ALYFTREK 125MG/50MG/10MG Film-coated tablet

Pharmacotherapeutic group: Other respiratory system products, 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 processing and trafficking of selective mutant forms (including F508del-CFTR) within the cell, thereby increasing the amount of CFTR protein at the cell surface compared with either molecule alone.​‍​​​​​‍​‍‍‍‍​‍‍ D-IVA increases the probability of opening (gating) of the channel formed by the CFTR protein at the cell surface. The combined effect of VNZ, TEZ and D-IVA is to increase the quantity and function of CFTR at the cell surface, leading to enhanced CFTR activity as measured both by CFTR-mediated chloride ion transport in vitro and by sweat chloride (SwCl) determination in persons with CF. CFTR chloride ion transport assay in Fischer Rat Thyroid (FRT) cells expressing mutant CFTR The response of mutant CFTR protein to D-IVA/TEZ/VNZ in chloride ion transport was investigated in electrophysiological studies in an 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 selective CFTR mutations. Under in vitro conditions, the threshold for CFTR response in chloride ion transport was defined as a net increase of at least 10% of normal value over baseline, as this is predictive of, or can reasonably be expected to predict, clinical response. For individual mutations, the magnitude of the net change from baseline in CFTR-mediated chloride ion transport in vitro does not correlate with the magnitude of clinical response. Based on in vitro data obtained using FRT cells, the presence of one CFTR gene mutation responsive to D-IVA/TEZ/VNZ is likely to result in a clinical response in patients with CF. Table 4 lists the CFTR mutations included in the indication for treatment with Alyftrek. The presence of CFTR mutations listed in this table is not intended to replace the diagnosis of cystic fibrosis, nor to be the sole determining factor when prescribing treatment. 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 S308PS341P 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→G3141del9 E384KE403D # H939R;H949L‡ P1013LP1021L 3143del9 E474K H954P P1021T 314del9 E527G I1023R P111L 3195del6 E56K # I105N P1372T Table 4: CFTR mutations identified as responsive to D-IVA/TEZ/VNZ based on clinical or in vitro data 3199del6 E588V # I1139V # P140S S434P S492F S50P S519G S531P S549I S549N ⁎ S549R ⁎ S557F S589I S589N # S624R S686Y S737F # S821G S898R S912L # S912L;G1244 V ‡ S912T S945L ⁎ S955P S977F # S977F;R1438 W ‡ T1036N # T1057R T1086A T1086I T1246I T1299I T1299K T164P T338I # T351I T351ST351S;R851L‡T388M T465I T465N T501A T582S T604I T908N T990I V1008D V1010D V1153E # V11I V1240G # V1293G # V1293I V1415FV201M # 3272-26A→G † E60K # I1203V P205S # 3331del6 E822K # I1234L P439S 3410T→C E831X † I1234Vdel6a 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 F200IF311del # I148T;H609R‡ Q1100PQ1209P 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;D116 Q359K/T360K ‡ A1374D F932S 8G ‡ Q359R # A141D G1047D I521S Q372H A1466S G1047R I530N Q452P A155P G1061R I556V Q493L A234D # G1069R # I586V Q493R A234V G1123R I601F # Q552P A238V G1173S I601T Q98P A309D G1237V I618N Q98R # A349V # A357T G1244E ⁎ G1244R I618T # I86M R1048GR1066C 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;R66 L1011S R117C A561EA566D 8C ‡ G178E # L102R L102R;F101 R117C;G576A;R668C‡ A613T G178R # 6S ‡ R117G # A62P G194R # L1065P R117H A72D G194V # L1065R R117L # A872E G213E L1077P ⁎ R117L;L997F ‡ c.1367_1369dupTT G213E;R668C ‡ L1227S R117P # G G213V L1324P # R1239S C225R G226R L1335P # R1283G C491R G239R L137P R1283M # C590Y G253R L137R R1283S # Table 4: CFTR mutations identified as responsive to D-IVA/TEZ/VNZ based on clinical or in vitro data C866Y 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 L1388P R1438W V232A D110E # L1480P # R248K V232D # D110H # L159S R258G # V317A D110N L15P # R297Q V322M D1152AD1152H ⁎ L15P;L1253F‡ R31L # R334L # V392GV456A 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;R66 8C ‡ # L441PL453S R560S R560T V93DW1098C ⁎ D513G L467F R600S W1282G D529G L558F R709Q W1282R ⁎ D565G L594P R74Q # W202C D567N L610S R74Q;R297Q ‡ W361R D572N L619S R74Q;V201M;D127 W496R D579G # L633P 0N ‡ Y1014C # D58H L636P R74W # Y1032C # D58V L88S R74W;D1270N ‡# Y1032N D614G # L927P R74W;R1070W;D12 Y1073C D651H L967F;L109 70N ‡ Y1092H D651N 6R ‡ R74W;S945L ‡ Y109C D806G L973F R74W;V201M ‡# Y109H D924N # M1101K ⁎ R74W;V201M;D127 Y109N # D979A 0N‡# Y122C M1101R D979V # M1137R R74W;V201M;L997 Y1381H D985H F‡ Y161C M1137V D985Y M1210K R751L # Y161D D993A M150K R75L Y161S # D993G M150R R75Q;L1065P ‡ Y301C D993Y M152L R75Q;N1088D ‡ Y517C E1104K M152V # R75Q;S549N ‡ Y563N ⁎ E1104V M265R # R792G # Y569C E1126K M348K R792Q Y89C E116K # M394L R810G Y913C M469V R851L Y913S M498IM952I # R933G # S1045Y Y919C M952T # S108F 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 determines that the potential benefits outweigh the potential risks, treatment with Alyftrek may be considered under close medical supervision. Table 4: CFTR mutations identified as responsive to D-IVA/TEZ/VNZ based on clinical or in vitro data Each individual diagnosis of CF should be established based on 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 for which