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New Drugs Online Report for ivacaftor
Generic Name:
Trade Name: Kalydeco 
Synonym: VX770, VX-770 
Entry Type: New molecular entity  
Development and Regulatory status
UK: Launched 
EU: Launched 
US: Launched 
UK launch Plans: Available only to registered users
Actual UK launch date: May 2013 
May 15: The FDA approves ivacaftor for treatment of CF in children aged 2-5 years who have one of 10 mutations in the CFTR gene (previously only approved for use in those aged ≥6 years). An application to extend the license in the EU is currently under review by the EU CHMP [21]. 
23/03/2015 11:18:06
May 13: Launched in the UK [20]. 
17/05/2013 12:04:03
Dec 12: The list price for ivacaftor is £182,625 per year, equating to £15,218.75 per person treated per month [19]. 
31/12/2012 09:14:57
Dec 12: The four Specialised Commissioning Groups (SCGs) in England have announced that ivacaftor will be funded by the NHS in England for all pts aged 6 years & over with CF & the G551D gene mutation [19]. 
31/12/2012 09:14:17
Jul 12: Approved in EU for people with CF aged 6 and older who have at least one copy of the G551D mutation in the CFTR gene [16].  
06/08/2012 11:42:48
May 12: EU positive opinion for ivacaftor in the treatment of CF in pts age 6 years & older who have a G551D mutation in the CFTR gene [14].  
06/08/2012 11:42:39
Feb 12: Launched in the US [17]. 
06/08/2012 11:42:25
Ivacaftor has orphan drug status in the US [12]. 
01/02/2012 13:02:08
Jan 12: Kalydeco (ivacaftor) approved in the US for treating CF in pts ages 6 years & older who have the specific G551D mutation in the CFTR gene. The FDA reviewed & approved Kalydeco in approx 3 mths under the agency’s priority review program that is designed to expedite the review of drugs & uses a 6-mth review, instead of the standard 10 mths [11]. 
01/02/2012 13:01:01
The US application seeks approval for ivacaftor in people with the G551D mutation; the EU application includes a request for all gating mutations [10].  
19/12/2011 11:00:05
Dec 11: Filed in the EU [10]. 
19/12/2011 10:59:39
Dec 11: The FDA has accepted the New Drug Application (NDA) for ivacaftor & granted the company´s request for six-month priority review [10]. 
19/12/2011 10:58:57
Nov 11: FDA decision on approval expected by 19 Apr 12 [9] 
30/11/2011 14:22:23
Oct 11: Filed in the US to treat CF patients with ≥1 copy of the G551D mutation to the CFTR gene. The company has asked for a priority review. Filing expected in the EU before the end of this month. The EMA has already granted an expedited review so approval could be as early as 5 months away [7]. 
20/10/2011 10:40:12
Feb 11: Vertex plans to submit regulatory applications in the EU and US in 2H 2011 [4]. 
24/02/2011 09:13:46
PIII studies started in 2009 [1]. 
30/05/2010 18:41:27
Trial or other data
Dec 12: About 270 people in England are currently considered eligible to receive ivacaftor [19]. 
31/12/2012 09:16:35
Aug 12: FDA doctors, parents and patients about the potential for eye disorders linked to ivacaftor. The FDA says the warning is based on cases of cataract seen in juvenile rats studied by the drug´s manufacturer, Vertex Pharmaceuticals. [18] 
30/08/2012 17:00:27
Jul 12: US cost - $294,000 a year [16].  
27/07/2012 19:58:43
Jun 12: Further data reported from the PIII STRIVE study reported at the European Cystic Fibrosis Society conference. Patients on ivacaftor for 48 weeks were 67% less likely to require hospitalization and 59% less likely to require intravenous antibiotics for pulmonary exacerbations than those on placebo [15].  
