Kalydeco

KALYDECO is indicated for the treatment of cystic fibrosis (CF) in patients aged 1 month and older who have at least one mutation in the

[see

12.1 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 Fischer 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 3 below

[see also Clinical Studies (14.4)]

. 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 Clinical Studies (14.2)]

.

Ivacaftor also increased chloride transport in cultured human bronchial epithelial (HBE) cells derived from CF patients who carried

F508del

on one

CFTR

allele and either

G551D

or

R117H-5T

on the second

CFTR

allele.

Table 3 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 3: List of CFTR Gene Mutations that Produce CFTR Protein and are Responsive to KALYDECO

711+3A→GClinical data exist for these mutations [see Clinical Studies (14)] .	F311del	I148T	R75Q	S589N
2789+5G→A	F311L	I175V	R117C	S737F
3272-26A→G	F508C	I807M	R117G	S945L
3849+10kbC→T	F508C;S1251N 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.	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
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

and

14 CLINICAL STUDIES

14.1 Trials in Patients with CF who have a

G551D

Mutation in the

CFTR

Gene

Dose Ranging:

Dose ranging for the clinical program consisted primarily of one double-blind, placebo-controlled, crossover trial in 39 adult (mean age 31 years) Caucasian patients with CF who had FEV₁≥40% predicted. Twenty patients with median predicted FEV₁at baseline of 56% (range: 42% to 109%) received KALYDECO 25, 75, 150 mg, or placebo every 12 hours for 14 days and 19 patients with median predicted FEV₁at baseline of 69% (range: 40% to 122%) received KALYDECO 150, 250 mg, or placebo every 12 hours for 28 days. The selection of the 150 mg every 12 hours dose was primarily based on nominal improvements in lung function (pre-dose FEV₁) and changes in pharmacodynamic parameters (sweat chloride and nasal potential difference). The twice-daily dosing regimen was primarily based on an apparent terminal plasma half-life of approximately 12 hours.

Efficacy:

The efficacy of KALYDECO in patients with CF who have a

G551D

mutation in the

CFTR

gene was evaluated in two randomized, double-blind, placebo-controlled clinical trials in 213 clinically stable patients with CF (109 receiving KALYDECO 150 mg twice daily). All eligible patients from these trials were rolled over into an open-label extension study.

Trial 1 evaluated 161 patients with CF who were 12 years of age or older (mean age 26 years) with FEV₁at screening between 40-90% predicted [mean FEV₁64% predicted at baseline (range: 32% to 98%)]. Trial 2 evaluated 52 patients who were 6 to 11 years of age (mean age 9 years) with FEV₁at screening between 40-105% predicted [mean FEV₁84% predicted at baseline (range: 44% to 134%)]. Patients who had persistent

Burkholderia cenocepacia, Burkholderia dolosa

, or

Mycobacterium abscessus

isolated from sputum at screening and those with abnormal liver function defined as 3 or more liver function tests (ALT, AST, AP, GGT, total bilirubin) ≥3 times the ULN were excluded.

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

The primary efficacy endpoint in both studies was improvement in lung function as determined by the mean absolute change from baseline in percent predicted pre-dose FEV₁through 24 weeks of treatment.

In both studies, treatment with KALYDECO resulted in a significant improvement in FEV₁. The treatment difference between KALYDECO and placebo for the mean absolute change in percent predicted FEV₁from baseline through Week 24 was 10.6 percentage points (

P

<0.0001) in Trial 1 and 12.5 percentage points (

P

<0.0001) in Trial 2 (Figure 3). These changes persisted through 48 weeks. Improvements in percent predicted FEV₁were observed regardless of age, disease severity, sex, and geographic region.

Figure 3: Mean Absolute Change from Baseline in Percent Predicted FEV1Primary endpoint was assessed at the 24-week time point.

Other efficacy variables included absolute change from baseline in sweat chloride [

see

Clinical Pharmacology (12.2)

], time to first pulmonary exacerbation (Trial 1 only), absolute change from baseline in weight, and improvement from baseline in Cystic Fibrosis Questionnaire Revised (CFQ-R) respiratory domain score, a measure of respiratory symptoms relevant to patients with CF such as cough, sputum production, and difficulty breathing. For the purpose of the study, a pulmonary exacerbation was defined as a change in antibiotic therapy (IV, inhaled, or oral) as a result of 4 or more of 12 pre-specified sino-pulmonary signs/symptoms. Patients treated with KALYDECO demonstrated statistically significant improvements in risk of pulmonary exacerbations, CF symptoms (in Trial 1 only), and gain in body weight (Table 5). Weight data, when expressed as body mass index normalized for age and sex in patients <20 years of age, were consistent with absolute change from baseline in weight.

