Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Other respiratory system products, ATC code: R07AX02 
Mechanism of action
Ivacaftor is a potentiator of the CFTR protein. The CFTR protein is a chloride channel present at the surface of epithelial cells in multiple organs. Ivacaftor facilitates increased chloride transport by potentiating the channel open probability (or gating) of CFTR protein located at the cell surface. The overall level of ivacaftor-mediated CFTR chloride transport is dependent on the amount of CFTR protein at the cell surface and how responsive a particular mutant CFTR protein is to ivacaftor potentiation.

CFTR Chloride Transport Assay in Fisher Rat Thyroid (FRT) cells expressing mutant CFTR 
The chloride transport response of mutant CFTR protein to ivacaftor was determined in Ussing chamber electrophysiology studies using a panel of FRT cell lines transfected with individual CFTR mutations.
Ivacaftor increased chloride transport in FRT cells expressing CFTR mutations that result in CFTR protein being delivered to the cell surface.

The in vitro CFTR chloride transport response threshold was designated as a net increase of at least 10% of normal over baseline because it is predictive or reasonably expected to predict clinical benefit. For individual mutations, the magnitude of the net change over baseline in CFTR-mediated chloride transport in vitro is not correlated with the magnitude of clinical response. A patient must have at least one CFTR mutation responsive to ivacaftor to be indicated.

Note that splice site mutations cannot be studied in the FRT assay. Evidence of clinical efficacy exists for non-canonical splice mutations 2789+5G→A, 3272-26A→G, 3849+10kbC→T, 711+3A→G and E831X and these are listed in Table 6 below [see section 5.1 Pharmacodynamic properties (Clinical efficacy and Safety)].

The G970R mutation causes a splicing defect resulting in little-to-no CFTR protein at the cell surface that can be potentiated by ivacaftor [see section 5.1 Pharmacodynamic effects and Clinical efficacy and safety data].

Ivacaftor also increased chloride transport in cultured human bronchial epithelial (HBE) cells derived from CF patients who carried F508del on one CFTR allele and G551D or R117H-5T on the second CFTR allele.

In vitro responses seen in single channel patch clamp experiments using membrane patches from rodent cells expressing mutant CFTR forms do not necessarily correspond to in vivo pharmacodynamic response (e.g., sweat chloride) or clinical benefit. The exact mechanism leading ivacaftor to potentiate the gating activity of normal and some mutant CFTR forms in this system has not been completely elucidated.

Table 6 lists mutations that are responsive to ivacaftor based on 1) a positive clinical response and/or 2) in vitro data in FRT cells indicating that ivacaftor increases chloride transport to at least 10% over baseline (% of normal).
Table 6: List of CFTR Gene Mutations that Produce CFTR Protein and are Responsive to Kalydeco 711+3A→G *              F311del                I148T               R75Q                  S589N 2789+5G→A *               F311L                 I175V              R117C*                  S737F
3272-26A→G *              F508C                I807M               R117G                  S945L* 3849+10kbC→T *         F508C;S1251N †           I1027T              R117H                  S977F* A120T                F1052V                I1139V              R117L                  S1159F A234D                 F1074L               K1060T              R117P                  S1159P A349V                 G178E                L206W*              R170H                 S1251N * A455E *               G178R *               L320V               R347H*                S1255P * A1067T                 G194R                 L967S              R347L                   T338I D110E                 G314E                L997F               R352Q*                 T1053I D110H                G551D *               L1480P              R553Q                  V232D 
KALY_50_75_150-SPC-0424-V1                     Page 10 of 22
D192G                        G551S *                      M152V                       R668C                          V562I D579G*                        G576A                        M952I                       R792G                         V754M D924N                        G970D                        M952T                       R933G                         V1293G D1152H*                      G1069R                         P67L*                     R1070Q                         W1282R D1270N                       G1244E *                      Q237E                      R1070W*                        Y1014C E56K                        G1249R                        Q237H                      R1162L                         Y1032C E193K                       G1349D *                      Q359R                      R1283M E822K                        H939R                        Q1291R                     S549N * E831X *                      H1375P                         R74W                      S549R * * Clinical data exist for these mutations [see section 5.1 Pharmacodynamic properties (Clinical efficacy and Safety) (5.1)].
†
Complex/compound mutations where a single allele of the CFTR gene has multiple mutations; these exist independent of the presence of mutations on the other allele.

