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Clinical Trials

Date: 2014-06-12

Type of information: Presentation of results at a congress

phase: 3

Announcement: presentation of results at the 37th European Cystic Fibrosis Society (ECFS) Conference , June 11-14, 2014 , in Gothenburg, Sweden

Company: Vertex Pharmaceuticals (USA - MA)

Product: Kalydeco® (ivacaftor)

Action mechanism: CFTR potentiator. Ivacaftor is an oral agent that increases ion-function of activated cell-surface CFTR.  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 the G551D-CFTR protein.  In vitro, ivacaftor increased CFTR-mediated transepithelial current (IT) in rodent cells expressing G551D-CFTR protein following addition of a cyclic adenosine monophosphate (cAMP) agonist with an EC50 of 100 ± 47 nM; however, ivacaftor did not increase IT in the absence of cAMP agonist. Ivacaftor also increased IT in human bronchial epithelial cells expressing G551D-CFTR protein following addition of a cAMP agonist with an EC50 of 236 nM. Ivacaftor increased the open probability of G551D-CFTR protein in single channel patch clamp experiments using membrane patches from rodent cells expressing G551D-CFTR protein by 10-fold versus untreated cells after addition of PKA and ATP. Kalydeco® was first approved by the FDA in January 2012 for use in people with CF ages 6 and older who have at least one copy of the G551D mutation and in February 2014 for use in people with CF ages 6 and older who have the following additional CFTR mutations: G178R, S549N, S549R, G551S, G1244E, S1251N, S1255P and G1349D. It was approved by the European Medicines Agency in July 2012, by Health Canada in November 2012 and by the Therapeutic Goods Administration in Australia in July 2013 for use in people with CF ages 6 and older who have at least one copy of the G551D mutation in the CFTR gene.  

Disease: patients with cystic fibrosis (CF) who have the G551D mutation

Therapeutic area: Rare diseases - Genetic diseases

Country: USA

Trial details: KONDUCT Study (NCT01614457)

Latest news: * On June 12, 2014, Vertex Pharmaceuticals announced the presentation of new Kalydeco™ (ivacaftor) data at the 37th European Cystic Fibrosis Society (ECFS) Conference , June 11-14, 2014 , in Gothenburg, Sweden. New data from an analysis of the Phase 3 STRIVE and ENVISION studies, and from patients who rolled over into the long-term extension study PERSIST, were presented at the conference and showed that treatment with Kalydeco™ in people with CF ages 6 and older with the G551D mutation appeared to modify the rate of lung function decline, reducing the annual loss of lung function by half over three years. The annual rate of decline among those receiving Kalydeco™ was 0.81 FEV1 percentage points compared to an untreated group of people matched on clinical criteria with two copies of the F508del mutation, whose annual rate of decline was 1.73 percentage points (p=0.02). This analysis was conducted by comparing the change in lung function in people who received Kalydeco™ in the Phase 3 STRIVE, ENVISION and PERSIST trials (n=189) with lung function changes in a matched control group derived from the U.S. Cystic Fibrosis Foundation Patient Registry who had two copies of the F508del mutation and similar disease severity (n=886). Historical data have previously shown a similar rate of lung function decline among people with two copies of the F508del mutation and those with the G551D mutation. In addition, the first data from a rollover study following the Phase 3 KONDUCT study in people with the R117H mutation confirmed earlier results that demonstrated lung function improvements in people ages 18 and older. Sixty-five of the 67 eligible people who completed the KONDUCT study continued into this rollover study. As previously announced, the KONDUCT study did not meet its primary endpoint of absolute change from baseline in FEV1 (forced expiratory volume in one second) through 24 weeks in the overall study population. However, a pre-specified subset analysis showed that the mean absolute improvement in lung function compared to placebo (treatment difference) for patients ages 18 and older was 5.0 (p=0.01) percentage points, which corresponded to a mean relative improvement of 9.1 (p=0.008) percent. Statistically significant improvements in key secondary endpoints, including sweat chloride and patient-reported respiratory symptoms as measured by the respiratory domain of the Cystic Fibrosis Questionnaire Revised (CFQ-R), were also observed regardless of age. In the rollover study, all patients received ivacaftor after a washout period of at least three weeks following the KONDUCT study. The interim data announced were obtained following a pre-planned analysis conducted after all patients reached the 12-week timepoint in the rollover study. After the first 12 weeks of the rollover study, the mean absolute improvement from baseline in lung function (percent predicted FEV1) was 5.5 percentage points (p < 0.0001) among all patients (n=62; intent-to-treat analysis). For patients ages 18 and older (n=46), the mean absolute improvement in lung function was 5.1 percentage points (p < 0.0001). For patients ages 6 to 11 (n=15), the mean absolute improvement in lung function was 6.5 percentage points; the decline in FEV1 observed in the KONDUCT study for patients ages 6 to 11 who received ivacaftor was not observed in the rollover study. Similar to the KONDUCT study, treatment with ivacaftor, regardless of age, resulted in decreases in sweat chloride and improvements in CFQ-R. In the 24-week KONDUCT study and through 12 weeks in the rollover study, the safety and tolerability results were consistent with those observed in prior Phase 3 studies of ivacaftor monotherapy in people with CF who have the G551D and other gating mutations. In KONDUCT, the most commonly observed adverse events in those who received ivacaftor were infective pulmonary exacerbation, cough and headache, which occurred with similar frequency compared to those who received placebo. Serious adverse events occurred in 17 percent of patients who received placebo versus 12 percent of patients who received ivacaftor. In the rollover study, the most common serious adverse events were infective pulmonary exacerbations. Based on these data, Vertex plans to submit a supplemental New Drug Application (sNDA) in the U.S. and a marketing authorization application (MAA) variation in Europe for people ages 18 and older who have the R117H mutation. The sNDA submission is planned for mid-2014, followed by the MAA variation submission in the second half of 2014.

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