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Pharmacotherapeutic group: Other respiratory system drugs, ATC code: R07AX33. Mechanism of action VNZ and TEZ are CFTR correctors that bind to different sites on the CFTR protein and have an additive effect in facilitating the cellular processing and trafficking of selected mutant forms (including F508del-CFTR), thereby increasing the amount of CFTR protein at the cell surface compared with either molecule alone. D-IVA increases the channel-open probability (gating) of CFTR protein at the cell surface. The combined action of VNZ, TEZ, and D-IVA increases the quantity and function of CFTR at the cell surface, leading to increased CFTR activity as measured by both CFTR-mediated chloride ion transport in vitro and sweat chloride (SwCl) measurements in people with CF. CFTR chloride transport assay in Fischer Rat Thyroid (FRT) follicular cells expressing mutant CFTR The response of mutant CFTR protein to D-IVA/TEZ/VNZ in chloride ion transport was evaluated in electrophysiological studies in the Ussing chamber using a panel of FRT cell lines transfected with individual CFTR mutations. D-IVA/TEZ/VNZ increased chloride ion transport in FRT cells expressing select CFTR mutations. In vitro, the threshold of CFTR response in chloride transport was defined as a net increase of at least 10% over baseline above normal value, as this is predictive of, or can reasonably be expected to predict, a clinical response. For individual mutations, the magnitude of net change from baseline in CFTR-mediated chloride transport in vitro does not correlate with the magnitude of clinical response. Based on in vitro data using FRT cells, it is likely that the presence of one CFTR mutation responsive to D-IVA/TEZ/VNZ will lead to a clinical response in patients with CF. Table 4 lists the CFTR mutations included in the indication for treatment with Alyftrek. Detection of the CFTR mutations listed in this table is not intended to replace a diagnosis of cystic fibrosis or to be the sole determinant for prescribing therapy. Table 4: CFTR mutations identified as responsive to D-IVA/TEZ/VNZ based on clinical or in vitro data 1140-1151dup, E116Q, H147del, N1088D, S1118F, S1159F⁎, S1159P#, S1188L, S1251N⁎, S1255P, S13F, S13P, S158N, S182R, S18I, S18N, S308P, S341P, S364P, 1461insGAT, E1221V, H147P, N1195T, 1507_1515del9, E1228K, H199Q, N1303I, 2055del9, E1409K, H199R, N1303K¶, 2183A→G, E1433K, H199Y, N186K, 2789+5G→A†, E193K#, H609L, N187K, 2851A/G, E217G, H609R, N396Y, 293A→G, E264V, H620P, N418S, 3007del6, E282D, H620Q, N900K, 3131del15, E292K, H939R#, P1013H, 3132T→G, 3141del9, E384K, E403D#, H939R;H949L‡, P1013L, P1021L, 3143del9, E474K, H954P, P1021T, 314del9, E527G, I1023R, P111L, 3195del6, E56K#, I105N, P1372T Table 4 (continued): 3199del6, E588V#, I1139V#, P140S, S434P, S492F, S50P, S519G, S531P, S549I, S549N⁎, S549R⁎, S557F, S589I, S589N#, S624R, S686Y, S737F#, S821G, S898R, S912L#, S912L;G1244V‡, S912T, S945L⁎, S955P, S977F#, S977F;R1438W‡, T1036N#, T1057R, T1086A, T1086I, T1246I, T1299I, T1299K, T164P, T338I#, T351I, T351S, T351S;R851L‡, T388M, T465I, T465N, T501A, T582S, T604I, T908N, T990I, V1008D, V1010D, V1153E#, V11I, V1240G#, V1293G#, V1293I, V1415F, V201M#, 3272-26A→G†, E60K#, I1203V, P205S#, 3331del6, E822K#, I1234L, P439S, 