Trials 1 & 2

Trials 1 and 2 Overview: Patients With a G551D Mutation

KALYDECO® was studied in patients with CF age 12 years and older (Trial 1) and age 6-11 years (Trial 2) with a G551D mutation

Additional Nomenclature13

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

G5515 Mutation

Trial Design1

  • Trials 1 and 2 were 48-week, Phase 3, randomized, double-blind, placebo-controlled trials in patients with CF and a G551D mutation
    • Trial 1: Patients 12 years of age and older (mean age 26 years; FEV1 40%-90% predicted at screening; mean FEV1 64% predicted at baseline [range: 32% to 98%])
    • Trial 2: Patients 6 to 11 years of age (mean age 9 years; FEV1 40%-105% predicted at screening; mean FEV1 84% predicted at baseline [range: 44% to 134%])
  • Patients received either KALYDECO 150 mg or placebo every 12 hours with fat-containing food, in addition to their prescribed CF therapies (e.g., tobramycin, dornase alfa) for 48 weeks. The use of inhaled hypertonic saline was not permitted

Selected Inclusion Criteria:

  • Confirmed CF diagnosis
  • G551D mutation
  • Aged ≥12 years (Trial 1);
    6-11 years (Trial 2)
  • Clinically stable
  • FEV1: 40%-90% predicted (Trial 1);
    40%-105% predicted (Trial 2)

Selected Exclusion Criteria:

  • Persistent infection with Burkholderia cenocepacia, Burkholderia dolosa, or Mycobacterium abscessus at screening
  • Abnormal liver function (3 or more tests ≥3x the upper limit of normal)

Primary and Other Efficacy Endpoints1

Primary Endpoint:

The primary efficacy endpoint for both trials was improvement in lung function as determined by the mean absolute change from baseline in percent predicted FEV1 through Week 24 of treatment.

KALYDECO + prescribed cystic fibrosis therapy - trials’ endpoints

Other Efficacy Endpoints:

  • Improvement from baseline in CFQ-R respiratory domain score through Weeks 24 and 48
  • Time to first pulmonary exacerbation (Trial 1) through Weeks 24 and 48
  • Absolute change from baseline in body weight at Weeks 24 and 48
  • Absolute change from baseline in sweat chloride concentration through Weeks 24 and 48

CFQ-R, Cystic Fibrosis Questionnaire-Revised.

ISI-Tray

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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

Indications and Usage

KALYDECO® (ivacaftor) is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator indicated for the treatment of cystic fibrosis (CF) in patients age 12 months 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.

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Indications and Usage

KALYDECO® (ivacaftor) is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator indicated for the treatment of cystic fibrosis (CF) in patients age 12 months 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

Cataracts

  • 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 12 months of age have not been studied. The use of KALYDECO in children under the age of 12 months 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, oropharyngeal pain, upper respiratory tract infection, nasal congestion, abdominal pain, nasopharyngitis, diarrhea, rash, nausea, and dizziness
  • The safety profiles for patients with additional approved mutations enrolled in Trials 4, 5, and 7; and for patients ages 2 to less than 6 years enrolled in Trial 6; and for patients aged 12 months to less than 24 months enrolled in Trial 8; 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; August 2018. 2. Zielenski J. Genotype and phenotype in cystic fibrosis. Respiration. 2000;67(2):117-133. 3. 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. https://ommbid.mhmedical.com/content.aspx?bookid=971&sectionid=62656007. Accessed July 5, 2018. 4. Bombieri C, Seia M, Castellani C. Genotypes and phenotypes in cystic fibrosis and cystic fibrosis transmembrane regulator-related disorders. Semin Respir Crit Care Med. 2015;36(2):180-193. 5. Nick JA, Nichols DP. Diagnosis of adult patients with cystic fibrosis. Clin Chest Med. 2016;37(1):47-57. 6. Welsh MJ, Smith AE. Molecular mechanisms of CFTR chloride channel dysfunction in cystic fibrosis. Cell. 1993;73(7):1251-1254. 7. 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. 8. Sheppard DN, Rich DP, Ostedgaard LS, Gregory RJ, Smith AE, Welsh MJ. Mutations in CFTR associated with mild-disease-form Cl channels with altered pore properties. Nature. 1993;362(6416):160-164. 9. Van Goor F, Yu H, Burton B, Hoffman BJ. Effect of ivacaftor on CFTR forms with missense mutations associated with defects in protein processing or function. J Cyst Fibros. 2014;13(1):29-36. 10. Pettit RS. Cystic fibrosis transmembrane conductance regulator-modifying medications: the future of cystic fibrosis treatment. Ann Pharmacother. 2012;46(7-8):1065-1075. 11. Clain J, Fritsch J, Lehrmann-Che J, et al. Two mild cystic fibrosis-associated mutations result in severe cystic fibrosis when combined in cis and reveal a residue important for cystic fibrosis transmembrane conductance regulator processing and function. J Biol Chem. 2001;276(12):9045-9049. 12. Selvadurai HC, McKay KO, Blimkie CJ, Cooper PH, Mellis CM, Van Asperen PP. The relationship between genotype and exercise tolerance in children with cystic fibrosis. Am J Respir Crit Care Med. 2002;165(6):762-765. 13. 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. 14. 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. 15. 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. 16. Elborn JS. Cystic fibrosis. Lancet. 2016;388(10059):2519-2531. 17. Sosnay P, et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013;45(10):1160-1167. 18. Davis P, et al. Cystic fibrosis. Am J Respir Crit Care Med. 1996;154(5):1229-1256. 19. Data on file. Vertex Pharmaceuticals Incorporated. Boston, MA. VXR-HQ-88-00079(3); 2017. 20. Quittner AL, Modi AC, Wainwright C, Otto K, Kirihara J, Montgomery AB. Determination of the minimal clinically important difference scores for the Cystic Fibrosis Questionnaire-Revised respiratory symptom scale in two populations of patients with cystic fibrosis and chronic Pseudomonas aeruginosa airway infection. Chest. 2009;135(6):1610-1618. 21. Rosenfeld M, Wainwright CE, Higgins M, et al. Ivacaftor treatment of cystic fibrosis in children aged 12 to <24 months and with a CFTR gating mutation (ARRIVAL): a phase 3 single-arm study. Lancet Respir Med. 2018. http://dx.doi.org/10.1016/S2213-2600(18)30202-9. 22. Rosenfeld M, Wainwright CE, Higgins M, et al. Ivacaftor treatment of cystic fibrosis in children aged 12 to <24 months and with a CFTR gating mutation (ARRIVAL): a phase 3 single-arm study. Lancet Respir Med. 2018 (suppl1-11). http://dx.doi.org/10.1016/S2213-2600(18)30202-9. 23. Data on file. Vertex Pharmaceuticals Incorporated. Boston, MA. VX15770124; 2017.

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