Table 5: Effect of KALYDECO on Other Efficacy Endpoints in Trials 1 and 2

	Trial 1		Trial 2
Endpoint	Treatment differenceTreatment difference = effect of KALYDECO – effect of Placebo. (95% CI)	P value	Treatment difference (95% CI)	P value
CI: confidence interval; NA: not analyzed due to low incidence of events.
Mean absolute change from baseline in CFQ-R respiratory domain score (points)
Through Week 24	8.1 (4.7, 11.4)	<0.0001	6.1 (-1.4, 13.5)	0.1092
Through Week 48	8.6 (5.3, 11.9)	<0.0001	5.1 (-1.6, 11.8)	0.1354
Relative risk of pulmonary exacerbation
Through Week 24	0.40Hazard ratio for time to first pulmonary exacerbation.	0.0016	NA	NA
Through Week 48	0.46	0.0012	NA	NA
Mean absolute change from baseline in body weight (kg)
At Week 24	2.8 (1.8, 3.7)	<0.0001	1.9 (0.9, 2.9)	0.0004
At Week 48	2.7 (1.3, 4.1)	0.0001	2.8 (1.3, 4.2)	0.0002
Absolute change in sweat chloride (mmol/L)
Through Week 24	-48 (-51, -45)	<0.0001	-54 (-62, -47)	<0.0001
Through Week 48	-48 (-51, -45)	<0.0001	-53 (-61, -46)	<0.0001

14.2 Trial in Patients with a

G1244E

,

G1349D

,

G178R

,

G551S

,

G970R

,

S1251N

,

S1255P

,

S549N

, or

S549R

Mutation in the

CFTR

Gene

The efficacy and safety of KALYDECO in patients with CF who have a

G1244E

,

G1349D

,

G178R

,

G551S

,

G970R

,

S1251N

,

S1255P

,

S549N

, or

S549R

mutation in the

CFTR

gene were evaluated in a two-part, randomized, double-blind, placebo-controlled, crossover design clinical trial in 39 patients with CF (Trial 4). Patients who completed Part 1 of this trial continued into the 16-week open-label Part 2 of the study. The mutations studied were

G178R

,

S549N

,

S549R

,

G551S

,

G970R

,

G1244E

,

S1251N

,

S1255P

, and

G1349D.

See

Clinical Studies (14.1)

for efficacy in patients with a

G551D

mutation.

Patients were 6 years of age or older (mean age 23 years) with FEV₁≥40% at screening [mean FEV₁at baseline 78% predicted (range: 43% to 119%)]. Patients with evidence of colonization with

Burkholderia cenocepacia, Burkholderia dolosa

, or

Mycobacterium abscessus

and those with abnormal liver function defined as 3 or more liver function tests (ALT, AST, AP, GGT, total bilirubin) ≥3 times the ULN at screening were excluded.

Patients were randomized 1:1 to receive either 150 mg of KALYDECO or placebo every 12 hours with fat-containing food for 8 weeks in addition to their prescribed CF therapies during the first treatment period and crossed over to the other treatment for the second 8 weeks. The two 8-week treatment periods were separated by a 4- to 8-week washout period. The use of inhaled hypertonic saline was not permitted.

The primary efficacy endpoint was improvement in lung function as determined by the mean absolute change from baseline in percent predicted FEV₁through 8 weeks of treatment. Other efficacy variables included absolute change from baseline in sweat chloride through 8 weeks of treatment [

see Clinical Pharmacology (12.2)

], absolute change from baseline in body mass index (BMI) at 8 weeks of treatment (including body weight at 8 weeks), and improvement in CFQ-R respiratory domain score through 8 weeks of treatment. For the overall population of the 9 mutations studied, treatment with KALYDECO compared to placebo resulted in significant improvement in percent predicted FEV₁[10.7 through Week 8 (

P

<0.0001)], BMI [0.66 kg/m²at Week 8 (

P

<0.0001)], and CFQ-R respiratory domain score [9.6 through Week 8 (

P

=0.0004)]; however, there was a high degree of variability of efficacy responses among the 9 mutations (Table 6).

Table 6: Effect of KALYDECO for Efficacy Variables in the Overall Populations and for Specific CFTR Mutations

