SYMDEKO (Page 7 of 9)

14.2 Trial in Patients with CF Who Were Heterozygous for the F508del Mutation and a Second Mutation Predicted to be Responsive to Tezacaftor/Ivacaftor (Trial 2)

Trial 2 evaluated 244 patients with CF age 12 years and older (mean age 34.8 years). The mean ppFEV1 at baseline was 62.3% (range: 34.6 to 93.5). Of the 244 patients included in the efficacy analysis, 146 patients had a splice mutation and 98 patients had a missense mutation as the second allele. 161 patients received SYMDEKO, 156 patients received ivacaftor, and 161 patients received placebo. 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 SYMDEKO compared to placebo resulted in significant improvement in ppFEV1 (6.8 percentage points [95% CI: 5.7, 7.8]; P <0.0001) and CFQ-R Respiratory Domain Score (11.1 points (95% CI 8.7, 13.6); P <0.0001). Treatment difference for ppFEV1 between ivacaftor- and placebo-treated patients was 4.7 percentage points (95% CI: 3.7, 5.8; P <0.0001) and 2.1 percentage points (95% CI: 1.2, 2.9; P <0.0001) between SYMDEKO- and ivacaftor-treated patients, which were statistically significant. Improvements in ppFEV1 were observed regardless of age, baseline ppFEV1 , sex, mutation class, colonization with Pseudomonas , concomitant use of standard-of-care medications for CF, and geographic region. Statistically significant improvements compared to placebo were also observed in the subgroup of patients with splice mutations and missense mutations (Table 12).

Table 12: Effect of SYMDEKO for Efficacy Variables in Splice and Missense CFTR Mutation Subgroups
Mutation (n) Absolute Change in percent predicted FEV1 * Absolute Change in CFQ-R Respiratory Domain Score (Points)* Absolute Change in Sweat Chloride (mmol/L)*
(n=) patient numbers analysed
*
Average of Week 4 and 8 values
Absolute change in ppFEV1 by individual mutations is an ad hoc analysis.
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.
§
Patients enrolled did not receive tezacaftor/ivacaftor treatment.
Splice mutations (n= 93 for TEZ/IVA, n=97 for PBO)Results shown as difference in mean (95% CI) change from study baseline for SYMDEKO vs. placebo-treated patients:
7.4 (6.0, 8.7) 9.5 (6.3, 12.7) -5.4 (-8.0, -2.7)
By individual splice mutation (n). Results shown as mean (minimum, maximum) for change from study baseline for SYMDEKO-treated patients
2789+5G→A (25 ) 8.6 (-1.5, 23.4) 12.0 (-8.3, 38.9) -3.2 (-16.5, 9.0)
3272-26A→G (23) 5.7 (-2.1, 25.9) 5.7 (-22.2, 44.4) -3.8 (-22.3, 16.5)
3849+10kbC→T (43) 5.8 (-7.2, 22.3) 8.2 (-25.0, 47.2) -5.6 (-27.0, 8.5)
711+3A→G (2) 4.3 (2.0, 6.7) -4.2 (-5.6, -2.8) -15.4 (-21.0, -9.8)
E831X § (0) NA NA NA
Missense mutations (n=66 for TEZ/IVA, n=63 for PBO)Results shown as difference in mean (95% CI) change from study baseline for SYMDEKO vs. placebo-treated patients:
5.9 (4.2, 7.5) 13.4 (9.6, 17.3) -16.3 (-19.7, -12.9)
By individual missense mutation (n). Results shown as mean (minimum, maximum) for change from study baseline for SYMDEKO-treated patients
D579G (2) 8.1 (-0.2, 16.4) 11.1 (5.6, 16.7) -23.1 (-24.8, -21.5)
D110H (1) -1.0 (-1.0, -1.0) -11.1 (-11.1, -11.1) -22.5 (-22.5, -22.5)
D1152H (21) 3.8 (-2.5, 12.5) 15.2 (-8.3, 55.6) -4.1 (-15.0, 11.5)
A455E (11) 8.5 (2.6, 16.1) 11.6 (-11.1, 44.4) -0.3 (-8.8, 14.0)
L206W (4) 3.0 (-4.5, 10.2) 12.5 (-2.8, 38.9) -36.1 (-44.5, -27.5)
P67L (11) 9.4 (0.0, 31.9) 11.7 (-12.5, 72.2) -29.3 (-50.0, 0.8)
R1070W (2) 6.1 (2.0, 10.1) 29.2 (16.7, 41.7) -13.8 (-26.8, -0.8)
R117C (1) 2.9 (2.9, 2.9) 16.7 (16.7, 16.7) -38.8 (-38.8, -38.8)
R347H (2) -0.5 (-2.8, 1.7) 5.6 (-5.6, 16.7) -13.8 (-19.0, -8.5)
R352Q (2) 4.9 (2.6, 7.1) 8.3 (8.3, 8.3) -43.3 (-49.8, -36.8)
S945L (7) 9.6 (0.7, 19.5) 11.3 (-4.2, 25.0) -29.0 (-42.5, -8.0)
S977F (2) 10.1 (5.5, 14.7) -1.4 (-8.3, 5.6) -13.9 (-22.3, -5.5)

In an analysis of BMI at Week 8, an exploratory endpoint, patients treated with SYMDEKO had a mean improvement of 0.2 kg/m2 (95% CI [0.0, 0.3]), 0.1 kg/m2 (95% CI [-0.1, 0.3]), and 0.3 kg/m2 (95% CI [0.1, 0.5]) versus placebo for the overall, splice, and missense mutation populations of patients, respectively.

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