Pharmacodynamic effects
In studies 1 and 2, in patients with the G551D mutation in one allele of the CFTR gene, ivacaftor led to rapid (15 days), substantial (the mean change in sweat chloride from baseline through week 24 was -48 mmol/L [95% CI -51, -45] and -54 mmol/L [95% CI -62, -47], respectively) and sustained (through 48 weeks) reductions in sweat chloride concentration.

In study 5 Part 1, in patients who had a non-G551D gating mutation in the CFTR gene, treatment with ivacaftor led to a rapid (15 days) and substantial mean change from baseline in sweat chloride of -49 mmol/L (95% CI -57, -41) through 8 weeks of treatment. However, in patients with the G970R-CFTR mutation, the mean (SD) absolute change in sweat chloride at week 8 was -6.25 (6.55) mmol/L. Similar results to part 1 were seen in part 2 of the study. At the 4-week follow-up visit (4 weeks after dosing with ivacaftor ended), mean sweat chloride values for each group were trending to pre-treatment levels.

In study 7 in patients aged 2 to less than 6 years with a gating mutation on at least 1 allele of the CFTR gene administered either 50 mg or 75 mg of ivacaftor twice daily, the mean absolute change from baseline in sweat chloride was -47 mmol/L (95% CI -58, -36) at week 24.

Clinical efficacy and safety
Studies 1 and 2: studies in patients with CF with G551D gating mutations The efficacy of Kalydeco has been evaluated in two phase 3 randomised, double-blind, placebo-controlled, multi-centre studies of clinically stable patients with CF who had the G551D mutation in the CFTR gene on at least 1 allele and had FEV1 ≥40% predicted.

Patients in both studies were randomised 1:1 to receive either 150 mg of ivacaftor or placebo every 12 hours with food containing fat for 48 weeks in addition to their prescribed CF therapies (e.g., tobramycin, dornase alfa). The use of inhaled hypertonic sodium chloride was not permitted.

Study 1 evaluated 161 patients who were 12 years of age or older; 122 (75.8%) patients had the F508del mutation in the second allele. At the start of the study, patients in the placebo group used some medicinal products at a higher frequency than the ivacaftor group. These medications included dornase alfa (73.1% versus 65.1%), salbutamol (53.8% versus 42.2%), tobramycin (44.9% versus 33.7%) and salmeterol/fluticasone (41.0% versus 27.7%). At baseline, mean predicted FEV1 was 63.6% (range: 31.6% to 98.2%) and mean age was 26 years (range: 12 to 53 years).

Study 2 evaluated 52 patients who were 6 to 11 years of age at screening; mean (SD) body weight was 30.9 (8.63) kg; 42 (80.8%) patients had the F508del mutation in the second allele. At baseline, mean predicted FEV1 was 84.2% (range: 44.0% to 133.8%) and mean age was 9 years (range: 6 to 12 years); 8 (30.8%) patients in the placebo group and 4 (15.4%) patients in the ivacaftor group had an FEV1 less than 70% predicted at baseline.

The primary efficacy endpoint in both studies was the mean absolute change from baseline in percent predicted FEV1 through 24 weeks of treatment.


KALY_50_75_150-SPC-0424-V1                                 Page 11 of 22 The treatment difference between ivacaftor and placebo for the mean absolute change (95% CI) in percent predicted FEV1 from baseline through week 24 was 10.6 percentage points (8.6, 12.6) in study 1 and 12.5 percentage points (6.6, 18.3) in study 2. The treatment difference between ivacaftor and placebo for the mean relative change (95% CI) in percent predicted FEV1 from baseline through week 24 was 17.1% (13.9, 20.2) in study 1 and 15.8% (8.4, 23.2) in study 2. The mean change from baseline through week 24 in FEV1 (L) was 0.37 L in the ivacaftor group and 0.01 L in the placebo group in study 1 and 0.30 L in the ivacaftor group and 0.07 L in the placebo group in study 2. In both studies, improvements in FEV1 were rapid in onset (day 15) and durable through 48 weeks.

The treatment difference between ivacaftor and placebo for the mean absolute change (95% CI) in percent predicted FEV1 from baseline through week 24 in patients 12 to 17 years of age in study 1 was 11.9 percentage points (5.9, 17.9). The treatment difference between ivacaftor and placebo for the mean absolute change (95% CI) in percent predicted FEV1 from baseline through week 24 in patients with baseline predicted FEV1 greater than 90% in study 2 was 6.9 percentage points (-3.8, 17.6).

The results for clinically relevant secondary endpoints are shown in Table 7.

