Original Title: Arzneimittel-Richtlinie/Anlage XII: Ivacaftor/Tezacaftor/Elexacaftor (Überschreitung 50 Mio. € Grenze, zystische Fibrose, Kombinationsbehandlung mit Ivacaftor bei Patienten ab 12 Jahren (heterozygot bzgl. F508del- und MF-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: 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 heterozygous for F508del in the CFTR gene with a minimal function (MF) mutation. The benefit assessment of ivacaftor/tezacaftor/elexacaftor plus ivacaftor is based on the pivotal study VX17-445-102, a multicenter, randomized, double-blind, placebo-controlled Phase III study to evaluate the efficacy and safety of 24 weeks of treatment with IVA/TEZ/ELX plus IVA in CF patients 12 years of age and older who are heterozygous for the F508del mutation in the CFTR gene and have an MF mutation. The benefit assessment was based on the pivotal study VX17-445-102 (NCT03525444; hereafter referred to as Study 102), a randomized, multicenter, double-blind study to investigate the efficacy and safety of IVA/TEZ/ELX in combination with IVA compared to placebo in patients with CF 12 years of age and older who are heterozygous for the F508del mutation in the CFTR gene and have an MF mutation. Randomization was performed in a 1:1 ratio, stratified by baseline FEV1% (< 70 vs. ≥ 70%), age at screening (< 18 vs. ≥ 18 years) and gender (male/female). A total of 405 study participants ≥ 12 years of age were analyzed in the study arm with triple therapy or in the control arm with Placebo, depending on the randomization sequence. The study consisted of a 28-day screening period, a 28-day run-in period, a 24-week treatment period, and a 28-day safety follow-up. The largest proportion of study participants (58%) achieved FEV1% values in the range of ≥ 40 to < 70% at baseline, whereas approximately 33.0% of study participants achieved FEV1% values of ≥ 70 to ≤ 90%. There were 16 study participants included in the placebo arm and 18 in the intervention arm with FEV1% values < 40%. In addition, there were 5 study participants in the placebo arm and 2 in the intervention arm with FEV1% values > 90%. Both study participants with FEV1% values < 40% and > 90% did not meet the study inclusion criterion, according to which FEV1% values of ≥ 40 and ≤ 90% were defined. The primary endpoint was defined as the absolute change in FEV1% (one-second capacity) from baseline to week 24. 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". With regard to morbidity, statistically significant and predominantly clinically relevant effects in favor of the IVA/TEZ/ELX arm are shown with low potential bias. In study 102, statistically significant benefits of IVA/TEZ/ELX plus IVA over placebo were observed with respect to the domains of the CFQ-R “pulmonary exacerbations” (rate ratio 0.37 [95%CI 0.25; 0.55]; p< 0.0001), “hospitalization due to pulmonary exacerbations” (rate ratio 0.29 [95%CI 0.14; 0.61]; p=0.0010), and in both the “respiratory system” (mean difference 20.23 [95%CI 17.50; 22.96]; p< 0.0001) and “weight problems” (mean difference 13.11 [95%CI 8.35; 17.88]; p< 0.0001). No statistically significant differences were observed in the morbidity domain "gastrointestinal symptoms" of the CFQ-R. With regard to disease-specific quality of life, a statistically significant advantage in favor of the IVA/TEZ/ELX arm was found in all 9 domains of the CFQ-R with a low bias potential. In the domains "Physical well-being", "Role function", "Vitality", "Social limitations", "Eating disorders", "Therapy burden" and "Subjective health assessment", the improvements in quality of life under IVA/TEZ/ELX are also clinically relevant. With regard to safety, there were no statistically significant differences between the study arms with unclear potential for bias for severe AEs (grade ≥ 3 or 4), SUEs, and AEs that led to discontinuation of study medication or study participation. Safety significance is limited by the fact that disease symptoms attributable to the underlying disease were included in the UE ascertainment. Overall, the potential for bias at the study level is rated as low.

Project Status: Completed

URL for project: https://www.g-ba.de/bewertungsverfahren/nutzenbewertung/583/#english

Year Published: 2021

URL for published report: https://www.g-ba.de/downloads/39-1464-4707/2021-02-18_AM-RL-XII_Ivacaftor-Tezacaftor-Elexacaftor_D-584_EN.pdf

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

URL for additional information: https://www.g-ba.de/bewertungsverfahren/nutzenbewertung/583/#nutzenbewertung

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/