efficacy is extrapolated from clinical data of other CFTR modulators, as these mutations cannot be subjected to the FRT cell assay. ‡ Complex/compound mutations where one allele of the CFTR gene carries multiple mutations; these may exist independently of the presence of mutations on the other allele. ¶ Data for N1303K are extrapolated based on clinical data from IVA/TEZ/ELX in combination with IVA and supported by data from the Human Bronchial Epithelial (HBE) cell assay. # Mutations extrapolated based on the assay performed in FRT cells with TEZ/IVA or IVA monotherapy, in which a positive response is indicative of clinical response. Mutations without annotation are included based on the assay performed in FRT cells with D-IVA/TEZ/VNZ, in which a positive response is indicative of clinical response. Pharmacodynamic effects Effects on sweat chloride levels In Study 121-102 (persons with CF who are heterozygous carriers of 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 ions and is not responsive to other CFTR modulators (IVA and TEZ/IVA) in vitro), the treatment difference for D-IVA/TEZ/VNZ compared with IVA/TEZ/ELX for the 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 (persons with CF who are homozygous carriers of the F508del mutation, heterozygous carriers of the F508del mutation and either a gating mutation or a residual function mutation, or at least one mutation responsive to IVA/TEZ/ELX without the F508del mutation), the treatment difference for D-IVA/TEZ/VNZ compared with IVA/TEZ/ELX for the 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 (persons with CF aged 6 years to less than 12 years with at least one mutation responsive to IVA/TEZ/ELX), 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 QT interval At exposures corresponding to up to 6-fold the exposures observed at the maximum recommended dose of VNZ and doses corresponding to up to 3-fold the maximum recommended doses of TEZ and D-IVA, the QT/QTc interval was not prolonged to any clinically relevant extent in healthy subjects. Clinical efficacy and safety The efficacy of D-IVA/TEZ/VNZ in persons with CF aged 12 years and older was evaluated in two randomised, double-blind, Phase 3 studies controlled with IVA/TEZ/ELX (Studies 121-102 and 121-103). The pharmacokinetic profile, safety, and efficacy of D-IVA/TEZ/VNZ in persons with CF aged 6 to less than 12 years are supported by evidence from studies of D-IVA/TEZ/VNZ in persons 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 persons with CF who are heterozygous carriers of 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 ions and does not respond to other CFTR modulators [IVA and TEZ/IVA] in vitro. A total of 398 persons 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 years to 71.6 years; 14.3% under 18 years), 41% 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), 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 persons with CF who had one of the following genotypes: homozygous carriers of the F508del mutation, heterozygous carriers of the F508del mutation and either a gating mutation or a residual function mutation, or at least one mutation responsive to IVA/TEZ/ELX without the F508del mutation. A total of 573 persons 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 years to 71.2 years; 13.8% under 18 years), 48.9% 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), 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 mean absolute change in SwCl from baseline through Week 24. For a summary of key efficacy results for Studies 121-102 and 121-103, see Table 5. Table 5: Efficacy analyses from Studies 121-102 and 121-103 Analysis * Statistic Study 121-102 Study 121-103 D-IVA/TEZ/ VNZ n = 196 IVA/TEZ/ELX n = 202 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) p-value (one-sided) non-inferiority † < 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) p-value (two-sided) < 0.0001 0.0034 Table 5: Efficacy analyses from Studies 121-102 and 121-103 Analysis * Statistic Study 121-102 Study 121-103 D-IVA/TEZ/ VNZ n = 196 IVA/TEZ/ELX n = 202 D-IVA/TEZ/ VNZ n = 284 IVA/TEZ/ELX n = 289 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 Rate difference, 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 IVA/TEZ/ELX run-in treatment period was used to establish the baseline for treatment. † Pre-specified non-inferiority margins were -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 persons with CF with at least one mutation responsive to IVA/TEZ/ELX. Cohort B1 evaluated the safety, tolerability, and efficacy of D-IVA/TEZ/VNZ in a total of 78 persons 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 receiving IVA/TEZ/ELX at baseline. The mean baseline ppFEV1 while receiving IVA/TEZ/ELX was 99.7 percentage points (range: 29.3 to 146.0), the mean baseline CFQ-R RD score while receiving IVA/TEZ/ELX was 84.8 (range 16.7 to 100), and the mean baseline SwCl while receiving 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 key efficacy results is presented 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) Table 6: Efficacy analyses, Study 121-105 (Cohort B1) Analysis Statistic D-IVA/TEZ/VNZ n = 78 Secondary efficacy 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).