11/06/2012 10:13:53
Jun 12: Data on long-term treatment with ivacaftor reported at the European Cystic Fibrosis Society conference. 74 adults and adolescents (ages 12 or older) who were first treated with ivacaftor in the STRIVE study and continued treatment in the PERSIST study, had a 9.5% mean absolute improvement from the STRIVE baseline in lung function (% predicted FEV1) at week 96. In 25 children (ages 6 to 11) who were enrolled into PERSIST from the ENVISION study and have completed 72 weeks of treatment with ivacaftor, there was a 10.1% mean absolute improvement from the ENVISION baseline in lung function. Those who had switched to ivacaftor after receiving 48 weeks of treatment with placebo in the PIII studies (n=86), experienced improvements in lung function, respiratory symptoms and weight gain comparable to those seen in people who received ivacaftor from the beginning of the PIII studies. The most commonly reported serious adverse events in PERSIST were pulmonary exacerbations, haemoptysis and intestinal obstruction. At the time of this PERSIST analysis, ~1% of study participants had discontinued treatment due to an AE [15]. 
11/06/2012 10:13:21
If ivacaftor is approved, it will be the first treatment to target the underlying cause of CF [10]. 
19/12/2011 11:01:06
Nov 11: Final results from ENVISION as well as the first data from PERSIST, the long-term follow-up study of adolescents and adults treated in the Phase III STRIVE study, are being presented at the 25th Annual North American CF Conference (NACFC) in Anaheim, California, November 2011. Results from ENVISION showed that children who received Kalydeco experienced rapid and sustained improvements in lung function (forced expiratory volume in one second, FEV1) and other key measures of disease throughout the 48-week study vs. those treated with a placebo. The mean absolute improvement in lung function for children treated with Kalydeco was 10% points vs. placebo and the relative mean improvement was 15.1% from baseline vs. placebo at week 48. [8] 
04/11/2011 16:55:08
STRIVE data was published in the New England Journal of Medicine (NEJM) on 03 November 2011. Data from a second pivotal Phase III study, ENVISION, which assessed Kalydeco in children with CF ages six to 11 years who had at least one copy of the G551D mutation, will be presented at the North American CF Conference in Anaheim, California on 03 to 05 November 2011.  
03/11/2011 16:33:42
June 11: Interim results from PII RCT: Part 1 of the study enrolled 62 pts aged 18yrs or over with 2 copies of F508del mutation in CFTR gene. Pts randomised to VX-809 (200mg) or placebo alone for 14 days, then VX-809 (200mg) + VX-770 (150 or 250mg) or placebo for 7 days. Primary goal was to evaluate safety and tolerability and effect on CFTR function of the combination of VX-770 + VX-809. No serious adverse events were reported. A statistically significant reduction in sweat chloride from baseline to day 21 of -13.17mmol/L (p<0.001) was seen in the VX-809+VX-770 arm. In this arm, a -9.10 mmol/L (p<0.001) reduction was observed after VX-770 (250mg) was added to VX-809 for 7 days. Part 2 of the study will be initiated in Q4 2011, and will evaluate VX-770+VX-809 for longer dosing periods. [6] 
10/06/2011 08:35:50
Mar 11: positive results from a 24-week analysis of the ongoing PIII ENVISION study reported. ENVISION randomised 52 children (aged 6 to 11) with the G551D mutation in the CFTR gene to VX-770 (150mg twice daily) or placebo. Baseline FEV1 was 84.7% and 83.7% in those on VX-770 and placebo, respectively. For those on VX-770, the difference in mean absolute improvement in FEV1 from baseline to 24 weeks vs placebo (primary endpoint) was 12.5% (p<0.0001) and the difference in mean relative improvement from baseline was 17.4%. Significant improvements in other measures, including weight gain and a reduction in sweat chloride, were also observed. The study is ongoing, and additional assessments will be conducted at 48-weeks. All children who complete this study and meet certain criteria may enroll in the PERSIST extension study [5]. 
