Givosiran (1) – Givlaari®

Patients aged 12 years and over with acute hepatic porphyria (AHP)

• Overall, there is an indication of a considerable additional benefit of Givosiran compared with placebo.
• mortality
  • Deaths were recorded as adverse events (AEs) in the ENVISION trial. No deaths occurred during the trial period.
• Morbidity – Acute porphyria attacks
  • The occurrence of a porphyria attack is a patient-relevant event.
  • During the 6-month treatment phase, 317 acute porphyria attacks occurred in 40 patients in the placebo arm and 109 acute porphyria attacks in 30 patients in the givosiran arm.
  • The number of attacks and the calculated annual attack rate differed statistically significantly between the treatment arms in favour of givosiran.
  • The number of patients without an attack (attack-free status) also differed statistically significantly between the treatment arms in favour of givosiran.
  • In detail, with regard to the individual attack components, a statistically significant difference in the number of attacks was observed between the treatment arms in favour of givosiran for porphyria attacks requiring emergency treatment.
  • The number of porphyria attacks requiring hospitalisation or the administration of intravenous haemin at home did not differ significantly between the treatment arms.
• Morbidity – pain intensity as measured by item 3 of the BPI-SF (Brief Pain Inventory – Short Form)
  • This endpoint is taken into account despite the remaining uncertainties in the benefit assessment.
  • There is no statistically significant difference between the treatment arms in the difference in mean changes. The AUC changes on average (SEM) by –12.06 (4.34) in the givosiran arm and by –0.27 (4.46) in the placebo arm. The difference is not statistically significant (mean difference [95% CI]: -11.80 [-24.15; 0.56]; p = 0.0610).
• Morbidity – Fatigue assessed using Item 3 of the BFI (Brief Fatigue Inventory)
  • This endpoint is taken into account despite the remaining uncertainties in the benefit assessment.
  • There is no statistically significant difference between the treatment arms in the difference in mean changes. The AUC changes on average (SEM) by -10.46 (4.35) in the givosiran arm and by -3.68 (4.46) in the placebo arm. The difference is not statistically significant (mean difference [95% CI]: 6.79 [-19.09; 5.51]; p = 0.2759).
• Quality of life – SF-12
  • The changes from baseline to month 6 were statistically significantly greater in the PCS in the givosiran arm than in the placebo arm.
  • As Hedges’ g (0.46 [0.05; 0.88]) does not lie entirely outside the irrelevance range of −0.2 to 0.2, it cannot be concluded with sufficient certainty that this represents a clinically relevant effect. This result is not taken into account in the assessment of additional benefit.
  • At month 6, there is no statistically significant difference between the treatment arms in the SF-12 MCS.
• Side effects
  • Adverse events occurred in the majority of patients in both study arms.
  • The number of patients with severe AEs and the number of patients with severe unspecified AEs did not differ significantly between the treatment arms; no effect estimator could be calculated for the number of patients who experienced therapy discontinuation or stopped taking the study medication due to an AE.
  • Major differences (≥ 10% in one arm) between the groups were observed in the system organ class ‘General disorders and administration site conditions’, including the preferred terms ‘fever’ and ‘injection site reaction’, as well as in the system organ class ‘Renal and urinary disorders’ with the preferred term ‘Chronic kidney disease’ and in the preferred term ‘Nausea’ (system organ class ‘Gastrointestinal disorders’).
  • With the exception of the preferred term ‘fever’, more events occurred in the givosiran arm in each case. With the exception of the preferred term ‘nausea’, where a statistically significant difference to the detriment of Givosiran was observed, there was no statistically significant difference between the treatment arms, or no effect estimator could be calculated.
• Overall assessment
  • For the treatment of acute hepatic porphyria (AHP) in adults and adolescents aged 12 years and over, the following results are available from the pivotal Phase III registration trial ENVISION (ALN-AS1-003) results on mortality, morbidity, quality of life and side effects from a 6-month randomised, blinded and placebo-controlled study phase.
  • No deaths occurred in the ENVISION study.
  • In the morbidity category, a statistically significant advantage of givosiran over placebo was observed for the clinically relevant endpoint ‘acute porphyria attacks’, both in terms of the number of attacks and the calculated annual attack rate, as well as the number of patients without attacks (absence of attacks). An advantage of Givosiran over Placebo.
  • In detail, with regard to the individual attack components, a statistically significant advantage of givosiran over placebo was observed for porphyria attacks requiring emergency treatment.
  • The results regarding health status, as assessed by patients using the Patient Global Impression of Change, support the finding for the porphyria attack endpoint: an improvement in health status was observed significantly more frequently in the givosiran arm.
  • For the other morbidity endpoints relevant to the assessment – pain intensity, fatigue, nausea and health status as measured by the EQ-5D-VAS – no statistically significant differences were observed between the treatment arms.
  • In the quality of life category, givosiran showed a statistically significant advantage over placebo in the Physical Component Summary (PCS) of the SF-12; however, this cannot be taken into account in the assessment of additional benefit due to uncertain clinical relevance. In the Mental Component Summary (MCS) of the SF-12, there was no statistically significant difference between the treatment arms.
  • In the ‘side effects’ endpoint category, there were no relevant differences in the overall rates between the treatment groups.
  • In summary, the statistically significant and clinically relevant advantages of Givosiran over placebo in the ‘morbidity’ category are, on balance, classified as substantial on the basis of the criteria set out in Section 5(7) of the AM-NutzenV, taking into account the severity of the disease, the written submissions and the oral hearing, are classified as considerable in their extent.

Courtesy translation only, please refer to the German original.