NEW PERSPECTIVES OF PHARMACOGENETICS OF CYSTIC FIBROSIS IN COMBINED THERAPY (VX-659-TEZACAFTORIVACAFTOR)

Yakovleva O. O., Hoina-Kardasevich O. Y., Zhamba A. O., Doroshkevych I. O., Luschnikov D. S.

LITERATURE REVIEWS

Scentific article

Cystic fibrosis is a serious, autosomal-recessive, multisystem disease that affects approximately 80,000 people worldwide and is associated with early death due to progressive lung disease. The Phe508delCFTRmutation causes severe processing and trafficking defects, which result in decreased quantity and function of CFTR protein at the cell surface, and has proven to be a challenging molecular target. The article is devoted to the problem of genetic defects in cystic fibrosis and the most successful recent study results of the treatment of cystic fibrosis, based on pharmacogenetics, completed in autumn 2018 by a group of authors (VX16-659-101 Study Group). For patients with the Phe508del–Phe508del genotype, dual combinations of a first-generation CFTR corrector (lumacaftor or tezacaftor) and ivacaftor provide both short-term and long-term clinical benefit and are now accepted as the standard of care. Nonetheless, these dual combinations do not fully restore function to Phe508del CFTR protein and are not sufficiently active to improve outcomes in patients with Phe508del–MF genotypes. VX-659 triple-combination therapy led to improvements in all evaluated efficacy outcomes in patients with cystic fibrosis and Phe508del–MF or Phe508del– Phe508del genotypes. An additive response was seen for VX-659 triple-combination therapy in comparison with the dual combination of tezacaftor–ivacaftor in patients with the Phe508del–Phe508del genotype. As a consequence, there remains a need for highly effective CFTR modulation that will more adequately treat the underlying cause of disease in most patients with cystic fibrosis. Taking into account the various genetic defects, the most optimal therapy should be recognized as combination of several drugs, in order to maximize the impact and coverage of these genes of the defective CFTR protein. It has been proven that in vitro additivity of VX-659 to tezacaftor and ivacaftor increases the biosynthesis of Phe508del CFTR protein in the cell and its transfer to its surface. Clinical trials confirm the concept: that targeting the Phe508del CFTR protein with a triple-combination corrector–potentiator regimen can restore CFTR function and has the potential to represent a clinical advance for patients with cystic fibrosis who harbor either one or two Phe508del alleles, approximately 9 of every 10 patients with the disease.

cystic fibrosis, pharmacogenetics, combined therapy

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«Bulletin of problems biology and medicine» Issue 1 Part 1 (148), 2019 year, 75-80 pages, index UDK 615.015.2:[616.24+616.3+616.53/.56]-002.17-008.9

10.29254/2077-4214-2019-1-1-148-75-80