3410T→C, E831X†, I1234V, del6a, P499A, 3523A→G, E92K#a, P574H, 3601A→C, F1016S#, I125T, P5L#, 3761T→G, F1052V#, I1269N#, P67L#, 3791C/T, F1074L#, I1366N#, P750L, 3849+10kbC→T†, F1078S, I1366T, P798S, 3850G→A, F1099L#, I1398S, P988R, 3978G→C, F1107L, I148L, P99L, 4193T→G, F191V#, I148N, Q1012P, 546insCTA#, 548insTAC, F200I, F311del#, I148T;H609R‡, Q1100P, Q1209P, 711+3A→G†, F311L#, I175V#, Q1291H, A1006E#, F312del, I331N, Q1291R#, A1025D, F433L, I336K⁎, Q1313K, A1067P, F508C;S1251N‡#, I336L, Q1352H, A1067T#, F508del⁎, I444S, Q151K, A1067V, F508del;R1438W‡, I497S, Q179K, A107G, F575Y#, I502T⁎, Q237E#, A1081V, F587I, I506L, Q237H#, A1087P, F587L, I506T, Q237P, A120T#, F693L(TTG), I506V, Q30P, A1319E, F87L, I506V;D1168G‡, Q359K/T360K‡, A1374D, F932S, I521S, Q359R#, A141D, G1047D, I530N, Q372H, A1466S, G1047R, I556V, Q452P, A155P, G1061R, I586V, Q493L, A234D#, G1069R#, I601F#, Q493R, A234V, G1123R, I601T, Q552P, A238V, G1173S, I618N, Q98P, A309D, G1237V, I618T#, Q98R#, A349V#, A357T, G1244E⁎, G1244R, I86M, R1048G, R1066C, A455E⁎, G1247R, I980K#, R1066G, A455V, G1249E, K1060T#, R1066H⁎, A457T, G1249R#, K162E, R1066L, A462P, G1265V, K464E, R1066M, A46D, G126D#, K464N, R1070P, A534E, G1298V, K522E, R1070Q#, A554E#, G1349D#, K522Q, R1070W#, A559T, G149R, K951E, R1162Q, A559V, G149R;G576A;R668C‡, L1011S, R117C, A561E, A566D, G178E#, L102R, L102R;F1016S‡, R117C;G576A;R668C‡, A613T, G178R#, L1065P, R117G#, A62P, G194R#, L1065R, R117H, A72D, G194V#, L1077P⁎, R117L#, A872E, G213E, L1227S, R117L;L997F‡, c.1367_1369dupTTG, G213E;R668C‡, L1324P#, R117P#, C225R, G213V, L1335P#, R1239S, C491R, G226R, L137P, R1283G, C590Y, G239R, L137R, R1283M#, C866Y, G253R, L1388P, R1283S#, G27E, G27R, G314E#, G314R, G424S, G437D, G451V, G461R, G461V, G463V, G480C, G480D, G480S, G500D, G545R, G551A, G551D⁎, G551R, G551S#, G576A;R668C‡#, G576A;S1359Y‡, G622D#, G622V, G628A, G628R, G85E⁎, G85V, G91R, G930E, G970D#, G970S, G970V, H1054D⁎, H1079P, H1085P, H1085R, H1375N, H1375P#, H139L, H139R, H146R, R1438W, V232A, D110E#, L1480P#, R248K, V232D#, D110H#, L159S, R258G#, V317A, D110N, L15P#, R297Q, V322M, D1152A, D1152H⁎, L15P;L1253F‡, R31L#, R334L#, V392G, V456A, D1270N#, L165S, R334Q#, V456F, D1270Y, L167R, R347H#, V520F, D1312G, L206W⁎, R347L#, V520I, D1377H, D1445N, L210P, L293P, R347P⁎, R352Q⁎, V562I;A1006E‡, D192G#, L327P, R352W#, V562L, D192N, L32P, R516G, V591A, D373N, L333F, R516S, V603F, D426N, L333H, R553Q#, V920L, D443Y#, L346P#, R555G, V920M, D443Y;G576A;R668C‡#, L441P, L453S, R560S, R560T, V93D, W1098C⁎, D513G, L467F, R600S, W1282G, D529G, L558F, R709Q, W1282R⁎, D565G, L594P, R74Q#, W202C, D567N, L610S, R74Q;R297Q‡, W361R, D572N, L619S, R74Q;V201M;D1270N‡, W496R, D579G#, L633P, R74W#, Y1014C#, D58H, L636P, R74W;D1270N‡#, Y1032C#, D58V, L88S, R74W;R1070W;D1270N‡#, Y1032N, D614G#, L927P, R74W;S945L‡, Y1073C, D651H, L967F;L1096R‡, R74W;V201M‡#, Y1092H, D651N, L973F, R74W;V201M;D1270N‡#, Y109C, D806G, M1101K⁎, R74W;V201M;L997F‡, Y109H, D924N#, M1101R, Y109N#, D979A, M1137R, Y122C, D979V#, M1137V, R751L#, Y1381H, D985H, M1210K, R75L, Y161C, D985Y, M150K, R75Q;L1065P‡, Y161D, D993A, M150R, R75Q;N1088D‡, Y161S#, D993G, M152L, R75Q;S549N‡, Y301C, D993Y, M152V#, R792G#, Y517C, E1104K, M265R#, R792Q, Y563N⁎, E1104V, M348K, R810G, Y569C, E1126K, M394L, R851L, Y89C, E116K#, M469V, R933G#, Y913C, S1045Y, Y913S, M498I, M952I#, S108F, Y919C, M952T, M961L