Table 7: Effect of ivacaftor on other efficacy endpoints in studies 1 and 2 Study 1                                 Study 2

Treatment                            Treatment differencea                          differencea

Endpoint                         (95% CI)               P value       (95% CI)                P value 
Mean absolute change from baseline in CFQ-Rb respiratory domain score (points)c 
Through week 24                      8.1               < 0.0001           6.1                 0.1092 
(4.7, 11.4)                          (-1.4, 13.5)

Through week 48                      8.6               < 0.0001           5.1                 0.1354 
(5.3, 11.9)                          (-1.6, 11.8)

Relative risk of pulmonary exacerbation
Through week 24                     0.40d               0.0016            NA                   NA 
Through week 48                     0.46d               0.0012            NA                   NA 
Mean absolute change from baseline in body weight (kg)

At week 24                           2.8               < 0.0001           1.9                 0.0004 
(1.8, 3.7)                           (0.9, 2.9)

At week 48                           2.7                0.0001            2.8                 0.0002 
(1.3, 4.1)                           (1.3, 4.2)

Mean absolute change from baseline in BMI (kg/m2)
At week 24                          0.94               < 0.0001          0.81                 0.0008 
(0.62, 1.26)                         (0.34, 1.28)

KALY_50_75_150-SPC-0424-V1                       Page 12 of 22
Study 1                                            Study 2

Treatment                                       Treatment differencea                                     differencea

Endpoint                                    (95% CI)                 P value                (95% CI)                    P value 
At week 48                                     0.93                  < 0.0001                   1.09                     0.0003 
(0.48, 1.38)                                     (0.51, 1.67)

Mean change from baseline in z-scores
Weight-for-age z-score at                      0.33                   0.0260                    0.39                   < 0.0001 week 48e
(0.04, 0.62)                                     (0.24, 0.53)

BMI-for-age z-score at                         0.33                   0.0490                    0.45                   < 0.0001 week 48e
(0.002, 0.65)                                    (0.26, 0.65)
CI: confidence interval; NA: not analyzed due to low incidence of events a
Treatment difference = effect of ivacaftor – effect of placebo b
CFQ-R: Cystic Fibrosis Questionnaire-Revised is a disease-specific, health-related quality-of-life measure for CF.
c
Study 1 data were pooled from CFQ-R for adults/adolescents and CFQ-R for children 12 to 13 years of age; Study 2 data were obtained from CFQ-R for children 6 to 11 years of age.
d
Hazard ratio for time to first pulmonary exacerbation e
In patients under 20 years of age (CDC growth charts)


Study 5: study in patients with CF with non-G551D gating mutations
Study 5 was a phase 3, two-part, randomised, double-blind, placebo-controlled, crossover study (part 1) followed by a 16-week open-label extension period (part 2) to evaluate the efficacy and safety of ivacaftor in patients with CF aged 6 years and older who have a G970R or non-G551D gating mutation in the CFTR gene (G178R, S549N, S549R, G551S, G1244E, S1251N, S1255P or G1349D).

In part 1, patients were randomised 1:1 to receive either 150 mg of ivacaftor or placebo every 12 hours with fat-containing food for 8 weeks in addition to their prescribed CF therapies and crossed over to the other treatment for the second 8 weeks after a 4- to 8-week washout period. The use of inhaled hypertonic saline was not permitted. In part 2, all patients received ivacaftor as indicated in part 1 for 16 additional weeks. The duration of continuous ivacaftor treatment was 24 weeks for patients randomised to part 1 placebo/ivacaftor treatment sequence and 16 weeks for patients randomised to the part 1 ivacaftor/placebo treatment sequence.

Thirty-nine patients (mean age 23 years) with baseline FEV1 ≥ 40% predicted (mean FEV1 78% predicted [range: 43% to 119%]) were enrolled. Sixty-two percent (24/39) of them carried the F508del-CFTR mutation in the second allele. A total of 36 patients continued into part 2 (18 per treatment sequence).

In part 1 of study 5, the mean FEV1 percent predicted at baseline in placebo-treated patients was 79.3% while in ivacaftor-treated patients this value was 76.4%. The mean overall post-baseline value was 76.0% and 83.7%, respectively. The mean absolute change from baseline through week 8 in percent predicted FEV1 (primary efficacy endpoint) was 7.5% in the ivacaftor period and -3.2% in the placebo period. The observed treatment difference (95% CI) between ivacaftor and placebo was 10.7% (7.3, 14.1) (P<0.0001).

