Clinical Trials

Date: 2014-10-09

Type of information: Presentation of results at a congress

phase: 3

Announcement: presentation of results at the 28th Annual North American Cystic Fibrosis Conference (NACFC), Atlanta, Georgia, USA, October 9-11, 2014.

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.

Disease: cystic fibrosis

Therapeutic area: Rare diseases - Genetic diseases

Country:

Trial details:

Latest news:

• • On October 9, 2014, Vertex Pharmaceuticals reviewed recent progress and announced upcoming milestones in its efforts to develop multiple combinations of medicines that treat the underlying cause of cystic fibrosis (CF) for the majority of people with the disease. These updates were made in conjunction with the 28th Annual North American Cystic Fibrosis Conference (NACFC).
• Study of Ivacaftor in People with the R117H Mutation: Data from a Phase 3 study of ivacaftor in people ages 6 and older who have the R117H mutation have been presented at NACFC (\"Effects of ivacaftor in CF patients with R117H-CFTR.\" Poster 17. An oral presentation of these data will also be delivered during Workshop Session II on October 10 at 3:25 p.m. ET ). As previously announced, the Phase 3 study did not meet its primary endpoint of the absolute change from baseline in percent predicted forced expiratory volume in one second (ppFEV1) through 24 weeks of treatment, however a pre-specified subset analysis in patients ages 18 and older showed statistically significant improvements in lung function and other key secondary endpoints. The safety and tolerability results observed in this study were consistent with those observed in prior Phase 3 studies of ivacaftor monotherapy in people with CF who have the G551D or other gating mutations. Based on the Phase 3 data, Vertex submitted an sNDA in the U.S. and MAA variation in Europe for approval of ivacaftor in people with the R117H mutation. Vertex\'s sNDA for the use of ivacaftor in people with the R117H mutation will be the subject of an FDA Advisory Committee Meeting of the Pulmonary-Allergy Drugs Division on October 21, 2014 . In the United States , Vertex is seeking approval of ivacaftor in people ages 6 and older with the R117H mutation.
• NDA and MAA Line Extension Submissions for Use of Ivacaftor in Children Ages 2 to 5: Vertex  announced the submission of an NDA in the United States for the approval of ivacaftor in children with CF ages 2 to 5 who have one of the following nine mutations in the CFTR gene: G551D, G178R, S549N, S549R, G551S, G1244E, S1251N, S1255P or G1349D. Vertex expects to complete the MAA line extension application in Europe this week. The submissions were based on results announced  and being presented at NACFC from an open-label Phase 3 study that was designed to evaluate the pharmacokinetics and safety of weight-based dosing of ivacaftor to support approval in children ages 2 to 5. In the second part of the study (n=34), ivacaftor was generally well tolerated and the majority of adverse events were mild or moderate in severity. Five patients who had elevated liver enzymes at baseline (greater than two times the upper limit of normal) experienced further elevations of liver enzymes to greater than eight times the upper limit of normal during the study. One patient experienced a serious adverse event related to elevated liver enzymes, and this patient discontinued treatment from the study. For all five patients, liver enzymes returned to their baseline levels following interruption of ivacaftor. Serious adverse events occurred in 18 percent (6 of 34) of patients, and the most common adverse events, regardless of dose group, were cough, vomiting, nasal congestion, upper respiratory tract infection and rhinorrhea. In addition, secondary endpoints showed decreases in sweat chloride and improvements in nutritional status as measured by change in weight (weight-for-age z score) and body mass index (BMI-for-age z score). Based on results from this study, Vertex is seeking approval of a 50 mg and 75 mg weight-based dose of ivacaftor for children ages 2 to 5. For children in this age group, a granule (mini-tablet) formulation will be used to enable administration of ivacaftor in soft foods as opposed to the current tablet formulation for people 6 years and older.

 

Is general: Yes