October 2018 | Deireadh Fómhair 2018

New Hope for Patients with Cystic Fibrosis

Tue, 30 October 18 11:11

Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Correctors are novel medicines that treat the cause of cystic fibrosis, CFTR protein dysfunction. These therapies were developed by targeting the different genetic subtypes of Cystic Fibrosis. In 2012, the first CFTR corrector, ivacaftor (Kalydeco), was approved to treat a relatively rare genetic subtype of CF caused by the CFTR-G551D gating mutation. This therapy was highly effective in this genetic subtype of CF with substantial improvements in lung function, lung infection frequency and nutrition. The sweat test, which is the test used to diagnose CF, improved significantly to levels below the diagnostic threshold for CF. 
Unfortunately, this therapy was not effective in patients with the F508del mutation which is the most common cause of CF. Lumacaftor/ivacaftor (Orkambi) and tezacaftor/ivacaftor (Symkevi) have been approved to treat patients homozygous for F508del which is the genetic form of CF affecting 50% of patients. However, the effects of these drugs on lung function and sweat test were modest. There is a need to develop more potent drug combinations for F508del homozygotes and for other CFTR genotypes, especially those with heterozygotes for F508del which, including the F508del homozygotes, would cover 90% of CF patients.
In Oct 25th edition of the New England Journal of Medicine (NEJM), the results of two Phase II trials were published looking at CFTR Corrector triple therapy (tezacaftor/ivacaftro in combination with VX-659 and VX-445) in patients with CF. These trials included participants from St. Vincent’s University Hospital. Both studies demonstrated substantial improvements in lung function and sweat test, similar to that seen with ivacaftor in CFTR-G551D.
Prof Edward McKone, St. Vincent’s University Hospital, who was an author on both papers, commented that
“CFTR Corrector Triple-therapy shows great promise for patients with at least on copy of F508del, many of whom have no treatments available and severe progressive lung disease. Although the results of the Phase III trials are still awaited, there is great optimism that highly effective treatments for the most common type of genetic CF will be available to CF patients soon.”
VX-659 and VX-445 have been developed by Vertex Pharmaceuticals who funded these clinical trials VX16-659-101 and VX16-659-001 ClinicalTrials.gov numbers, NCT03224351 and NCT03029455.

VX-659–Tezacaftor–Ivacaftor in Patients with Cystic Fibrosis and One or Two Phe508del Alleles
Jane C. Davies, M.D., Samuel M. Moskowitz, M.D., Cynthia Brown, M.D., Alexander Horsley, Ph.D., Marcus A. Mall, M.D., Edward F. McKone, M.D., Barry J. Plant, M.D., Dario Prais, M.D., Bonnie W. Ramsey, M.D., Jennifer L. Taylor-Cousar, M.D., M.S.C.S., Elizabeth Tullis, M.D., Ahmet Uluer, D.O., et al., for the VX16-659-101 Study Group.  
N Engl J Med 2018; 379:1599-1611   DOI: 10.1056/NEJMoa1807119  [Link]
VX-445–Tezacaftor–Ivacaftor in Patients with Cystic Fibrosis and One or Two Phe508del Alleles
Dominic Keating, M.D., Gautham Marigowda, M.D., Lucy Burr, Ph.D., Cori Daines, M.D., Marcus A. Mall, M.D., Edward F. McKone, M.D., Bonnie W. Ramsey, M.D., Steven M. Rowe, M.D., M.S.P.H., Laura A. Sass, M.D., Elizabeth Tullis, M.D., Charlotte M. McKee, M.D., Samuel M. Moskowitz, M.D., et al., for the VX16-445-001 Study Group.
N Engl J Med 2018; 379:1612-1620    DOI: 10.1056/NEJMoa1807120 [Link]