Mutation (n)	Absolute change in percent predicted FEV1			BMI (kg/m2)	CFQ-R Respiratory Domain Score (Points)	Absolute Change in Sweat Chloride (mmol/L)
	At Week 2	At Week 4	At Week 8	At Week 8	At Week 8	At Week 8
All patients (n=39) Results shown as mean (95% CI) change from baseline KALYDECO vs. placebo-treated patients:
	8.3 (4.5, 12.1)	10.0 (6.2, 13.8)	13.8 (9.9, 17.6)	0.66Result for weight gain as a component of body mass index was consistent with BMI.(0.34, 0.99)	12.8 (6.7, 18.9)	-50 (-58, -41)n=36 for the analysis of absolute change in sweat chloride.
Patients grouped under mutation types (n) Results shown as mean (minimum, maximum) for change from baseline for KALYDECO-treated patients:Statistical testing was not performed due to small numbers for individual mutations.
G1244E (5)	11 (-5, 25)	6 (-5, 13)	8 (-1, 18)	0.63 (0.34, 1.32)	3.3 (-27.8, 22.2)	-55 (-75, -34)
G1349D (2)	19 (5, 33)	18 (2, 35)	20 (3, 36)	1.15 (1.07, 1.22)	16.7 (-11.1, 44.4)	-80 (-82, -79)
G178R (5)	7 (1, 17)	10 (-2, 21)	8 (-1, 18)	0.85 (0.33, 1.46)	20.0 (5.6, 50.0)	-53 (-65, -35)
G551S (2)	0 (-5, 5)	0.3 (-5, 6)	3Reflects results from the one patient with the G551S mutation with data at the 8-week time point.	0.16	16.7	-68
G970R (4)	7 (1, 13)	7 (1, 14)	3 (-1, 5)	0.48 (-0.38, 1.75)	1.4 (-16.7, 16.7)	-6 (-16, -2)
S1251N (8)	2 (-23, 20)	8 (-13, 26)	9 (-20, 21)	0.73 (0.08, 1.83)	23.3 (5.6, 50.0)	-54 (-84, -7)
S1255P (2)	11 (8, 14)	9 (5, 13)	3 (-1, 8)	1.62 (1.39, 1.84)	8.3 (5.6, 11.1)	-78 (-82, -74)
S549N (6)	11 (5, 16)	8 (-9, 19)	11 (-2, 20)	0.79 (0.00, 1.91)	8.8 (-8.3, 27.8)	-74 (-93, -53)
S549R (4)	3 (-4, 8)	4 (-4, 10)	5 (-3, 13)	0.53 (0.33, 0.80)	6.9 (0.0, 11.1)	-61n=3 for the analysis of absolute change in sweat chloride.(-71, -54)

14.3 Trial in Patients with CF who have an

R117H

Mutation in the

CFTR

Gene

The efficacy and safety of KALYDECO in patients with CF who have an

R117H

mutation in the

CFTR

gene were evaluated in a randomized, double-blind, placebo-controlled, parallel-group clinical trial (Trial 5). Fifty-nine of 69 patients completed 24 weeks of treatment. Two patients discontinued and 8 patients did not complete treatment due to study termination. Trial 5 evaluated 69 clinically stable patients with CF who were 6 years of age or older (mean age 31 years). Patients who were aged 12 years and older had FEV₁at screening between 40-90% predicted, and patients who were 6-11 years of age had FEV₁at screening between 40-105% predicted. The overall mean FEV₁was 73% predicted at baseline (range: 33% to 106%). The patients had well preserved BMIs (mean overall: 23.76 kg/m²) and a high proportion were pancreatic sufficient as assessed by a low rate of pancreatic enzyme replacement therapy use (pancreatin: 11.6%; pancrelipase: 5.8%). Patients who had persistent

Burkholderia cenocepacia, Burkholderia dolosa

, or

Mycobacterium abscessus

isolated from sputum at screening, and those with abnormal liver function defined as 3 or more liver function tests (ALT, AST, AP, GGT, total bilirubin) ≥3 times the ULN, were excluded.

Patients were randomized 1:1 to receive either 150 mg of KALYDECO (n=34) or placebo (n=35) every 12 hours with fat-containing food for 24 weeks in addition to their prescribed CF therapies.

The primary efficacy endpoint was improvement in lung function as determined by the mean absolute change from baseline in percent predicted FEV₁through 24 weeks of treatment. The treatment difference for absolute change in percent predicted FEV₁through Week 24 was 2.1 percentage points (analysis conducted with the full analysis set which included all 69 patients) and did not reach statistical significance (Table 7).

Other efficacy variables that were analyzed included absolute change in sweat chloride from baseline through Week 24, improvement in cystic fibrosis respiratory symptoms through Week 24 as assessed by the CFQ-R respiratory domain score (Table 7), absolute change in body mass index (BMI) at Week 24, and time to first pulmonary exacerbation. The overall treatment difference for the absolute change from baseline in BMI at Week 24 was 0.3 kg/m²and the calculated hazard ratio for time to first pulmonary exacerbation was 0.93, which were not statistically significant.

Statistically significant improvements in clinical efficacy (FEV₁, CFQ-R respiratory domain score) were seen in several subgroup analyses and decreases in sweat chloride were observed in all subgroups. The mean baseline sweat chloride for all patients was 70 mmol/L. Subgroups analyzed included those based on age, lung function, and poly-T status (Table 7).