There are patients with CF who carry two rare non-F508del CFTR mutations not listed in Table 4. If they do not carry two class I mutations (null mutations known not to produce CFTR protein) (see section 4.1), they may respond to treatment. In such cases, if the physician judges that the potential benefits outweigh the potential risks, use of Alyftrek may be considered under close medical supervision. Each individual CF diagnosis should be made on the basis of recommended diagnostic procedures and clinical assessment, as there is considerable phenotypic variability among patients with the same genotype. ⁎ Mutations supported by clinical data. † Non-canonical splice mutations whose efficacy is extrapolated from clinical data of other CFTR modulators, as these mutations cannot be tested in FRT cells. ‡ Complex/compound mutations, where one CFTR allele carries multiple mutations; these may exist independently of mutations on the other allele. ¶ Data for N1303K are extrapolated from clinical data on IVA/TEZ/ELX in combination with IVA and supported by data from a Human Bronchial Epithelial (HBE) assay. # Mutations extrapolated from FRT cell testing with TEZ/IVA or IVA monotherapy, in which a positive response is indicative of a clinical response. Mutations without annotation are included on the basis of FRT cell testing with D-IVA/TEZ/VNZ, in which a positive response is indicative of a clinical response. Pharmacodynamic effects Effects on sweat chloride In Study 121-102 (people with CF heterozygous for the F508del mutation and a CFTR mutation predicted to result in either no CFTR protein production or a CFTR protein that does not transport chloride and is not responsive to other CFTR modulators (IVA and TEZ/IVA) in vitro), the treatment difference for D-IVA/TEZ/VNZ versus IVA/TEZ/ELX in mean absolute change in SwCl from baseline through Week 24 was −8.4 mmol/L (95% CI: −10.5, −6.3; p < 0.0001). In Study 121-103 (people with CF homozygous for the F508del mutation, heterozygous for the F508del mutation and either a gating mutation or a residual function mutation, or with at least one IVA/TEZ/ELX-responsive mutation without F508del), the treatment difference for D-IVA/TEZ/VNZ versus IVA/TEZ/ELX in mean absolute change in SwCl from baseline through Week 24 was −2.8 mmol/L (95% CI: −4.7, −0.9; p = 0.0034). In Cohort B1 of Study 121-105 (people with CF aged 6 to less than 12 years with at least one IVA/TEZ/ELX-responsive mutation), the mean absolute change in SwCl from baseline through Week 24 was −8.6 mmol/L (95% CI: −11.0, −6.3). Effects on the cardiovascular system Effect on the QT interval At exposures up to 6-fold those observed at the maximum recommended dose of VNZ and at doses up to 3-fold the maximum recommended doses of TEZ and D-IVA, no clinically relevant prolongation of the QT/QTc interval was observed in healthy subjects. Clinical efficacy and safety The efficacy of D-IVA/TEZ/VNZ in people with CF aged 12 years and older was evaluated in two randomised, double-blind, IVA/TEZ/ELX-controlled Phase 3 studies (Studies 121-102 and 121-103). The pharmacokinetic profile, safety, and efficacy of D-IVA/TEZ/VNZ in people with CF aged 6 to less than 12 years are supported by evidence