November 2019 | Samhain 2019

Major Milestone in Cystic Fibrosis Treatment

Mon, 4 November 19 16:16

A major milestone in the treatment of patients with cystic fibrosis has been reported with the publication of two Phase III clinical trials evaluating a triple-drug combination therapy for the life-threatening condition which has particular relevance in Ireland.  Professor Edward McKone, consultant respiratory physician at St Vincent’s University Hospital and UCD Clinical Professor, was a senior author in both papers publish last week by the New England Journal of Medicine and the Lancet.

Commenting on the significance of these trials, Prof McKone said,

These clinical trial results are very exciting for patients with CF, their families and the entire CF community. Highly effective CFTR modulation is now possible in the most common genetic subtypes of CF. Based on our experience to date with highly effective CFTR modulation in rarer CFTR genetic subtypes, this new triple therapy should lead to substantial clinical benefits for the majority of people with CF.

Cystic fibrosis is caused by mutations in the gene coding for the cystic fibrosis transmembrane conductance regulator (CFTR), a membrane protein and chloride channel regulator in epithelial cells.  Although there are over 2,000 known mutations of the CFTR gene, 90% of patients with cystic fibrosis have at least one copy of a specific Phe508del CFTR mutation.  Ireland has the highest incidence of Cystic Fibrosis in the world with approximately 7 in every 10,000 with the condition.  CF incidence in Ireland is almost 3 times the average rate in other European countries and the United States.

The studies evaluated a next generation CFTR corrector, Elexacaftor in combination with current therapies, Tezacaftor (a CFTR corrector) and Ivacaftor (a potentiator of defective ion channels) in two multi-centre randomised clinical trials.  Each of the three drugs were developed by Vertex Pharmaceuticals.  Both Elexacaftor and Tezacaftor are CFTR correctors which chaperone the CFTR protein to apical surfaces of epithelial cells.  Ivacaftor is a CFTR potentiator which improves chloride and bicarbonate transport through the cell’s ion channels. 

Heterozygous CFTR Mutations

One study published in the New England Journal of Medicine examined the triple drug combination in a Phase III randomised double-blind, placebo-controlled trial to study the efficacy and safety in patients aged 12 years or older with cystic fibrosis who were heterozygous for the Phe508del mutation and a minimal function mutation (Phe508del-minimal function genotypes).  Patients were recruited who had a percentage predicted forced expiratory volume in one second) ppFEV1 of 40% to 90% at screening and had stable disease during the 28-day screening period.  Over 400 patients were recruited at 115 sites in 13 countries including at St Vincent’s University Hospital.  Following the 4-week screening period, the trial continued for a 24-week intervention period with patients randomly assigned to receive the triple drug combination or matched placebos.  All patients who completed the intervention period were recruited into an ongoing 96-week open-label extension study in which all patients received active treatment. The primary end point for this trial was absolute change from baseline in ppFEV1 at week 4 with secondary end points the absolute change at week 24, number of pulmonary exacerbations, absolute change in sweat chloride concentrations at week 24 and absolute change from baseline in the Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score.  Treatment with the triple drug combination resulted in a significant improvement in the primary end point with an absolute change of 13.8 points in ppFEV1 relative to the placebo.  This improvement was sustained throughout the 24-week trial and was consistent across several prespecified cohort subgroups.  The treatment group exhibited substantially lower pulmonary exacerbations, significantly improved sweat chloride concentrations, higher quality of life CFQ-R scores and improved body mass index measurements.  The treatment was found to be generally safe with an acceptable side-effects profile consistent with an earlier Phase II study.  This study confirms the hypothesis that the triple therapy effectively modulates CFTR gene function from a single allele and offers pronounced benefit to a patient population that previous CFTR modulators were not effective.  This combination therapy demonstrates impact on a scale similar to the highly effective CFTR modulation therapy which exists for patients with a specific, less common mutation (Gly551Asp).  This study demonstrates that the modulation of a single Phe508del allele can address the underlying cause of disease for the majority of patients with cystic fibrosis.  Unlike previous CFTR modulator therapies, the triple drug combination was also effective in patients with Phe508del-minimal function genotypes.  Further research is required extend the benefit of CFTR modulation to patients with responsive mutations other than the Phe508del mutation.

Homozygous CFTR Mutations

The restoration of Ph508del CFTR function by elexacaftor-tezacaftor-ivacaftor was confirmed in a concomitant second study, published in the Lancet, involving patients with two Phe508del alleles.  This Phase III multi-centre study consisted of a randomised, double-blind active-controlled trial of elexacaftor in combination with tezacaftor plus ivacaftor.  Over 100 patients with cystic fibrosis aged 12 years and older who were confirmed as homozygous for the Phe508del mutation and with a percentage predicted forced expiratory volume in one second (ppFEV1) between 40% and 90% were recruited across 44 sites in 4 countries.  Subjects are randomly assigned to receive either elexacaftor plus tezacaftor and ivacaftor or receive tezacaftor plus ivacaftor alone.  As the control leg of this study involves the current standard of care for patients with cystic fibrosis homozygous for Phe508del, to ensure a reliable on-treatment baseline before the triple therapy, participants completed a 4 week tezacaftor plus ivacaftor run-in period following a 4-week screening period.  Participants then received 4 weeks of treatment with either elexacaftor 200mg once daily in combination with tezacaftor 100mg once daily and ivacaftor 150mg every 12 hours or the dual combination of tezacaftor 100mg once daily and ivacaftor 150mg every 12 hours.  The primary outcome was the absolute change from baseline (measured at the end of the study run-in period) in ppFEV1 at week 4.  Secondary end points were absolute change in sweat chloride and Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score.  107 participants were randomised across the two groups and completed the 4-week treatment period.  The triple therapy group had improvements in the primary outcome of pFEV1 treatment difference of 10.0 percentage points and an improvement in sweat chloride concentration of -45.1 mmol/L at week 4 compared with the current treatment regime.  There was a substantial improvement in CFQ-R score also in the elexacaftor plus tezacaftor plus ivacaftor treatment group compared with the dual combination of tezacaftor plus ivacaftor.  The triple therapy was well tolerated with a safety profile comparable to the reference group. 


Elexacaftor–Tezacaftor–Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele

Peter G. Middleton, M.D., Marcus A. Mall, M.D., Pavel Dřevínek, M.D., Larry C. Lands, M.D., Edward F. McKone, M.D., Deepika Polineni, M.D., Bonnie W. Ramsey, M.D., Jennifer L. Taylor-Cousar, M.D., Elizabeth Tullis, M.D., François Vermeulen, M.D., Gautham Marigowda, M.D., Charlotte M. McKee, M.D., et al., for the VX17-445-102 Study Group*  N Engl J Med 2019 Oct 31; DOI: 10.1056/NEJMoa1908639

Efficacy and safety of the elexacaftor plus tezacaftor plus ivacaftor combination regimen in people with cystic fibrosis homozygous for the F508del mutation: a double-blind, randomised, phase 3 trial.

Heijerman HGM, McKone EF, Downey DG, Van Braeckel E, Rowe SM, Tullis E, Mall MA, Welter JJ, Ramsey BW, McKee CM, Marigowda G, Moskowitz SM, Waltz D, Sosnay PR, Simard C, Ahluwalia N, Xuan F, Zhang Y, Taylor-Cousar JL, McCoy KS; VX17-445-103 Trial Group.  Lancet. 2019 Oct 30.  DOI: 10.1016/S0140-6736(19)32597-8.