Table 7: Effect of KALYDECO on Overall Population (Percent Predicted FEV_1,CFQ-R Respiratory Domain Score, and Sweat Chloride) and in Relevant Subgroups Through 24 Weeks

		Absolute Change through Week 24MMRM analysis with fixed effects for treatment, age, week, baseline value, treatment by week, and subject as a random effect.- All Randomized Patients
		% Predicted FEV1 (Percentage Points)			CFQ-R Respiratory Domain Score (Points)			Sweat Chloride (mmol/L)
Subgroup Parameter	Study Drug	n	Mean	Treatment Difference (95% CI)	n	Mean	Treatment Difference (95% CI)	n	Mean	Treatment Difference (95% CI)
R117H–All Patients
	Placebo KALYDECO	35 34	0.5 2.6	2.1 (-1.1, 5.4)	34 33	-0.8 7.6	8.4 (2.2, 14.6)	35 32	-2.3 -26.3	-24.0 (-28.0, -19.9)
Subgroup by Age
6-11	Placebo KALYDECO	8 9	3.5 -2.8	-6.3 (-12.0, -0.7)	7 8	-1.6 -7.7	-6.1 (-15.7, 3.4)	8 8	1.0 -26.6	-27.6 (-37.2, -18.1)
12-17	Placebo KALYDECO	1 1	---	---	1 1	---	---	1 1	---	---
≥18	Placebo KALYDECO	26 24	-0.5 4.5	5.0 (1.1, 8.8)	26 24	-0.5 12.2	12.6 (5.0, 20.3)	26 23	-4.0 -25.9	-21.9 (-26.5, -17.3)
Subgroup by Poly-T Status(n=54) Poly-T status confirmed by genotyping.
5T	Placebo KALYDECO	24 14	0.7 6.0	5.3 (1.3, 9.3)	24 14	-0.6 14.7	15.3 (7.7, 23.0)	24 13	-4.6 -28.7	-24.2 (-30.2, -18.2)
7T	Placebo KALYDECO	5 11	-0.9 -0.7	0.2 (-8.1, 8.5)	5 11	-6.0 -0.7	5.2 (-13.0, 23.4)	5 10	3.9 -20.2	-24.1 (-33.9, -14.3)
Subgroup by Baseline FEV1% Predicted
<70%	Placebo KALYDECO	15 13	0.4 4.5	4.0 (-2.1, 10.1)	15 13	3.0 14.4	11.4 (1.2, 21.6)	15 12	-3.8 -29.3	-25.5 (-31.8, -19.3)
70-90%	Placebo KALYDECO	14 14	0.2 2.8	2.6 (-2.3, 7.5)	13 14	-3.6 5.2	8.8 (-2.6, 20.2)	14 14	-3.1 -23.0	-20.0 (-26.9, -12.9)
>90%	Placebo KALYDECO	6 7	2.2 -2.1	-4.3 (-9.9, 1.3)	6 6	-2.5 -3.2	-0.7 (-10.4, 9.0)	6 6	1.0 -25.9	-26.8 (-39.5, -14.1)

14.4 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 7). 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 FEV₁at screening between 40-90 [mean ppFEV₁at study baseline 62 (range: 35 to 94)]. Patients with evidence of colonization with organisms 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 ULN or total bilirubin ≥2 times the ULN, or a single increase in ALT/AST ≥5 times the ULN.

The primary efficacy endpoint was the mean absolute change from study baseline in percent predicted FEV₁averaged 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 8).

Table 8: Effect of KALYDECO for Efficacy Variables

Mutation (n)	Absolute Change in percent predicted FEV1Average of Week 4 and 8 values.Absolute change in ppFEV1by individual mutations is an ad hoc analysis.	Absolute Change in CFQ-R Respiratory Domain Score (Points) 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.	Absolute Change in Sweat Chloride (mmol/L)
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:
	5.4 (4.1, 6.8)	8.5 (5.3, 11.7)	-2.4 (-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 (40)	5.1 (-6.8, 16.2)	7.5 (-30.6, 55.6)	-4.6 (-80.5, 23.0)
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 (1.9, 5.2)	11.5 (7.5, 15.4)	-7.8 (-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)

In an analysis of BMI at Week 8, an exploratory endpoint, 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.

14.5 Trial in Patients Homozygous for the

F508del

Mutation in the

CFTR

Gene

Trial 3 was a 16-week, randomized, double-blind, placebo-controlled, parallel-group trial 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. Patients were randomized 4:1 to receive KALYDECO 150 mg (n=112) every 12 hours or placebo (n=28) in addition to their prescribed CF therapies. The mean age of patients enrolled was 23 years and the mean baseline FEV₁was 79% predicted (range: 40% to 129%). As in Trials 1 and 2, patients who had persistent

Burkholderia cenocepacia, Burkholderia dolosa

, or

Mycobacterium abscessus

isolated from sputum at screening and those with abnormal liver function defined as 3 or more liver function tests (ALT, AST, AP, GGT, total bilirubin) ≥3 times the ULN were excluded. The use of inhaled hypertonic saline was not permitted.