from D-IVA/TEZ/VNZ studies in people with CF aged 12 years and older (Studies 121-102 and 121-103) and additional data from an open-label Phase 3 study (Cohort B1 of Study 121-105). Studies 121-102 and 121-103 Study 121-102 was a 52-week, randomised, double-blind, IVA/TEZ/ELX-controlled study in people with CF heterozygous for the F508del mutation and a CFTR mutation predicted to result in either no CFTR protein production or a CFTR protein that does not transport chloride and is unresponsive to other CFTR modulators [IVA and TEZ/IVA] in vitro. A total of 398 people with CF aged 12 years and older received IVA/TEZ/ELX during a 4-week run-in period and were then randomised to receive D-IVA/TEZ/VNZ or IVA/TEZ/ELX during a 52-week treatment period. The mean age was 30.8 years (range 12.2 to 71.6 years; 14.3% under 18 years), 41% were female and 59% male. After the 4-week run-in period, the mean baseline ppFEV1 was 67.1 percentage points (range: 28.0 to 108.6), the mean baseline CFQ-R RD score was 84.4 (range 22.2 to 100), and the mean baseline SwCl was 53.9 mmol/L (range: 10.0 mmol/L to 113.5 mmol/L). Study 121-103 was a 52-week, randomised, double-blind, IVA/TEZ/ELX-controlled study in people with CF who had one of the following genotypes: homozygous for the F508del mutation, heterozygous for the F508del mutation and either a gating mutation or a residual function mutation, or at least one IVA/TEZ/ELX-responsive mutation without F508del. A total of 573 people with CF aged 12 years and older received IVA/TEZ/ELX during a 4-week run-in period and were then randomised to receive D-IVA/TEZ/VNZ or IVA/TEZ/ELX during a 52-week treatment period. The mean age was 33.7 years (range 12.2 to 71.2 years; 13.8% under 18 years), 48.9% were female and 51.1% male. After the 4-week run-in period, the mean baseline ppFEV1 was 66.8 percentage points (range: 36.4 to 112.5), the mean baseline CFQ-R RD score was 85.7 (range 27.8 to 100), and the mean baseline SwCl was 42.8 mmol/L (range: 10.0 mmol/L to 113.3 mmol/L). In both studies, the primary endpoint assessed non-inferiority of the absolute change in ppFEV1 from baseline through Week 24. The key secondary endpoint assessed superiority in the mean absolute change in SwCl from baseline through Week 24. A summary of the key efficacy results for Studies 121-102 and 121-103 is provided in Table 5. Table 5: Efficacy analyses from Studies 121-102 and 121-103 Analysis*; Statistic; Study 121-102 D-IVA/TEZ/VNZ n = 196; IVA/TEZ/ELX n = 202; Study 121-103 D-IVA/TEZ/VNZ n = 284; IVA/TEZ/ELX n = 289 Primary Baseline ppFEV1 (percentage points): Mean (SD): 67.0 (15.3); 67.2 (14.6); 67.2 (14.6); 66.4 (14.9) Absolute change in ppFEV1 from baseline through Week 24 (percentage points): n: 187; 193; 268; 276. LS mean (SE): 0.5 (0.3); 0.3 (0.3); 0.2 (0.3); 0.0 (0.2). LS mean difference, 95% CI: 0.2 (−0.7, 1.1); 0.2 (−0.5, 0.9). One-sided non-inferiority p-value†: < 0.0001; < 0.0001 Key secondary Baseline SwCl (mmol/L): Mean (SD): 53.6 (17.0); 54.3 (18.2); 43.4 (18.5); 42.1 (17.9) Absolute change in SwCl from baseline through Week 24 (mmol/L): n: 185; 194; 270; 276. LS mean (SE): −7.5 (0.8); 0.9 (0.8); −5.1 (0.7); −2.3 (0.7). LS mean difference, 95% CI: −8.4 (−10.5, −6.3); −2.8 (−4.7, −0.9). Two-sided p-value: < 0.0001; 0.0034 Other