Additional CFTR Mutations

Trial 4 Overview: Trial in Patients With Additional CFTR Mutations

KALYDECO (ivacaftor) was studied in patients with a G1244E, G1349D, G178R, G551S, G970R,* S1251N, S1255P, S549N, or S549R mutation1

*Based on the clinical and pharmacodynamic (sweat chloride) responses to ivacaftor, efficacy in patients with the G970R mutation could not be established.1

Additional Nomenclature9,10

CFTR mutations may also be known by their cDNA (Human Genome Variation Society) names.

Human Genome Variation Society

Trial Design1

  • Trial 4 (N=39) was a Phase 3, two-part, randomized, double-blind, placebo-controlled, crossover-design clinical trial conducted in patients with CF (FEV1 ≥40% predicted at screening; mean FEV1 at baseline 78% predicted [range: 43% to 119%]) who were 6 years of age or older (mean age: 23 years)
  • Patients received either KALYDECO 150 mg or placebo every 12 hours with fat-containing food for 8 weeks (treatment period 1), followed by a 4- to 8-week washout period and an 8-week crossover to the other treatment (treatment period 2). Patients continued to take their prescribed CF therapies (e.g., tobramycin, dornase alfa). The use of inhaled hypertonic saline was not permitted
  • Open-label period: Patients who completed Part 1 continued into the 16-week open-label study (Part 2), during which all patients received KALYDECO along with their other prescribed CF therapies
KALYDECO + prescribed cystic fibrosis therapy - trials’ endpoints

Primary Efficacy Endpoint1

The primary efficacy endpoint was absolute change from baseline in percent predicted FEV1 through 8 weeks of treatment.

Selected Inclusion and Exclusion Criteria1

Selected Inclusion Criteria:

  • Confirmed CF diagnosis
  • One of the following CFTR gene mutations on at least one allele: G1244E, G1349D, G178R, G551S, G970R, S1251N, S1255P, S549N, S549R
  • Aged ≥6 years
  • Clinically stable
  • FEV1: ≥40% predicted

Selected Exclusion Criteria:

  • G551D mutation
  • Persistent infection with Burkholderia cenocepacia, Burkholderia dolosa, or Mycobacterium abscessus
  • Abnormal liver function

Other Efficacy Endpoints1

Trial Endpoints:

  • Primary efficacy endpoint:
  • Absolute change from baseline in percent FEV1 through 8 weeks of treatment
  • Other endpoints:
  • Absolute change in baseline in:
  • Sweat chloride concentration through 8 weeks
  • BMI at 8 weeks
  • Improvement in CFQ-R respiratory domain score through 8 weeks

Important Safety Information—
Pediatric Use

  • The safety and efficacy of KALYDECO in patients with CF younger than 2 years of age have not been studied. The use of KALYDECO in children under the age of 2 years is not recommended

Please click here for additional Important Safety Information.

Indications and Usage

KALYDECO is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator indicated for the treatment of cystic fibrosis (CF) in patients age 2 years and older who have one mutation in the CFTR gene that is responsive to ivacaftor potentiation based on clinical and/or in vitro assay data.

If the patient’s genotype is unknown, an FDA-cleared CF mutation test should be used to detect the presence of a CFTR mutation followed by verification with bi‑directional sequencing when recommended by the mutation test instructions for use.

Important Safety Information

Transaminase (ALT or AST) Elevations

  • Elevated transaminases have been reported in patients with CF receiving KALYDECO. Transaminase elevations were more common in patients with a history of transaminase elevations or in patients who had abnormal transaminases at baseline. It is recommended that ALT and AST be assessed prior to initiating KALYDECO, every 3 months during the first year of treatment, and annually thereafter. For patients with a history of transaminase elevations, more frequent monitoring of liver function tests should be considered
  • Patients who develop increased transaminase levels should be closely monitored until the abnormalities resolve. Dosing should be interrupted in patients with ALT or AST of greater than 5 times the upper limit of normal (ULN). Following resolution of transaminase elevations, consider the benefits and risks of resuming KALYDECO dosing

