) is a randomised, single-blind, placebo-controlled Phase II trial investigating the efficacy and safety of caplacizumab as an adjunctive treatment in patients with acquired thrombotic thrombocytopenic purpura (aTTP).

Adults suffering from an episode of acquired thrombotic thrombocytopenic purpura (aTTP)

• Consequently, on the basis of the criteria set out in Section 5(7) of the AM-NutzenV, the G-BA recommends caplacizumab for the treatment of adults suffering from an episode of acquired thrombotic thrombocytopenic purpura (acquired thrombotic thrombocytopenic purpura, aTTP), in combination with plasmapheresis and immunosuppression, taking into account the severity of the disease and the therapeutic objective, a non-quantifiable additional benefit.
• mortality
  • Overall mortality and aTTP-related mortality are patient-relevant endpoints and are numerically identical in the present study.
  • Treatment with caplacizumab did not result in a statistically significant prolongation of survival in the HERCULES registration trial.
  • In the mortality endpoint category, based on the results of the HERCULES trial, there is neither an advantage nor a disadvantage for caplacizumab compared with placebo.
• Morbidity – Combined endpoints comprising aTTP-related mortality, aTTP recurrences (exacerbation or relapse) or serious thromboembolic events, as well as aTTP-related mortality or serious thromboembolic events
  • The composite endpoint planned in the study comprises the individual components of aTTP-related mortality, aTTP recurrence (exacerbation or relapse) or serious thromboembolic events, and thus consists of individual components of varying severity.
  • A statistically significant advantage for caplacizumab compared with the control arm was observed during the double-blind treatment phase (relative risk (RR): 0.257 [95% confidence interval (CI): 0.122; 0.475]; p-value <0.0001)] as well as when considering the entire study duration (RR: 0.400 [95% CI: 0.226; 0.665]; p-value 0.0002)].
  • The results for the combined endpoints are not used in the assessment of additional benefit, as the advantages are already factored into the benefit assessment via the result for the recurrence endpoint.
• Morbidity – Recurrences (exacerbations and relapses)
  • In the HERCULES trial, an exacerbation was defined as recurrent thrombocytopenia following an initial recovery in platelet count, occurring within 30 days of the end of daily plasma exchange, which required the resumption of daily plasma exchange.
  • Relapse was operationalised as recurrent thrombocytopenia following an initial recovery in platelet count, occurring more than 30 days after the end of daily plasma exchange, which requires the resumption of daily plasma exchange.
  • There was a statistically significant advantage in favour of caplacizumab in terms of the number of exacerbations during the double-blind treatment phase (RR: 0.11 [95% confidence interval (CI): 0.03; 0.34]; p-value < 0.001)] as well as for the number of relapses over the entire study duration (p-value 0.0004).
  • This difference is considered clinically relevant.
• Morbidity – Serious thromboembolic events
  • According to the operational definition, serious thromboembolic events include, for example, myocardial infarction, cerebrovascular events, pulmonary embolism or confirmed deep vein thrombosis.
  • The event rates for the intervention arm, when compared with the placebo arm, show neither an advantage nor a disadvantage for caplacizumab compared with the comparator therapy.
• quality of life
  • No data on health-related quality of life were collected in the HERCULES study.
• Side effects – adverse events (AEs), therapy discontinuations due to adverse events (AEs), severe AEs, serious adverse events (SAEs), AEs of particular interest
  • With regard to the double-blind treatment phase of the HERCULES study, at least one adverse event occurred in 95.8% of patients in the caplacizumab arm and 95.9% of the comparator group.
  • 7.0% of patients in the caplacizumab group and 12.3% in the comparator group discontinued treatment due to adverse events.
  • When considering the double-blind treatment phase, no statistically significant differences were observed between the study arms in the overall rate of therapy discontinuation due to AEs.
  • With regard to severe AEs, it is unclear how the severity was operationalised.
  • Overall, the endpoints are not interpretable, partly due to the lack of statistical data.
  • In accordance with the study protocol, TTP relapses had to be reported as SAE.
  • The SAE endpoint is therefore not meaningful and cannot be taken into account for the assessment.
  • The results submitted by the pharmaceutical manufacturer on bleeding events as AEs of particular interest via the SMQ ‘Haemorrhage’ include TTP episodes.
  • The endpoint cannot therefore be used for the assessment of additional benefit.
  • For the endpoint category ‘side effects’, there is no statistically significant difference in therapy discontinuations due to AEs; consequently, neither an advantage nor a disadvantage for caplacizumab can be inferred for this endpoint.
• Overall assessment
  • Due to the study design, there are uncertainties regarding the interpretation of the results for the entire study period.
  • In the ‘mortality’ endpoint category, based on the results of the HERCULES study, there is neither an advantage nor a disadvantage for caplacizumab compared with placebo.
  • In the morbidity category, the endpoint of relapses (exacerbations and relapses) shows a statistically significant advantage for caplacizumab over the entire study duration.
  • The advantage of caplacizumab with regard to recurrences is classified as clinically relevant.
  • However, with regard to morbidity, it remains unclear overall what effect treatment with caplacizumab has on patients’ clinical symptoms, as no usable results have been presented regarding either symptoms or the long-term consequences of treatment.
  • For the endpoint category of side effects, there is no statistically significant difference in therapy discontinuations due to AEs, meaning that neither an advantage nor a disadvantage for caplacizumab can be inferred for this endpoint.
  • For the remaining endpoints in this category, the data are not interpretable.
  • Furthermore, no data on health-related quality of life were collected as part of the HERCULES study.

Courtesy translation only, please refer to the German original.