29/03/2011 18:02:01
Feb 11: Results from the PIII STRIVE study reported. 161 people with at least one copy of the G551D CFTR mutation were enrolled and received at least one dose of either VX-770 150mg or placebo twice daily. The primary endpoint of the study was mean absolute change from baseline in predicted FEV1 at week 24. Baseline lung function in STRIVE was 63.5 and 63.7% predicted in the VX-770 and placebo groups respectively. The mean absolute improvement in FEV1 from baseline vs placebo was 10.6% (p<0.0001) and this was sustained to 48 weeks (10.5%; p<0.0001). Significant improvements in secondary endpoints were also observed at week 48 including a 55% lower risk of a pulmonary exacerbation, a reduction in sweat chloride (a marker of CFTR protein dysfunction, which is the underlying molecular mechanism responsible for CF), an increase in body weight and a reduction in patient reported-respiratory symptoms. Adverse events that were >5% more frequent with VX-770 vs placebo were headache, URTI, nasal congestion, rash, dizziness and bacteria in the sputum. The most commonly reported serious AEs were pulmonary exacerbation (13% vs 33%) and haemoptysis (1% vs 5%). !% vs 5% of patients discontinued treatment by week 48. All patients who completed 48 weeks of treatment in STRIVE (n=144) were eligible to receive VX-770 as part of the PERSIST extension study and receive VX-770 for up to an additional 96 weeks or until VX-770 is approved [4].  
24/02/2011 09:25:01
Feb 11: Results of the PII DISCOVER study, which was primarily designed to provide additional safety data for VX-770 and is part of the registration program, have been reported. DISCOVER enrolled 140 people who had two copies of the F508del mutation, which prevents the CFTR protein from moving to its proper location at the cell surface. The majority of people with CF have at least one copy of the F508del mutation. The primary endpoints of DISCOVER were safety and absolute change from baseline in FEV1 at 16 weeks. AEs were similar between the treatment groups; those that occurred more frequently (≥5 percent) in the VX-770 group were cough, nausea, rash and contact dermatitis. None were serious or led to discontinuation. The VX-770 group achieved a mean absolute improvement in FEV1 from baseline vs placebo of 1.6% (p=0.25). The improvement was not statistically significant and was not considered clinically meaningful [4]. 
24/02/2011 09:13:07
Feb 11: Vertex is conducting a PIIa trial to evaluate multiple combination regimens of VX-770 and VX-809 in people with two copies of the F508del mutation. The first part of the study is designed to evaluate VX-809 (200mg), or placebo dosed alone for 14 days and in combination with VX-770 (150mg or 250mg), or placebo, for 7 days. Vertex expects to obtain data from this part of the trial in 1H 2011 [4]. 
24/02/2011 09:12:51
Feb 11: CF is caused by defective or missing CFTR proteins, which result in poor ion flow across cell membranes, including in the lung, and the accumulation of abnormally thick, sticky mucus that leads to chronic lung infections and progressive lung damage. In people with the G551D mutation, CFTR proteins are present on the cell surface but do not function normally. VX-770 (know as a potentiator), aims to increase the function of defective CFTR proteins by increasing the ability to transport ions across the cell membrane (gating activity), of CFTR once it reaches the cell surface. In people with the F508del mutation, CFTR proteins do not reach the cell surface in normal amounts. VX-809, known as a CFTR corrector, aims to increase CFTR function by increasing the amount of CFTR at the cell surface [4]. 
24/02/2011 09:12:27
Nov 10: In a PII study, 39 adults with CF & at least one G551D-CFTR allele were randomised to receive oral VX-770 every 12 hours at a dose of 25, 75, or 150 mg, or placebo, for 14 days (in part 1 of the study) or VX-770 every 12 hours at a dose of 150 or 250 mg or placebo for 28 days (in part 2 of the study). VX-770 150 mg resulted in a median change from baseline in the nasal potential difference of −3.5 mV (range, −8.3 to 0.5; p=0.02 for the within-subject comparison, p=0.13 vs. placebo). The median change in the level of sweat chloride was −59.5 mmol per liter (range, −66.0 to −19.0; p=0.008 within-subject, p=0.02 vs. placebo). The median change from baseline in the percent of predicted FEV1 was 8.7% (range, 2.3 to 31.3; p=0.008 for the within-subject comparison, p=0.56 vs. placebo). There were six severe adverse events occurring in two subjects (diffuse macular rash in one subject & five incidents of elevated blood & urine glucose levels in one subject with diabetes). All severe AEs resolved without stopping VX-770 [3]. 