The effect of ivacaftor in the overall population of study 5 (including the secondary endpoints of absolute change in BMI at 8 weeks of treatment and absolute change in the respiratory domain score of the CFQ-R through 8 weeks of treatment) and by individual mutation (absolute change in sweat chloride and in percent predicted FEV1 at week 8) is shown in Table 8. Based on clinical (percent predicted FEV1) and pharmacodynamic (sweat chloride) responses to ivacaftor, efficacy in patients with the G970R mutation could not be established.
KALY_50_75_150-SPC-0424-V1                                   Page 13 of 22 Table 8: Effect of ivacaftor for efficacy variables in the overall population and for specific CFTR mutations

Absolute change in percent                  BMI                    CFQ-R respiratory domain predicted FEV1                     (kg/m2)                         score (points) Through week 8                     At week 8                      Through week 8 All patients (N=39)
Results shown as mean (95% CI) change from baseline ivacaftor vs placebo-treated patients: 10.7 (7.3, 14.1)               0.66 (0.34, 0.99)                   9.6 (4.5, 14.7) 
Patients grouped under mutation types (n)
Results shown as mean (minimum, maximum) change from baseline for ivacaftor-treated patients at Week 8*:
Mutation (n)      Absolute change in sweat chloride   Absolute change in percent predicted (mmol/L)                     FEV1 (percentage points)
At week 8                              At week 8
G1244E (5)                 -55 (-75, -34)                            8 (-1, 18) G1349D (2)                 -80 (-82, -79)                           20 (3, 36) G178R (5)                  -53 (-65, -35)                            8 (-1, 18) -68†
†
G551S (2)                                                               3 #
G970R (4)                    -6 (-16, -2)                             3 (-1, 5) S1251N (8)                  -54 (-84, -7)                           9 (-20, 21) S1255P (2)                 -78 (-82, -74)                             3 (-1, 8) S549N (6)                 -74 (-93, -53)                           11 (-2, 20) S549R (4)                     ††
-61 (-71, -54)                             5 (-3, 13)
*
Statistical testing was not performed due to small numbers for individual mutations.
†
Reflects results from the one patient with the G551S mutation with data at the 8-week time point.
†† n=3 for the analysis of absolute change in sweat chloride.
#
Causes a splicing defect resulting in little-to-no CFTR protein at the cell surface 

In part 2 of study 5, the mean (SD) absolute change in percent predicted FEV1 following 16 weeks (patients randomised to the ivacaftor/placebo treatment sequence in part 1) of continuous ivacaftor treatment was 10.4% (13.2%). At the follow-up visit, 4 weeks after ivacaftor dosing had ended, the mean (SD) absolute change in percent predicted FEV1 from part 2 week 16 was -5.9% (9.4%). For patients randomised to the placebo/ivacaftor treatment sequence in part 1 there was a further mean (SD) change of 3.3% (9.3%) in percent predicted FEV1 after the additional 16 weeks of treatment with ivacaftor. At the follow up visit, 4 weeks after ivacaftor dosing had ended, the mean (SD) absolute change in percent predicted FEV1 from Part 2 week 16 was -7.4% (5.5%).

Study 8: Trial in Patients with CF Heterozygous for the F508del Mutation and a Second Mutation Predicted to be Responsive to ivacaftor

The efficacy and safety of Kalydeco and an ivacaftor-containing combination product in 246 patients with CF was evaluated in a randomized, double-blind, placebo-controlled, 2-period, 3-treatment, 8-week crossover design clinical trial (Trial 8). Mutations predicted to be responsive to ivacaftor were selected for the study based on the clinical phenotype (pancreatic sufficiency), biomarker data (sweat chloride), and in vitro responsiveness to ivacaftor.

Eligible patients were heterozygous for the F508del mutation with a second mutation predicted to be responsive to ivacaftor. Of the 244 patients included in the efficacy analysis, who were randomized and dosed, 146 patients had a splice mutation and 98 patients had a missense mutation, as the second allele.
156 patients received Kalydeco and 161 patients received placebo. Patients were aged 12 years and older (mean age 35 years [range 12-72]) and had a percent predicted FEV1 at screening between 40-90 [mean ppFEV1 at study baseline 62 (range: 35 to 94)]. Patients with evidence of colonization with organisms KALY_50_75_150-SPC-0424-V1                                 Page 14 of 22 associated with a more rapid decline in pulmonary status (e.g. Burkholderia cenocepacia, Burkholderia dolosa, or Mycobacterium abscessus) and those with abnormal liver function at screening were excluded.
Abnormal liver function was defined as 2 or more liver function tests (ALT, AST, ALP, GGT) ≥3 times the upper limit of normal or total bilirubin ≥2 times the upper limit of normal, or a single increase in ALT/AST ≥5 times the upper limit of normal.