The primary endpoint was improvement in lung function as determined by the mean absolute change from baseline through Week 16 in percent predicted FEV₁. The treatment difference from placebo for the mean absolute change in percent predicted FEV₁through Week 16 in patients with CF homozygous for the

F508del

mutation in the

CFTR

gene was 1.72 percentage points (1.5% and -0.2% for patients in the KALYDECO and placebo-treated groups, respectively) and did not reach statistical significance (Table 9).

Other efficacy variables that were analyzed included absolute change in sweat chloride from baseline through Week 16, change in cystic fibrosis respiratory symptoms through Week 16 as assessed by the CFQ-R respiratory domain score (Table 9), change in weight through Week 16, and rate of pulmonary exacerbation. The overall treatment difference for change from baseline in weight through Week 16 was -0.16 kg (95% CI -1.06, 0.74); the rate ratio for pulmonary exacerbation was 0.677 (95% CI 0.33, 1.37).

Table 9: Effect of KALYDECO on Overall Population (Percent Predicted FEV₁, CFQ-R Respiratory Domain Score, and Sweat Chloride) Through 16 Weeks

		Absolute Change through Week 16MMRM analysis with fixed effects for treatment, age week, baseline value, treatment by week, and subject as a random effect.- Full Analysis Set
		% Predicted FEV1 (Percentage Points)			CFQ-R Respiratory Domain Score (Points)			Sweat Chloride (mmol/L)
Subgroup Parameter	Study Drug	n	Mean	Treatment Difference (95% CI)	n	Mean	Treatment Difference (95% CI)	n	Mean	Treatment Difference (95% CI)
F508del homozygous
	Placebo KALYDECO	28 111	-0.2 1.5	1.72 (-0.6, 4.1)	28 111	-1.44 -0.12	1.3 (-2.9, 5.6)	28 109	0.13 -2.74	-2.9 (-5.6, -0.2)

]

If the patient's genotype is unknown, an FDA-cleared CF mutation test should be used to detect the presence of a

• See full prescribing information for the recommended dosage in patients aged 6 months and older with moderate or severe hepatic impairment. (
  2.3 Recommended Dosage for Patients with Hepatic Impairment

  KALYDECO is not recommended in patients less than 6 months of age with any level of hepatic impairment. The following is the recommended dosage of KALYDECO taken with fat-containing food

  [see Dosage and Administration (2.5)]

  for patients aged 6 months and older with hepatic impairment:

  • Mild Hepatic Impairment (Child-Pugh Class A):
    • Less than 6 months of age: KALYDECO is not recommended.
    • No dosage adjustment is necessary for patients aged 6 months or older
      [see Clinical Pharmacology (12.3)]
      .
  • Moderate Hepatic Impairment (Child-Pugh Class B):
    • Less than 6 months of age: KALYDECO is not recommended.
    • 6 months to less than 6 years of age: one packet (containing 25 mg, 50 mg, or 75 mg ivacaftor) of oral granules once daily based on dosing recommended for age and weight in Table 1
      [see Dosage and Administration (2.2)].
    • 6 years of age and older: 150 mg orally once daily.
  • Severe Hepatic Impairment (Child-Pugh Class C):
    Should not be used in patients less than 6 months of age. In patients aged 6 months and older should be used with caution. KALYDECO has not been studied in patients with severe hepatic impairment (Child-Pugh Class C), but exposure is expected to be higher than in patients with moderate hepatic impairment. Therefore, use with caution at a reduced dosage, in patients aged 6 months or older with severe hepatic impairment after weighing the risks and benefits of treatment
    [see Dosage and Administration (2.1, 2.2)and Clinical Pharmacology (12.3)]
    .
    • Less than 6 months of age: KALYDECO is not recommended.
    • 6 months to less than 6 years of age: one packet (containing 25 mg, 50 mg, or 75 mg ivacaftor) of oral granules once daily or less frequently based on dosing recommended for age and weight in Table 1
      [see Dosage and Administration (2.2)].
    • 6 years of age and older: 150 mg orally once daily or less frequently.
  ,
  8.6 Hepatic Impairment

  • Mild Hepatic Impairment (Child-Pugh Class A):
    No dosage adjustment is necessary for patients aged 6 months or older
    [see Clinical Pharmacology (12.3)]
    .
  • Moderate Hepatic Impairment (Child-Pugh Class B):
    A reduced dosage is recommended in patients aged 6 months or older
    [see Dosage and Administration (2.3)and Clinical Pharmacology (12.3)]
    .
  • Severe Hepatic Impairment (Child-Pugh Class C):
    Studies have not been conducted in patients with severe hepatic impairment (Child-Pugh Class C), but exposure is expected to be higher than in patients with moderate hepatic impairment. Therefore, use with caution at a reduced dosage, in patients aged 6 months or older with severe hepatic impairment after weighing the risks and benefits of treatment [
    see Dosage and Administration (2.3)and Clinical Pharmacology (12.3)
    ].

