Original Title: Arzneimittel-Richtlinie/Anlage XII: Ivacaftor/Tezacaftor/Elexacaftor (Überschreitung 50 Mio. € Grenze, zystische Fibrose, Kombinationsbehandlung mit Ivacaftor bei Patienten ab 12 Jahren (homozygot bzgl. F508del-Mutation))

Authors' objectives: The Federal Joint Committee [Gemeinsamer Bundesausschuss (G-BA)] has had the legal task of carrying out an (additional) benefit assessment for all newly approved drugs with new active ingredients immediately after market entry (§ 35a SGB V). The result of this assessment is the basis for deciding how much the statutory health insurance pays for a new drug with a new active ingredient. The G-BA was commissioned to carry out the benefit assessment through the Pharmaceuticals Market Reorganisation Act [Gesetz zur Neuordnung des Arzneimittelmarktes (AMNOG)]. In the context of the early benefit assessment of medicinal products containing new active substances, the following rules apply to orphan drugs: According to the legal requirements (§ 35a SGB V), the additional medical benefit of these drugs is already considered to be proven by the approval. The G-BA determines the extent of the additional benefit for orphan drugs that do not exceed a turnover of 50 million Euros in the last twelve calendar months, on the basis of the approval and the studies justifying the approval.

Authors' results and conclusions: Ivacaftor/tezacaftor/elexacaftor is indicated in a combination regimen with ivacaftor 150 mg tablets for the treatment of cystic fibrosis (CF) in patients aged 12 years and older who are homozygous for the F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The benefit assessment of ivacaftor/tezacaftor/elexacaftor plus ivacaftor is based on the pivotal study VX17-445-103, a randomized, controlled, double-blind phase III trial investigating the efficacy and safety of 4 weeks of treatment with IVA/TEZ/ELX plus IVA compared to TEZ/IVA plus IVA in CF, double-blind Phase III study evaluating the efficacy and safety of 4 weeks of treatment with IVA/TEZ/ELX plus IVA compared to TEZ/IVA plus IVA in CF patients 12 years of age and older who are homozygous for the F508del mutation in the CFTR gene. Randomization was performed in a 1:1 ratio, stratified by baseline FEV1% (< 70 vs. ≥ 70%) and age at screening (< 18 vs. ≥ 18 years). A total of 107 study participants ≥ 12 years of age were analyzed in the study arm with triple therapy or in the control arm with TEZ/IVA, depending on the randomization sequence. The FEV1% had to be between ≥ 40 and ≤ 90% at the screening visit. This inclusion criterion was not fully met, as approximately 11% of subjects in the intervention arm and 8% in the control arm had an FEV1% below 40% at baseline. The study consisted of a 28-day screening period, a 28-day run-in period, a 4-week treatment period, and a 28-day safety follow-up. The primary endpoint was defined as the absolute change in FEV1% (one-second capacity) from baseline to week 4. Endpoints used in the benefit assessment were "deaths", "pulmonary exacerbations", "symptomatology measured by the symptom domains of the CFQ-R", "health-related quality of life (CFQ-R)" and "adverse events". Regarding morbidity, statistically significant and clinically relevant effects in favor of the IVA/TEZ/ELX arm are shown for the domain "respiratory system" of the CFQ-R with low bias potential (mean difference 17.4 [95% CI 11.8; 23.0]; p< 0.0001). Regarding the domain "weight problems", statistically significant results in favor of IVA/TEZ/ELX were shown (mean difference 12.5 [95% CI 4.1; 20.9]; p=0.0041), but it cannot be deduced that these are clinically relevant. For the domain "gastrointestinal symptoms" and “pulmonary exacerbations”, there were no statistically significant differences. Regarding quality of life, statistically significant and clinically relevant effects in favor of the IVA/TEZ/ELX arm were found for the 3 domains "physical well-being” (mean difference 11.8 [95% CI 6.5; 17.0]; p< 0.0001), "vitality" (mean difference 12.5 [95% CI 6.0; 19.0]; p=0.0002) and "subjective health assessment" (mean difference 9.5 [95% CI 3.6; 15.4]; p=0.0018) of the CFQ-R with low bias potential. Regarding the domains "Role Functioning", "Social Restrictions" and "Eating Disorders", statistically significant results in favor of IVA/TEZ/ELX were found, but could not be inferred to be clinically relevant. For the domains "Emotional state", "Body image" and "Therapy burden" no statistically significant differences were found. With regard to safety, there were no significant differences between the study arms, although the potential for bias was unclear. The significance of safety is limited by the fact that symptoms of the primary disease were included in the assessment of AEs. Overall, the potential for bias at study level is rated as low. However, the significance of the results is clearly limited by the 4-week treatment duration. Statements on long-term effects of IVA/TEZ/ELX plus IVA compared to TEZ/IVA plus IVA are not possible on the basis of the study.

Project Status: Completed

URL for project: https://www.g-ba.de/bewertungsverfahren/nutzenbewertung/584/#english

Year Published: 2021

URL for published report: https://www.g-ba.de/downloads/39-1464-4711/2021-02-18_AM-RL-XII_Ivacaftor-Tezacaftor-Elexacaftor_D-585_EN.pdf

Requestor: The Federal Joint Committee [Gemeinsamer Bundesausschuss] (G-BA)

URL for additional information: https://www.g-ba.de/downloads/92-975-3965/2020-09-01_Nutzenbewertung-G-BA_Ivacaftor-Tezacaftor-Elexacaftor_D-585.pdf

English language abstract: An English language summary is available

Publication Type: Full HTA

Country: Germany

Organisation Name: The Federal Joint Committee

Contact Address: Gutenbergstr. 13, 10587 Berlin, Germany

Contact Name: Fachberatung Medizin [Department of Medical Consultancy]

Contact Email: Fachberatung-Medizin@g-ba.de

Copyright: https://www.g-ba.de/sys/impressum/