The primary efficacy endpoint was the mean absolute change from study baseline in percent predicted FEV1 averaged at Weeks 4 and 8 of treatment. The key secondary efficacy endpoint was absolute change in CFQ-R respiratory domain score from study baseline averaged at Weeks 4 and 8 of treatment. For the overall population, treatment with Kalydeco compared to placebo resulted in significant improvement in ppFEV1 [4.7 percent points from study baseline to average of Week 4 and Week 8 (P<0.0001)] and CFQ-R respiratory domain score [9.7 points from study baseline to average of Week 4 and Week 8 (P<0.0001)]. Statistically significant improvements compared to placebo were also observed in the subgroup of patients with splice mutations and missense mutations (Table 9).

Table 9: Effect of Kalydeco for Efficacy Variables

Mutation (n)      Absolute Change Absolute Change in        Absolute Change in in         CFQ-R Respiratory        Sweat Chloride percent predicted Domain Score (Points)         (mmol/L) *±
*±
FEV 1 *†
Splice mutations (n=94 for IVA and n=97 for PBO)
Results shown as difference in mean (95% CI) change from study baseline for Kalydeco vs. placebo-treated patients:
5.                    8.5                  -2.4
4
(4.1, 6.8)           (5.3, 11.7)            (-5.0, 0.3)
By individual splice mutation (n). Results shown as mean (minimum, maximum) for change from study baseline for Kalydeco-treated patients
2789+5G→A (28)          5.1 (-7.1, 17.0)      8.6 (-5.6, 27.8)        0.4 (-7.5, 8.8)
3272-26A→G (23)         3.5 (-9.1, 16.0)     8.0 (-11.1, 27.8)     -2.3 (-25.0, 11.8) 3849+10kbC→T            5.1 (-6.8, 16.2)     7.5 (-30.6, 55.6)     -4.6 (-80.5, 23.0) (40)
711+3A→G (2)             9.2 (8.9, 9.6)      -8.3 (-13.9, -2.8)    -9.9 (-13.5, -6.3) E831X (1)                7.1 (7.1, 7.1)         0.0 (0.0, 0.0)      -7.8 (-7.8, -7.8) Missense mutations (n=62 for IVA and n=63 for PBO)
Results shown as difference in mean (95% CI) change from study baseline for Kalydeco vs. placebo-treated patients:
3.6                  11.5                  -7.8
(1.9, 5.2)           (7.5, 15.4)         (-11.2, -4.5)
By individual missense mutation (n). Results shown as mean (minimum, maximum) for change from study baseline for Kalydeco-treated patients
D579G (2)              13.3 (12.4, 14.1)     15.3 (-2.8, 33.3)   -30.8 (-36.0, -25.5) D1152H (15)             2.4 (-5.0, 10.2)    13.7 (-16.7, 50.0)      -4.8 (-22.0, 3.0) A455E (14)              3.7 (-6.6, 19.7)     6.8 (-13.9, 33.3)     7.5 (-16.8, 16.0) L206W (2)                4.2 (2.5, 5.9)      12.5 (-5.6, 30.6)       3.9 (-8.3, 16.0) P67L (12)               4.3 (-2.5, 25.7)    10.8 (-12.5, 36.1)    -10.5 (-34.8, 9.8) R1070W (1)               2.9 (2.9, 2.9)      44.4 (44.4, 44.4)        0.3 (0.3, 0.3) R117C (1)                3.5 (3.5, 3.5)      22.2 (22.2, 22.2)   -36.0 (-36.0, -36.0) R347H (3)                2.5 (-0.6, 6.9)        6.5 (5.6, 8.3)    -19.2 (-25.8, -7.0) R352Q (2)                4.4 (3.5, 5.3)        9.7 (8.3, 11.1)    -21.9 (-45.5, 1.8) S945L (9)               8.8 (-0.2, 20.5)    10.6 (-25.0, 27.8)   -30.8 (-50.8, -17.3) S977F (1)                4.3 (4.3, 4.3)       -2.8 (-2.8, -2.8)  -19.5 (-19.5, -19.5) * Average of Week 4 and 8 values
† Absolute change in ppFEV1 by individual mutations is an ad hoc analysis.