  Due to variability in maturation of cytochrome (CYP) enzymes involved in ivacaftor metabolism, treatment with KALYDECO is not recommended in patients aged 1 month to less than 6 months with any level of hepatic impairment

  [see Dosage and Administration (2.3)]

  .
  )
• See full prescribing information for dosage modifications due to drug interactions with KALYDECO. (
  2.4 Dosage Modification for Patients Taking Drugs that are CYP3A Inhibitors

  Concomitant use of moderate or strong CYP3A inhibitors is not recommended in patients below 6 months of age. Food or drink containing grapefruit should be avoided

  [see Drug Interactions (7.1)and Clinical Pharmacology (12.3)].

  Take KALYDECO with fat-containing food

  [see Dosage and Administration (2.5)].

  Dosage modification for patients 6 months of age and older taking CYP3A inhibitors

  :

  • Moderate CYP3A inhibitors:
    • Less than 6 months of age: KALYDECO is not recommended.
    • 6 months to less than 6 years of age: one packet (containing 25 mg, 50 mg, or 75 mg ivacaftor) of oral granules once daily based on dosing recommended for age and weight in Table 1
      [see Dosage and Administration (2.2)].
    • 6 years of age and older: 150 mg orally once daily.
  • Strong CYP3A inhibitors

    :
    • Less than 6 months of age: KALYDECO is not recommended.
    • 6 months to less than 6 years of age: one packet (containing 25 mg, 50 mg, or 75 mg ivacaftor) of oral granules twice a week based on dosing recommended for age and weight in Table 1
      [see Dosage and Administration (2.2)].
    • 6 years of age and older: 150 mg orally twice weekly.
  ,
  7.1 Inhibitors of CYP3A

  Ivacaftor is a sensitive CYP3A substrate. Co-administration with ketoconazole, a strong CYP3A inhibitor, significantly increased ivacaftor exposure [measured as area under the curve (AUC)] by 8.5-fold. Based on simulations of these results, a reduction of the KALYDECO dosage is recommended for patients aged 6 months and older taking concomitant strong CYP3A inhibitors, such as ketoconazole, itraconazole, posaconazole, voriconazole, telithromycin, and clarithromycin. KALYDECO is not recommended for patients less than 6 months of age taking strong CYP3A inhibitors

  [see Dosage and Administration (2.4)and Clinical Pharmacology (12.3)]

  .

  Co-administration with fluconazole, a moderate inhibitor of CYP3A, increased ivacaftor exposure by 3-fold. Therefore, a reduction of the KALYDECO dosage is recommended for patients aged 6 months and older taking concomitant moderate CYP3A inhibitors, such as fluconazole and erythromycin. KALYDECO is not recommended for patients less than 6 months of age taking moderate CYP3A inhibitors

  [see Dosage and Administration (2.4)and Clinical Pharmacology (12.3)]

  .

  Co-administration of KALYDECO with grapefruit juice, which contains one or more components that moderately inhibit CYP3A, may increase exposure of ivacaftor. Therefore, avoid food or drink containing grapefruit during treatment with KALYDECO [

  see Clinical Pharmacology (12.3)

  ].
  )
• Not recommended in pediatric patients less than 1 month of age. (
  2.2 Recommended Dosage in Pediatric Patients Aged 1 Month to Less than 6 Years

  The recommended dosage of KALYDECO (oral granules) for pediatric patients aged 1 month to less than 6 years is weight-based provided in Table 1. Take KALYDECO orally with fat-containing food

  [see Dosage and Administration (2.5)]

  .

  Table 1: Recommended Dosage of KALYDECO Oral Granules by Body Weight in Pediatric Patients Aged 1 Month to Less than 6 Years

  Age	Body Weight (kg)	KALYDECO Dosage
  1 month to less than 2 monthsKALYDECO is not recommended for use in pediatric patients under 1 month of age.Use of KALYDECO in pediatric patients aged 1 to less than 6 months born at a gestational age less than 37 weeks has not been evaluated.	3 kg or greater	One packet (containing 5.8 mg ivacaftor) every 12 hours
  2 months to less than 4 months	3 kg or greater	One packet (containing 13.4 mg ivacaftor) every 12 hours
  4 months to less than 6 months	5 kg or greater	One packet (containing 25 mg ivacaftor) every 12 hours
  6 months to less than 6 years of age	5 kg to less than 7 kg	One packet (containing 25 mg ivacaftor) every 12 hours
  	7 kg to less than 14 kg	One packet (containing 50 mg ivacaftor) every 12 hours
  	14 kg or greater	One packet (containing 75 mg ivacaftor) every 12 hours
  ,
  8.4 Pediatric Use

  The safety and effectiveness of KALYDECO for the treatment of CF have been established in pediatric patients 1 month to 17 years of age who have at least one mutation in the

  CFTR

  gene that is responsive to ivacaftor potentiation based on clinical and/or

  in vitro

  assay data [

  see Clinical Pharmacology (12.1)and Clinical Studies (14)

  ].