Concomitant Use with CYP3A Inducers

  • Use of KALYDECO with strong CYP3A inducers, such as rifampin, substantially decreases the exposure of ivacaftor, which may reduce the therapeutic effectiveness of KALYDECO. Co-administration of KALYDECO with strong CYP3A inducers, such as rifampin, rifabutin, phenobarbital, carbamazepine, phenytoin, and St. John’s wort is not recommended


  • Cases of non-congenital lens opacities/cataracts have been reported in pediatric patients treated with KALYDECO. Baseline and follow-up ophthalmological examinations are recommended in pediatric patients initiating KALYDECO treatment

Pediatric Use

  • The safety and efficacy of KALYDECO in patients with CF younger than 2 years of age have not been studied. The use of KALYDECO in children under the age of 2 years is not recommended

Serious Adverse Reactions

  • Serious adverse reactions, whether considered drug-related or not by the investigators, which occurred more frequently in patients treated with KALYDECO included abdominal pain, increased hepatic enzymes, and hypoglycemia

Adverse Reactions

  • The most common adverse reactions in patients with a G551D mutation in the CFTR gene (Trials 1 and 2) with an incidence of ≥8% and at a higher incidence for patients treated with KALYDECO (N=109) than for placebo (N=104) were headache (24% vs 16%), oropharyngeal pain (22% vs 18%), upper respiratory tract infection (22% vs 14%), nasal congestion (20% vs 15%), abdominal pain (16% vs 13%), nasopharyngitis (15% vs 12%), diarrhea (13% vs 10%), rash (13% vs 7%), nausea (12% vs 11%), and dizziness (9% vs 1%)
  • The safety profiles for patients with a G1244E, G1349D, G178R, G551S, G970R, S1251N, S1255P, S549N, or S549R mutation enrolled in Trial 4, for patients with an R117H mutation enrolled in Trial 5, and for patients ages 2 to less than 6 years enrolled in
    Trial 6 were similar to that observed in Trials 1 and 2

Click here to access full Prescribing Information for KALYDECO (ivacaftor).

References: 1. KALYDECO (ivacaftor) [prescribing information]. Boston, MA: Vertex Pharmaceuticals Incorporated; March 2015. 2. Ramsey BW, Davies J, McElvaney NG, et al; VX08-770-102 Study Group. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med. 2011;365(18):1663-1672. 3. Davies JC, Wainwright CE, Canny GJ, et al; VX08-770-103 (ENVISION) Study Group. Efficacy and safety of ivacaftor in patients aged 6 to 11 years with cystic fibrosis with a G551D mutation. Am J Respir Crit Care Med. 2013;187(11):1219-1225. 4. Zielenski J. Genotype and phenotype in cystic fibrosis. Respiration. 2000;67(2):117-133. 5. Welsh MJ, Ramsey BW, Accurso F, Cutting GR. Cystic fibrosis: membrane transport disorders. In: Valle D, Beaudet A, Vogelstein B, et al, eds. The Online Metabolic & Molecular Bases of Inherited Disease. The McGraw-Hill Companies, Inc; 2004:part 21, chap 201. Accessed February 25, 2016. 6. Welsh MJ, Smith AE. Molecular mechanisms of CFTR chloride channel dysfunction in cystic fibrosis. Cell. 1993;73(7):1251-1254. 7. Orenstein DM, Spahr JE, Weiner DJ. Cystic Fribrosis: A Guide for Patient and Family. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2012. 8. Yu H, Burton B, Huang C-J, et al. Ivacaftor potentiation of multiple CFTR channels with gating mutations. J Cyst Fibros. 2012;11(3):237-245.
9. US CF Foundation, Johns Hopkins University. The Hospital for Sick Children. The Clinical and Functional TRanslation of CFTR (CFTR2). Accessed February 25, 2016. 10. Berwouts S, Morris MA, Girodon E, Schwarz M, Stuhrmann M, Dequeker E. Mutation nomenclature in practice: findings and recommendations from the cystic fibrosis external quality assessment scheme. Hum Mutat. 2011;32(11):1197-1203. 11. US Department of Agriculture, Agricultural Research Service, Nutrient Data Laboratory Web site. Accessed February 25, 2016.

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