secondary§ Number of pulmonary exacerbations through Week 52: Number of events: 67; 90; 86; 79. Annualised event rate: 0.32; 0.42; 0.29; 0.26. Difference in event rate, 95% CI: −0.10 (−0.24, 0.04); 0.03 (−0.07, 0.13) Absolute change in CFQ-R RD score from baseline through Week 24 (points): n: 186; 192; 268; 270. LS mean (SE): 0.5 (1.1); −1.7 (1.0); −1.2 (0.8); −1.2 (0.8). LS mean difference, 95% CI: 2.3 (−0.6, 5.2); −0.1 (−2.3, 2.1) ppFEV1: percent predicted forced expiratory volume in one second; CI: confidence interval; SD: standard deviation; SE: standard error; CFQ-R RD: Cystic Fibrosis Questionnaire–Revised Respiratory Domain; SwCl: sweat chloride. Note: Analyses were based on the full analysis set (FAS). The FAS was defined as all randomised subjects with the intended CFTR allele mutation who received at least 1 dose of study treatment. * A 4-week run-in period of IVA/TEZ/ELX was used to establish the treatment baseline. † The pre-specified non-inferiority margin was −3.0 percentage points. § Not controlled for multiplicity. In Studies 121-102 and 121-103, the mean absolute change from baseline in ppFEV1 and the absolute change from baseline in sweat chloride at Week 24 were maintained through Week 52. Study 121-105 Study 121-105 was an open-label study in people with CF with at least one IVA/TEZ/ELX-responsive mutation. Cohort B1 evaluated the safety, tolerability, and efficacy of D-IVA/TEZ/VNZ in a total of 78 people with CF aged 6 to less than 12 years (mean age 9.1 years (range 6.2 to 12.0 years), 43.6% female, 56.4% male) over a 24-week treatment period. In Cohort B1, all participants were taking IVA/TEZ/ELX at the start of treatment. The mean baseline ppFEV1 on IVA/TEZ/ELX was 99.7 percentage points (range: 29.3 to 146.0), the mean baseline CFQ-R RD score on IVA/TEZ/ELX was 84.8 (range 16.7 to 100), and the mean baseline SwCl on IVA/TEZ/ELX was 40.4 mmol/L (range: 11.5 mmol/L, 109.5 mmol/L). In Cohort B1 of Study 121-105, the primary endpoints were safety and tolerability. Efficacy endpoints included absolute change in ppFEV1, absolute change in SwCl, absolute change in CFQ-R Respiratory Domain score, and number of pulmonary exacerbations (PEx) through Week 24. A summary of the key efficacy results is provided in Table 6. Table 6: Efficacy analyses, Study 121-105 (Cohort B1) Analysis; Statistic; D-IVA/TEZ/VNZ n = 78 Secondary efficacy Baseline ppFEV1: Mean (SD): 99.7 (15.1) Baseline SwCl: Mean (SD): 40.4 (20.9) Absolute change in ppFEV1 from baseline through Week 24 (percentage points): LS mean (95% CI): 0.0 (−2.0, 1.9) Absolute change in SwCl from baseline through Week 24 (mmol/L): LS mean (95% CI): −8.6 (−11.0, −6.3) Absolute change in CFQ-R Respiratory Domain score from baseline through Week 24 (points): LS mean (95% CI): 3.9 (1.5, 6.3) Number of pulmonary exacerbations through Week 24: Annualised event rate: 0.15 CI: confidence interval; ppFEV1: percent predicted forced expiratory volume in one second; SD: standard deviation; CFQ-R: Cystic Fibrosis Questionnaire–Revised Paediatric population The European Medicines Agency has deferred the obligation to submit the results of studies with D-IVA/TEZ/VNZ in one or more subsets of the paediatric population in the treatment of cystic fibrosis (see section 4.2 for information on paediatric use).