19/11/2010 11:11:37
Three trials of VX-770 are now fully enrolled as part of a global PIII registration program focused on patients with the G551D mutation. The trials include the PIII STRIVE trial in patients aged ≥12 years with the G551D mutation, the PIII ENVISION trial in patients aged six to 11 years with the G551D mutation, and the PII DISCOVER trial in patients aged ≥12 homozygous for the F508del mutation. Data from the registration program are expected in 1H 2011 [2]. 
29/07/2010 22:05:38
NCT01117012 (Study 105): is an open-label, rollover study to evaluate the safety and efficacy of long-term VX-770 treatment. Around 200 patients (aged 6 or older) who were previously enrolled in Study 102 and Study 103 and have met certain criteria are eligible to enroll in this study. Study duration will be the sooner of 96 weeks or until VX 770 is commercially available in individually participating countries. The study will start Jul 10 and is due to complete May 13.  
30/05/2010 18:42:53
NCT00909727: A PIII, 2-part, randomized, double-blind, placebo-controlled, parallel-group 48 week study to evaluate the pharmacokinetics, efficacy and safety of VX-770 in 30 subjects aged 6 to 11 years with CF and the G551D mutation. The study started Jun 09 and is due to complete Feb 10. Dose of VX-770 being used is 100mg twice daily. The primary outcome is absolute change from baseline in % predicted FEV1 at week 24 [1]. 
30/05/2010 18:42:43
NCT00909532: A PIII, randomized, double-blind, placebo-controlled, parallel group 48 week study to evaluate the efficacy and safety of VX-770 in 80 subjects (aged 12 or over) With cystic fibrosis and the G551D CFTR mutation in at least 1 allele. The study started in May 09 and is due to complete Jan 12. VX 770 is given twice a day (150mg). The primary outcome is absolute change from baseline in % predicted FEV1 at week 24 [1]. 
30/05/2010 18:42:31
Evidence Based Evaluations
NHSEngland  http://www.england.nhs.uk/wp-content/uploads/2013/09/a01-p-a.pdf 
SMC  http://www.scottishmedicines.org.uk/files/advice/ivacaftor__Kalydeco__Resubmission_FINAL_May_2013.doc_for_website.pdf 
SMC  http://www.scottishmedicines.org/files/advice/ivacaftor_Kalydeco_FINAL_December_2012_amended_11_01_13_for_website.pdf 
EPAR  http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002494/human_med_001575.jsp&mid=WC0b01ac058001d124 
NHSC  http://www.nhsc-healthhorizons.org.uk/files/downloads/1423/1928.bd20058bc80c923f7cdd6a465b6d90cd.pdf 
Available only to registered users
BNF Category:
Mucolytics (03.07)
Pharmacology: Selective potentiator of wild-type, G551D, F508del, and R117H forms of human cystic fibrosis transmembrane conductance regulator (CFTR)  
Epidemiology: Patients with ≥1 copy of the G551D mutation to the CFTR gene represent 4% of the CF population [about 1,200 patients in the US] [7]. The most common mutation worldwide is delta F508, which occurs in 75% of patients with CF in the UK; G551D occurs in 2.3% in pts with CF the UK. CFTR is a protein that is found in various cell types, including lung epithelium, submucosal glands, pancreas, liver, sweat ducts and reproductive tract. [13]  
Indication: Cystic fibrosis 
Additional Details: ≥1 copy of the G551D mutation to the CFTR gene  
Method(s) of Administration
Company Information
Name: Vertex 
US Name: Vertex 
Further Information
Anticipated commissioning route (England) NHSE 
High cost drug list? Yes
Implications Available only to registered users