KALY_50_75_150-SPC-0424-V1                                   Page 15 of 22 Mutation (n)             Absolute Change Absolute Change in      Absolute Change in in          CFQ-R Respiratory     Sweat Chloride percent predicted Domain Score (Points)    (mmol/L) *±
*±
FEV 1 *†
± Absolute change in CFQ-R respiratory domain score and absolute change in sweat chloride by mutation subgroups and by individual mutations are ad hoc analyses.

In an analysis of BMI at Week 8, an exploratory end-point, patients treated with Kalydeco had a mean improvement of 0.28 kg/m2 [95% CI (0.14, 0.43)], 0.24 kg/m2 [95% CI (0.06, 0.43)], and 0.35 kg/m2 [95% CI (0.12, 0.58)] versus placebo for the overall, splice, and missense mutation populations of patients, respectively.

Study 3: study in patients with CF with the F508del mutation in the CFTR gene Study 3 (part A) was a 16-week, 4:1 randomised, double-blind, placebo-controlled, parallel-group phase 2 study of ivacaftor (150 mg every 12 hours) in 140 patients with CF aged 12 years and older who were homozygous for the F508del mutation in the CFTR gene and who had FEV1 ≥40% predicted.

The mean absolute change from baseline through week 16 in percent predicted FEV1 (primary efficacy endpoint) was 1.5 percentage points in the ivacaftor group and -0.2 percentage points in the placebo group. The estimated treatment difference for ivacaftor versus placebo was 1.7 percentage points (95% CI -0.6, 4.1); this difference was not statistically significant (P=0.15).

Study 4: open-label extension study
In Study 4, patients who completed treatment in studies 1 and 2 with placebo were switched to ivacaftor, while patients on ivacaftor continued to receive it for a minimum of 96 weeks, i.e., the length of treatment with ivacaftor was at least 96 weeks for patients in the placebo/ivacaftor group and at least 144 weeks for patients in the ivacaftor/ivacaftor group.

One hundred and forty-four (144) patients from study 1 were rolled over in study 4, 67 in the placebo/ivacaftor group and 77 in the ivacaftor/ivacaftor group. Forty-eight (48) patients from study 2 were rolled over in study 4, 22 in the placebo/ivacaftor group and 26 in the ivacaftor/ivacaftor group.

Table 10 shows the results of the mean (SD) absolute change in percent predicted FEV1 for both groups of patients. For patients in the placebo/ivacaftor group, baseline percent predicted FEV1 is that of study 4 while for patients in the ivacaftor/ivacaftor group, the baseline value is that of studies 1 and 2.

Table 10: Effect of ivacaftor on percent predicted FEV1 in study 4

Original study and                  Duration of ivacaftor              Absolute change from baseline in percent treatment group                      treatment (weeks)                   predicted FEV1 (percentage points) N                Mean (SD)
Study 1
Ivacaftor                                   48*                       77                         9.4 (8.3) 144                       72                        9.4 (10.8)
†
Placebo                                  0*                       67                        -1.2 (7.8) 96                       55                        9.5 (11.2)
Study 2
Ivacaftor                                   48*                       26                        10.2 (15.7) 144                       25                        10.3 (12.4)
†
Placebo                                  0*                       22                        -0.6 (10.1) 96                       21                        10.5 (11.5)
* Treatment occurred during blinded, controlled, 48-week phase 3 study.
†
Change from prior study baseline after 48 weeks of placebo treatment.


KALY_50_75_150-SPC-0424-V1                                  Page 16 of 22 When the mean (SD) absolute change in percent predicted FEV1 is compared from study 4 baseline for patients in the ivacaftor/ivacaftor group (n=72) who rolled over from study 1, the mean (SD) absolute change in percent predicted FEV1 was 0.0% (9.05), while for patients in the ivacaftor/ivacaftor group (n=25) who rolled over from study 2 this figure was 0.6% (9.1). This shows that patients in the ivacaftor/ivacaftor group maintained the improvement seen at week 48 of the initial study (day 0 through week 48) in percent predicted FEV1 through week 144. There were no additional improvements in study 4 (week 48 through week 144).

For patients in the placebo/ivacaftor group from study 1, the annualised rate of pulmonary exacerbations was higher in the initial study when patients were on placebo (1.34 events/year) than during the subsequent study 4 when patients rolled over to ivacaftor (0.48 events/year across day 1 to week 48, and 0.67 events/year across weeks 48 to 96). For patients in the ivacaftor/ivacaftor group from study 1, the annualised rate of pulmonary exacerbations was 0.57 events/year across day 1 to week 48 when patients were on ivacaftor. When they rolled over into study 4, the rate of annualised pulmonary exacerbations was 0.91 events/year across day 1 to week 48 and 0.77 events/year across weeks 48 to 96.

