**4. Correctors**

is the most common gating mutation, initial studies focused on patients with this particular

Phase 1 studies indicated that ivacaftor is primarily metabolized in the liver and moderate hepatic impairment may reduce its elimination. Since *in vitro* studies indicated that ivacaftor is a substrate of CYP3A4/5 and therefore, strong (e.g., ketoconazole) and moderate (e.g., fluconazole) CYP3A inhibitors as well as strong CYP3A inducers (e.g., rifampin) will affect ivacaftor's metabolism. A detailed list of the numerous drug interactions is found in the package insert of ivacaftor (Kalydeco®) (see http://www.accessdata.fda.gov/drugsatfda\_docs/

An initial phase 2 study by Accurso found that the safety profile of ivacaftor in adult patients with at least one G551D mutation was excellent for a wide variety of daily doses (from 50 mg to 500 mg for 2 to 4 weeks). An improvement in FEV1 and drop in sweat chloride were also noted (although these were not primary end points of the study). [9] This prompted two randomized, placebo-controlled, double blind studies eventually resulting in FDA approval. Ivacaftor 150 mg twice daily for 48 weeks was studied in 167 patients 12 years or older with at least one G551D mutation. There was a 10.6% improvement in predicted FEV1 from baseline versus placebo. Additionally, a 55% reduction in pulmonary exacerbation was also observed. Sweat chloride levels dropped to a mean of 47.8 mmol/L compared with 100.0 mmol/L in the placebo group. There was improvement in quality of life measurements as well as a more significant increase in weight gain (4.1 kg increase) in those receiving ivacaftor. [10] An additional pediatric study of 52 patients 6 to 12 years of age showed a 12.5% improvement in FEV1 and a 2.8 kg increase in weight. A decrease in sweat chloride of 54 mmol/L was also seen. [11] In both studies, the incidence of adverse events was similar in both treated and placebo

Similar results were observed in studies examining non-G551D gating mutations. [12] These 36 patients also showed significant improvements in FEV1, sweat chloride measurements, changes in BMI, and quality of life indices. Therefore, the FDA also approved ivacaftor for G178R, S549N, S549R, G551S, G970R, G1244E, S1251N, G1349D, and S1255P mutations in February 2014. Finally, in December 2014, one additional mutation, R117H, was added by the FDA to the list of approved CF mutations for ivacaftor administration after 69 patients greater

mutation.

groups.

label/2012/203188lbl.pdf).

**Figure 2.** Structural formula of ivacaftor

134 Cystic Fibrosis in the Light of New Research

Most patients with CF have the F508del mutation in which the defective CFTR protein has defective folding and processing in the endoplasmic reticulum, resulting in minimal amounts of CFTR at the cell surface. After screening a large number of molecules, Vertex Pharmaceut‐ icals found two in which the CFTR molecule appears to be "corrected" in its "trafficking" through the cytoplasmic to the cell membrane. Importantly, the F508del-CFTR corrected by VX-809 (subsequently named lumacaftor) appears to have biochemical and functional characteristics similar to normal CFTR such as biochemical susceptibility to proteolysis, time in the plasma membrane, and single-channel openness. [18]

Although there was a statistically significant reduction in sweat chloride values, no effect was seen in CFTR function in the nasal epithelium as measured by nasal potential difference (NPD) or in lung function as measured by FEV1. Therefore, although it appeared to be safe and was well tolerated at all doses, there did not appear to be any significant effect on CFTR function in upper and lower respiratory tracts. Indeed, a phase 2 study with 140 patients did not show any difference in lung function although there was a slight reduction in sweat chloride of 2.9 mmol/L which was barely significant (p=0.04).

VX-661 is another corrector with very similar structure to lumacaftor (see Figures 3 and 4). In a Phase 2 study of 128 adult patients with homozygous F508del mutation in whom four doses of VX-661 (10, 30, 100, and 150 mg) dosed once daily were given either alone or with ivacaf‐

**Figure 3.** Structural formula of lumacaftor (VX-809)

tor150 mg twice a day for 28 days. Interim results found decreases in sweat chloride with both treatments. However, significant increases in FEV1 were found in both doses 100 mg and 150 mg of VX-661 with ivacaftor at 9% and 7.5% over baseline, respectively. [19]

**Figure 4.** Please Add Caption

[20] There were significant improvements in the mean absolute change in percent predicted of FEV1 and BMI after 24 weeks. Because there appeared to be no difference in two doses studied, the submission to the FDA selected lumacaftor 400 mg BID plus ivacaftor 250 mg BID. An open label roll-over study is still in progress and expected to continue for another 24 weeks.

Patients receiving just VX-661 monotherapy in the Phase 2 study also did not show any improvement, further supporting the strategy of combining a corrector and potentiator in treating patients with F508del mutation. In 2015, Vertex is starting a series of large-scale Phase 3 studies examining the efficacy of the combined therapy with VC-661 and ivacaftor in patients with one or two copies of the F508del mutation.

### **5. Conclusions**

The capability of molecules to enhance CFTR protein activity offers potential new treatment options for patients with CF. Long-term follow-up studies on ivacaftor, the first CFTR modulator to obtain FDA approval, look very promising. However, the drawback with these targeted therapies is the wide range of CFTR dysfunction seen in CF. Expanding the use of ivacaftor to nine other gating mutations only benefit about 10% of the total CF patient population.

Combination therapy appears to offer the optimal opportunity for many more patients with CF to benefit from modulating CFTR protein. The preliminary studies on ivacaftor with lumacaftor for patients with homozygous F508del mutation look promising and may benefit another 50% of patients. Whether the combination of VC-661 and ivacaftor is more effective remains to be seen for these patients and those with one F508del and a gating mutation, which represents another 30% of patients.

Although Vertex has been the first to develop chemicals which correct trafficking of F508del-CFTR and restoring its activity, other companies such as Norvartis are also actively testing other molecules, such as picolinamide-based compounds. [21] It is hoped that with increased competition from other companies, the high cost of these medications can be lessened.