  The use of KALYDECO for this indication is supported by evidence from placebo-controlled clinical trials in the following pediatric patients with CF:

  • 12 to 17 years of age who are heterozygous for the
    F508del
    mutation and a second mutation predicted to be responsive to ivacaftor
    [see Adverse Reactions (6)and Clinical Studies (14)]
    .
  • 6 to 17 years of age with a
    G551D
    ,
    G1244E
    ,
    G1349D
    ,
    G178R
    ,
    G551S
    ,
    S1251N
    ,
    S1255P
    ,
    S549N
    ,
    S549R,
    or
    R117H
    mutation in the
    CFTR
    gene
    [see Adverse Reactions (6)and Clinical Studies (14)]
    .
  • The effectiveness of KALYDECO in patients aged 2 to less than 6 years was extrapolated from patients 6 years of age and older with support from population pharmacokinetic analyses showing similar drug exposure levels in adults and pediatric patients 2 to less than 6 years of age [see
    Clinical Pharmacology (12.3)
    ]
    .
    Safety of KALYDECO in this population was derived from a 24-week, open-label clinical trial in 34 patients ages 2 to less than 6 years (mean age 3 years) administered either 50 mg or 75 mg of ivacaftor granules twice daily (Trial 6). The type and frequency of adverse reactions in this trial were similar to those in patients aged 6 years and older. Transaminase elevations were more common in patients who had abnormal transaminases at baseline [
    see Warnings and Precautions (5.1)
    and
    Adverse Reactions (6.1)
    ]
    .
  • The effectiveness of KALYDECO in patients aged 1 month to less than 24 months was extrapolated from patients 6 years of age and older with support from population pharmacokinetic analyses showing that the exposure of ivacaftor in pediatric patients 1 month to less than 24 months of age is within the range of exposure in adults and pediatric patients 6 years of age and older
    [see Clinical Pharmacology (12.3)].
    Safety of KALYDECO in this population was derived from a cohort of 7 patients aged 1 month to less than 4 months (mean age 1.9 months at baseline), a cohort of 6 patients aged 4 months to less than 6 months (mean age 4.5 months at baseline), a cohort of 11 patients aged 6 months to less than 12 months (mean age 9.0 months at baseline), and a cohort of 19 patients aged 12 months to less than 24 months (mean age 15.2 months at baseline) in a 24-week, open-label clinical trial, administered 5.8 mg, 11.4 mg, 17.1 mg, 22.8 mg, 25 mg, 50 mg, or 75 mg (11.4 mg, 17.1 mg, and 22.8 mg are not recommended dosages) of ivacaftor granules twice daily (Trial 8). The safety profile of patients in this trial was similar to that observed in patients aged 2 years and older.
  • Safety of KALYDECO in patients aged 1 month and older was evaluated in a 96-week, open-label study (Trial 9) in 86 patients (38 rolled over from Trial 8, and 48 KALYDECO-naïve). Adverse reactions from Trial 9 were generally similar to those reported in Trial 8.

  The safety and effectiveness of KALYDECO in pediatric patients with CF younger than 1 month of age have not been established.

  Juvenile Animal Toxicity Data

  In a juvenile toxicology study in which ivacaftor was administered to rats from postnatal days 7 to 35, cataracts were observed at all dose levels, ranging from 0.1 to 0.8 times the MRHD (based on summed AUCs for ivacaftor and its metabolites at oral doses of 10-50 mg/kg/day). This finding has not been observed in older animals.
  )
• Not recommended in patients 1 month to less than 6 months of age with any level of hepatic impairment and/or taking concomitant moderate or strong CYP3A inhibitors. (
  2.3 Recommended Dosage for Patients with Hepatic Impairment

  KALYDECO is not recommended in patients less than 6 months of age with any level of hepatic impairment. The following is the recommended dosage of KALYDECO taken with fat-containing food

  [see Dosage and Administration (2.5)]

  for patients aged 6 months and older with hepatic impairment:

  • Mild Hepatic Impairment (Child-Pugh Class A):
    • Less than 6 months of age: KALYDECO is not recommended.
    • No dosage adjustment is necessary for patients aged 6 months or older
      [see Clinical Pharmacology (12.3)]
      .
  • Moderate Hepatic Impairment (Child-Pugh Class B):
    • Less than 6 months of age: KALYDECO is not recommended.
    • 6 months to less than 6 years of age: one packet (containing 25 mg, 50 mg, or 75 mg ivacaftor) of oral granules once daily based on dosing recommended for age and weight in Table 1
      [see Dosage and Administration (2.2)].
    • 6 years of age and older: 150 mg orally once daily.
  • Severe Hepatic Impairment (Child-Pugh Class C):
    Should not be used in patients less than 6 months of age. In patients aged 6 months and older should be used with caution. KALYDECO has not been studied in patients with severe hepatic impairment (Child-Pugh Class C), but exposure is expected to be higher than in patients with moderate hepatic impairment. Therefore, use with caution at a reduced dosage, in patients aged 6 months or older with severe hepatic impairment after weighing the risks and benefits of treatment
    [see Dosage and Administration (2.1, 2.2)and Clinical Pharmacology (12.3)]
    .
    • Less than 6 months of age: KALYDECO is not recommended.
    • 6 months to less than 6 years of age: one packet (containing 25 mg, 50 mg, or 75 mg ivacaftor) of oral granules once daily or less frequently based on dosing recommended for age and weight in Table 1
      [see Dosage and Administration (2.2)].
    • 6 years of age and older: 150 mg orally once daily or less frequently.
  ,
  2.4 Dosage Modification for Patients Taking Drugs that are CYP3A Inhibitors

  Concomitant use of moderate or strong CYP3A inhibitors is not recommended in patients below 6 months of age. Food or drink containing grapefruit should be avoided

  [see Drug Interactions (7.1)and Clinical Pharmacology (12.3)].

  Take KALYDECO with fat-containing food

  [see Dosage and Administration (2.5)].

  Dosage modification for patients 6 months of age and older taking CYP3A inhibitors

  :

  • Moderate CYP3A inhibitors:
    • Less than 6 months of age: KALYDECO is not recommended.
    • 6 months to less than 6 years of age: one packet (containing 25 mg, 50 mg, or 75 mg ivacaftor) of oral granules once daily based on dosing recommended for age and weight in Table 1
      [see Dosage and Administration (2.2)].
    • 6 years of age and older: 150 mg orally once daily.
  • Strong CYP3A inhibitors

    :
    • Less than 6 months of age: KALYDECO is not recommended.
    • 6 months to less than 6 years of age: one packet (containing 25 mg, 50 mg, or 75 mg ivacaftor) of oral granules twice a week based on dosing recommended for age and weight in Table 1
      [see Dosage and Administration (2.2)].
    • 6 years of age and older: 150 mg orally twice weekly.
  ,
  8.6 Hepatic Impairment

  • Mild Hepatic Impairment (Child-Pugh Class A):
    No dosage adjustment is necessary for patients aged 6 months or older
    [see Clinical Pharmacology (12.3)]
    .
  • Moderate Hepatic Impairment (Child-Pugh Class B):
    A reduced dosage is recommended in patients aged 6 months or older
    [see Dosage and Administration (2.3)and Clinical Pharmacology (12.3)]
    .
  • Severe Hepatic Impairment (Child-Pugh Class C):
    Studies have not been conducted in patients with severe hepatic impairment (Child-Pugh Class C), but exposure is expected to be higher than in patients with moderate hepatic impairment. Therefore, use with caution at a reduced dosage, in patients aged 6 months or older with severe hepatic impairment after weighing the risks and benefits of treatment [
    see Dosage and Administration (2.3)and Clinical Pharmacology (12.3)
    ].

  Due to variability in maturation of cytochrome (CYP) enzymes involved in ivacaftor metabolism, treatment with KALYDECO is not recommended in patients aged 1 month to less than 6 months with any level of hepatic impairment

  [see Dosage and Administration (2.3)]

  .
  )

Tablets: 150 mg, light blue, film-coated, oblong-shaped tablets, with the characters "V 150" on one side and plain on the other.

Oral granules: 5.8 mg, 13.4 mg, 25 mg, 50 mg, or 75 mg, white to off-white granules, in unit-dose packets.

There are limited and incomplete human data from clinical trials and postmarketing reports on use of KALYDECO in pregnant women. In animal reproduction studies, oral administration of ivacaftor to pregnant rats and rabbits during organogenesis demonstrated no teratogenicity or adverse effects on fetal development at doses that produced maternal exposures up to approximately 5 (rats) and 11 (rabbits) times the exposure at the maximum recommended human dose (MRHD). No adverse developmental effects were observed after oral administration of ivacaftor to pregnant rats from organogenesis through lactation at doses that produced maternal exposures approximately 3 times the exposures at the MRHD, respectively (

The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects is 2% to 4% and miscarriage is 15% to 20% in clinically recognized pregnancies.