For patients who rolled over from study 2 the number of events was, overall, low.

Study 7: study in paediatric patients with CF aged 2 to less than 6 years with G551D or another gating mutation
The pharmacokinetic profile, safety and efficacy of ivacaftor in 34 patients aged 2 to less than 6 years with CF who had a G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N or S549R mutation in the CFTR gene were assessed in a 24-week uncontrolled study with ivacaftor (patients weighing less than 14 kg received ivacaftor 50 mg and patients weighing 14 kg or more received ivacaftor 75 mg). Ivacaftor was administered orally every 12 hours with fat-containing food in addition to their prescribed CF therapies.

Patients in study 7 were aged 2 to less than 6 years (mean age 3 years). Twenty-six patients out of the 34 enrolled (76.5%) had a CFTR genotype G551D/F508del with only 2 patients with a non-G551D mutation (S549N). The mean (SD) sweat chloride at baseline (n=25) was 97.88 mmol/L (14.00). The mean (SD) faecal elastase-1 value at baseline (n=27) was 28 µg/g (95).

The primary endpoint of safety was evaluated through week 24 (see section 4.8). Secondary and exploratory efficacy endpoints evaluated were absolute change from baseline in sweat chloride through 24 weeks of treatment, absolute change from baseline in weight, body mass index (BMI) and stature
(supported by weight, BMI and stature z-scores) at 24 weeks of treatment, and measures of pancreatic function such as faecal elastase-1. Data on percent predicted FEV1 (exploratory endpoint) were available for 3 patients in the ivacaftor 50 mg group and 17 patients in the 75 mg dosing group.

The mean (SD) overall (both ivacaftor dosing groups combined) absolute change from baseline in BMI at week 24 was 0.32 kg/m2 (0.54) and the mean (SD) overall change in BMI-for-age z-score was 0.37 (0.42).
The mean (SD) overall change in stature-for-age z-score was -0.01 (0.33). The mean (SD) overall change from baseline in faecal elastase-1 (n=27) was 99.8 µg/g (138.4). Six patients with initial levels below 200 µg/g achieved, at week 24, a level of ≥200 µg/g. The mean (SD) overall change in percent predicted FEV1 from baseline at week 24 (exploratory endpoint) was 1.8 (17.81).

Pharmacokinetic Properties

5.2 Pharmacokinetic properties
The pharmacokinetics of ivacaftor are similar between healthy adult volunteers and patients with CF.

After oral administration of a single 150 mg dose to healthy volunteers in a fed state, the mean (±SD) for AUC and Cmax were 10600 (5260) ng*hr/mL and 768 (233) ng/mL, respectively. After every 12-hour dosing, steady-state plasma concentrations of ivacaftor were reached by days 3 to 5, with an accumulation ratio ranging from 2.2 to 2.9.


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Absorption
Following multiple oral dose administrations of ivacaftor, the exposure of ivacaftor generally increased with dose from 25 mg every 12 hours to 450 mg every 12 hours. When given with fat-containing food, the exposure of ivacaftor increased approximately 2.5- to 4-fold. Therefore, ivacaftor should be administered with fat-containing food. The median (range) tmax is approximately 4.0 (3.0; 6.0) hours in the fed state.

Ivacaftor granules (2 x 75 mg sachets) had similar bioavailability as the 150 mg tablet when given with fat-containing food to healthy adult subjects. The geometric least squares mean ratio (90% CI) for the granules relative to tablets was 0.951 (0.839, 1.08) for AUC0-∞ and 0.918 (0.750, 1.12) for Cmax. The effect of food on ivacaftor absorption is similar for both formulations, i.e., tablets and granules.

Distribution
Ivacaftor is approximately 99% bound to plasma proteins, primarily to alpha 1-acid glycoprotein and albumin. Ivacaftor does not bind to human red blood cells.

After oral administration of ivacaftor 150 mg every 12 hours for 7 days in healthy volunteers in a fed state, the mean (±SD) apparent volume of distribution was 353 L (122).

Biotransformation
Ivacaftor is extensively metabolised in humans. In vitro and in vivo data indicate that ivacaftor is primarily metabolised by CYP3A. M1 and M6 are the two major metabolites of ivacaftor in humans. M1 has approximately one-sixth the potency of ivacaftor and is considered pharmacologically active. M6 has less than one-fiftieth the potency of ivacaftor and is not considered pharmacologically active.

