Kalydeco can help more patients beyond those with G551D (4% worldwide, 8% aus). Kalydeco helps other gating mutations (1% worldwide) and it is thought that residual function mutations will be helped (5-10% worldwide, based on mutations and clinical presentation). This means Kalydeco may help about 15% of the CF population.
Gating Mutations (Class 3)
Kalydeco helps the gating mutations G178R, S549N, S549R, G551S, G1244E, S1251N, S1255P and G1349D. The phase 3 trial demonstrated an absolute FEV1 improvement of 7.5% from baseline at 8 weeks (p<0.0001). In Feb 2014 the FDA approved Kalydeco for use with these 8 additional mutations. 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. Vertex have also applied to the EMA to expand the Kalydeco label to include these mutations. There is further detail regarding the gating results here.
Residual Function (Classes 4, 5 and 6)
Kalydeco has been trialled with R117H (3% worldwide). The phase 3 trial demonstrated an overall absolute FEV1 change of 2.1% (p=0.2), with those aged 18 or older improving 5.0% (p=0.01). Vertex plans to meet with FDA in early 2014 to discuss this data and a potential FDA application. There is further detail regarding these results here.
Kalydeco is also being trialled with people who have other forms of residual function. The results from one of these phase 2 trials demonstrated an absolute FEV1 improvement of 4.7% (p < 0.0001) from baseline after 8 weeks and a 15.7 drop in sweat chloride (starting point 64.7). These results support initiating a phase 3 study with residual function patients. There is further detail regarding these results here.
There are specific mutations associated with residual function, as well as several clinical signs, including pancreatic sufficiency, a lower sweat test, a later age of diagnosis and milder than expected disease in patients with severe gene mutations. There are more details listed here: First Residual Function Trial & Second Residual Function Trial.
Known residual function mutations include (see graphs below): E56K, P67L, R74W, D110E, D110H, R117C, R117H, L206W, R347H, R352Q, A455E, D579G, R668C, S945L, L997F, S997F, R1070Q, R1070W, F1074L, D1152H, S1235R, D1270N, 2789+5G->A, 3272-26A->G & 3849+10kbC->T. Other rare mutations not included in this list may have residual function.
This image shows the effect of Kalydeco (Ivacaftor) with gating mutations:
These images show the effect of Kalydeco (VX770) with residual function mutations: