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38912911000001100

New Medicines

Kaftrio [EU], Trikafta [US]Treatment of cystic fibrosis in patients aged 12 years and older who have at least one F508del mutation in the CFTR gene

Information

Kaftrio [EU], Trikafta [US]
New formulation
Vertex
Vertex

Development and Regulatory status

Launched
Launched
Launched
August 2020
May 21MHRA approves licence extension for Kaftrio in combination with ivacaftor for treatment of CF in all patients aged ≥12 years, who have ≥1 F508del mutation in CFTR gene. Long-term reimbursement agreements means eligible patients will have access to this treatment [22].
Apr 21Licence extension approved in EU [21].
Mar 21EU CHMP issues a positive opinion recommending a change to the licence for Kaftrio to extend the use in all patients with at least one F508del mutation. The proposed full indication for Kaftrio will be use in a combination regimen with ivacaftor 150 mg tablets for the treatment of cystic fibrosis in patients aged 12 years and older who have at least one F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene [20].
Sep 20Price:75mg/50mg/100mg x 56=£8346.30 (hospital only). Adult dosage is 150mg/100mg/200mg in the morning plus ivacaftor 150mg in the evening [19].
Aug 20Available in the UK [18].
Aug 20Approved in EU [17].
Jun 20NHS England announce a four year deal with Vertex which will allow patients with cystic fibrosis to have access to Kaftrio (ivacaftor/tezacaftor/elexacaftor) as soon as a licence is granted by the European Medicines Agency [16].
Jun 20Recommended for EU approval by CHMP - the full indication is "in a combination regimen with ivacaftor 150 mg tablets for the treatment of cystic fibrosis (CF) in patients aged 12 years and older who are homozygous for the F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene or heterozygous for F508del in the CFTR gene with a minimal function (MF) mutation." It is proposed that the medicine is prescribed by physicians experienced in the treatment of cystic fibrosis [15].
Jan 20Launched in the US [13].
Nov 19Filed in EU under centralised procedure. Application is being reviewed under EMA´s accelerated assessment programme [12].
Oct 19Approved in US [9]
Aug 19Granted priority review in US with a target action date of 19/03/20 [8].
Aug 19NDA filed in US, with a request for priority review [7].
Jun 19Vertex plans to submit a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) in the third quarter of 2019 and a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) in the fourth quarter of 2019 [6].
Mar 19The company is planning to submit global regulatory approval applications later in 2019 [5].
Jan 19Initially VX-445 was developed as a single regimen and based on the positive data from the combination trials with ivacaftor and tezacaftor, Vertex is developing this fixed-dose combination [3].

Category

Fixed-dose combination of VX-445 with ivacaftor & tezacaftor. VX-445 is a fourth next-generation corrector of CF transmembrane conductance regulator, which enhances the number of channels of the CFTR protein at the cell membrane.
CF is the most common inherited disease in white populations. Prevalence is 1 in 2,500 newborn infants, with calculated carrier frequency of 1 in 25. Just over 10,000 people were recorded as having CF in the 2013 UK CF Registry [1].
Treatment of cystic fibrosis in patients aged 12 years and older who have at least one F508del mutation in the CFTR gene
Oral

Further information

Yes

Trial or other data

Aug 21PIII RCT (NCT04058353; n=258) reports elexacaftor–tezacaftor–ivacaftor was efficacious in patients with Phe508del–gating or Phe508del–residual function genotypes with percentage of predicted FEV1 that was higher by 3.7% relative to baseline & higher by 3.5% relative to active control (all p<0.001) [22].
Nov 19RCT (NCT03525548; n=113) is published; it found elexacaftor plus tezacaftor plus ivacaftor, provided a clinically significant benefit to forced expiratory volume compared to tezacaftor plus ivacaftor alone (treatment difference 10.0%; 95% CI 7.4 to 12.6, p<0.0001), with a favourable safety profile [11].
Nov 19RCT (NCT03525444; n=403) is published; it found elexacaftor–tezacaftor–ivacaftor, relative to placebo, improved forced expiratory volume by 14.3% and reduced rate of pulmonary exacerbations by 63% at 24 weeks (p<0.001 for all comparisons versus placebo) [10].
Jun 19Results from 24-week PIII study in people with one F508del mutation and one minimal function mutation and from a 4-week PIII study in people with two F508del mutations met their primary endpoints. Vertex PIII program for the VX-445 regimen consists of two randomized, double-blind trials in patients with CF caused by one F508del plus one minimal function mutation (NCT03525444) or by two F508 del mutations (NCT03525548) [6].
Mar 19Interim analysis from two PIII trials looking at triple therapy with VX-445, tezacaftor and ivacaftor in patients with late-stage CF demonstrated the combination improved percent predicted FEV1 (ppFEV1). In the trial where enrolled patients had one F508del mutation and one minimal function mutation, mean absolute improvement in ppFEV1 of 13.8% from baseline at 4 weeks. In the trial where patients had two F508del mutations, ppFEV1 improved by 10 percentage points from baseline at week 4. The combination was reported to be well-tolerated [5].
Jan 19PIII study (NCT03525574) to evaluate the long-term safety and tolerability of VX-445 in triple combination (TC) with tezacaftor (TEZ) and ivacaftor (IVA) in subjects with cystic fibrosis (CF) who are homozygous or heterozygous for the F508del mutation starts enrolling by invitation. 460 patients will be enrolled and collection of primary outcome data is due to complete Jun 21 [2].
Jan 19Results of PII dose-ranging study (NCT03227471) show 4 weeks of triple therapy with single-agent VX-445 (added to existing tezacaftor–ivacaftor) in those with Phe508del–Phe508del genotype, increased predicted percentage FEV1 by 11.0-13.8% [4].
Jan 19PIII trial to evaluate a triple combination regimen of VX 445, ivacaftor and tezacaftor in patients ages 12 years and older with CF who have two copies of the F508del mutation (homozygous) starts (NCT03525548). The primary endpoint of the study is the mean absolute change in lung function (ppFEV1) from baseline at week four of of triple combination treatment compared to triple placebo. The study is designed to support the submission of an NDA based on data from the 4-week primary efficacy analysis and on safety data through 24 weeks of treatment. 113 patients will be recruited in the US & EU. Collection of primary outcome data is due to complete Mar 19 [2].
Jan 19PIII trial to evaluate a triple combination regimen of VX 445, ivacaftor and tezacaftor in patients ages 12 years and older with CF who have one copy of the F508del mutation (heterozygous) and one minimal function mutation starts (NCT03525444). The primary endpoint of the study is the mean absolute change in lung function (ppFEV1) from baseline at week four of triple combination treatment compared to triple placebo. The study is designed to support the submission of an NDA based on data from the 4-week primary efficacy analysis and on safety data through 12 weeks of treatment. 405 patients will be recruited from countries around the world including the US & EU (plus UK). Collection of primary outcome data is due to complete Aug 19 [2].

Evidence based evaluations

Kaftrio [EU], Trikafta [US]Treatment of cystic fibrosis in patients aged 6-11 years who have at least one F508del mutation in the CFTR gene

Information

Kaftrio [EU], Trikafta [US]
Licence extension / variation
Vertex
Vertex

Development and Regulatory status

Launched
Launched
Launched
January 2022
Yes
Jan 22MHRA orphan drug register entry for Kaftrio (when used in a combination regimen with ivacaftor for CF in those who have at least one F508del mutation in the CFTR gene) updated to include patients ≥6 years. As the MHRA grants this status at the time of authorisation, it can be assumed that the MHRA has approved extension of license in ≥6-11years age group [13].
Jan 22Jan 22: Approved in EU [12]
Nov 21The proposed new indication in the EU is use in a combination regimen with ivacaftor for the treatment of cystic fibrosis (CF) in patients aged 6 years and older who have at least one F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene [10].
Nov 21EU positive opinion granted recommending a licence change to include use in children aged 6 years of age and older (previously licensed only for in patients 12 years of age and older) [10].
Jun 21Approved in US [9].
May 21EMA and MHRA validate applications to expand licence of Kaftrio in CF. Indication is use in combination with ivacaftor in patients age ≥6 years who have ≥1 F508del mutation in CFTR gene [8].
Jan 21Vertex Announces US FDA acceptance of sNDA for elexacaftor/tezacaftor/ivacaftor and ivacaftor in children with CF ages 6 through 11 with certain mutations [6].
Apr 20Pending the results of the PIII (NCT03691779) study the company plans to submit a supplemental New Drug Application to the FDA in 2020 followed by additional submissions to other global regulatory agencies [4].

Category

Fixed-dose combination of VX-445 with ivacaftor & tezacaftor. VX-445 is a fourth next-generation corrector of CF transmembrane conductance regulator, which enhances the number of channels of the CFTR protein at the cell membrane.
CF is the most common inherited disease in white populations. Prevalence is 1 in 2,500 newborn infants, with calculated carrier frequency of 1 in 25. Just over 10,000 people were recorded as having CF in the 2013 UK CF Registry [1].
Treatment of cystic fibrosis in patients aged 6-11 years who have at least one F508del mutation in the CFTR gene
Oral

Further information

Yes

Trial or other data

Sep 20Safety data from PIII study NCT03691779 were consistent with those observed in previous studies. Vertex Pharmaceuticals plans to submit sNDA to US FDA Q4 2020 [5].
Feb 20NCT03691779 is active but not recruiting. Collection of primary outcome should now complete Jul 20 [3]
Oct 18PIII trial to evaluate the pharmacokinetics, safety, tolerability, efficacy, and pharmacodynamic effect of VX 445, ivacaftor and tezacaftor in cystic fibrosis patients aged 6 to 11 years of age with F/F and F/MF genotypes starts (NCT03691779). The open-label, trial is enrolling approximately 56 patients in the US. Collection of primary outcome data is due to complete Jan 20 [2].

Evidence based evaluations