Kalydeco recently received FDA (US) approval for eight gating mutations: G178R, S549N, S549R, G551S, G1244E, S1251N, S1255P and G1349D. G970R was also involved in the gating trial, however based on the data from 4 patients, the efficacy was not established to support FDA approval.

The FDA prescribing information provides in-depth information regarding the gating mutation trial results:

Sweat Chloride
“In a two-part, randomized, double-blind, placebo-controlled, crossover clinical trial in patients with CF who had a G1244E, G1349D, G178R, G551S, G970R, S1251N, S1255P, S549N, or S549R mutation in the  CFTR gene (Trial 4), the treatment difference in mean change in sweat chloride from baseline through 8 weeks of treatment was -49 mmol/L (95% CI -57, -41). In Trial 4, mean changes in sweat chloride for the mutations for which KALYDECO is indicated ranged from -51 to -78, whereas the range for individual subjects with the G970R mutations was -1.0 to -11 mmol/L.”

FEV1, Weight & Symptoms
“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/m2 at Week 8 (P < 0.0001)], and cystic fibrosis respiratory symptom 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 3). Based on clinical and pharmacodynamic (sweat chloride) responses to ivacaftor, efficacy in patients with the G970R mutation could not be established.”

Table showing the results for each gating mutation:

Gating Mutations - Kalydeco Trial Results

Graph showing the in vitro effect of Kalydeco with each gating mutation:

CFTR Gating Mutations Kalydeco

There is a large degree of variation between the in vitro gating mutation responses. The gating mutation trial had a small number of patients per mutation, but it appears that in this trial, the in vitro responses did not strongly correspond to clinical results. The FDA prescribing information mentions “In vitro responses do not necessarily correspond to in vivo pharmacodynamic response or clinical benefit.”

Sources: FDA Prescribing Information & cftrsplicing.com

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1. Class 3 Gating Mutations & G551D, 3. Vertex - Kalydeco