The effect of the CYP3A4*22 heterozygous genotype on ivacaftor exposure is consistent with the effect of co-administration of a weak CYP3A4 inhibitor, which is not clinically relevant. No dose adjustment of ivacaftor is considered necessary. The effect of CYP3A4*22 homozygous genotype patients is expected to be stronger. However, no data are available for such patients.

Elimination
Following oral administration in healthy volunteers, the majority of ivacaftor (87.8%) was eliminated in the faeces after metabolic conversion. The major metabolites M1 and M6 accounted for approximately 65% of the total dose eliminated with 22% as M1 and 43% as M6. There was negligible urinary excretion of ivacaftor as unchanged parent. The apparent terminal half-life was approximately 12 hours following a single dose in the fed state. The apparent clearance (CL/F) of ivacaftor was similar for healthy patients and patients with CF. The mean (±SD) CL/F for a single 150 mg dose was 17.3 (8.4) L/hr in healthy patients.

Linearity/non-linearity
The pharmacokinetics of ivacaftor are generally linear with respect to time or dose ranging from 50 mg to 250 mg.

Special populations
Hepatic impairment
Following a single dose of 150 mg of ivacaftor, adult subjects with moderately impaired hepatic function (Child-Pugh Class B, score 7 to 9) had similar ivacaftor Cmax (mean [±SD] of 735 [331] ng/mL) but an approximately two-fold increase in ivacaftor AUC0-∞ (mean [±SD] of 16800 [6140] ng*hr/mL) compared with healthy subjects matched for demographics. Simulations for predicting the steady-state exposure of ivacaftor showed that by reducing the dosage from 150 mg q12h to 150 mg once daily, adults with moderate hepatic impairment would have comparable steady-state Cmin values as those obtained with a dose of 150 mg q12h in adults without hepatic impairment. Based on these results, a modified regimen of Kalydeco monotherapy is recommended for patients with moderate hepatic impairment (see section 4.2).


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The impact of severe hepatic impairment (Child-Pugh Class C, score 10 to 15) on the pharmacokinetics of ivacaftor has not been studied. The magnitude of increase in exposure in these patients is unknown but is expected to be higher than that observed in patients with moderate hepatic impairment.

For guidance on appropriate use and dose modification see Table 3 in section 4.2.

Renal impairment
Pharmacokinetic studies have not been performed with ivacaftor in patients with renal impairment. In a human pharmacokinetic study, there was minimal elimination of ivacaftor and its metabolites in urine (only 6.6% of total radioactivity was recovered in the urine). There was negligible urinary excretion of ivacaftor as unchanged parent (less than 0.01% following a single oral dose of 500 mg). Therefore, no dose adjustments are recommended for mild and moderate renal impairment. However, caution is recommended when administering ivacaftor to patients with severe renal impairment (creatinine clearance less than or equal to 30 mL/min) or end-stage renal disease (see sections 4.2 and 4.4).

Race
Race had no clinically meaningful effect on the PK of ivacaftor in white (n=379) and non-white (n=29) patients based on a population PK analysis.

Gender
The pharmacokinetic parameters of ivacaftor are similar in males and females.

Elderly
Clinical studies of ivacaftor as monotherapy did not include sufficient numbers of patients aged 65 years and older to determine whether pharmacokinetic parameters are similar or not to those in younger adults.

Paediatric population
Predicted ivacaftor exposure based on observed ivacaftor concentrations in phase 2 and 3 studies as determined using population PK analysis is presented by age group in Table 11.

Table 11: Mean (SD) ivacaftor exposure by age group

Age group                         Dose                                 Cmin, ss (ng/mL)                   AUCτ,ss (ng*h/mL) 2- to 5-year-olds                 50 mg q12h                           577 (317)                          10500 (4260)
(<14 kg)
2- to 5-year-olds                 75 mg q12h                           629 (296)                          11300 (3820)
(≥14 kg to <25 kg)
6- to 11-year-olds†               75 mg q12h                           641 (329)                          10760 (4470) (≥14 kg to <25 kg)
6- to 11-year-olds †              150 mg q12h                          958 (546)                          15300 (7340) (≥25 kg)
12- to 17-year-olds               150 mg q12h                          564 (242)                          9240 (3420) Adults (≥18 years old)            150 mg q12h                          701 (317)                          10700 (4100) *
Values based on data from a single patient; standard deviation not reported.

†
Exposures in 6- to 11-year-olds are predictions based on simulations from the population PK model using data obtained for this age group.