Unmet challenges in cystic fibrosis treatment with modulators

ABSTRACT

Introduction

‘Highly effective’ modulator therapies (HEMTs) have radically changed the Cystic Fibrosis (CF) therapeutic landscape.

Areas Covered

A comprehensive search strategy was undertaken to assess impact of HEMT in life of pwCF, treatment challenges in specific populations such as very young children, and current knowledge gaps.

Expert Opinion

HEMTs are prescribed for pwCF with definite genotypes. The heterogeneity of variants complicates treatment possibilities and around 10% of pwCF worldwide remains ineligible. Genotype-specific treatments are prompting theratyping and personalized medicine strategies. Improvement in lung function and quality of life increase survival rates, shifting CF from a pediatric to an adult disease. This implies new studies addressing long-term efficacy, side effects, emergence of adult co-morbidities and possible drug–drug interactions. More sensitive and predictive biomarkers for both efficacy and toxicity are warranted. As HEMTs cross the placenta and are found in breast milk, studies addressing the potential consequences of treatment during pregnancy and breastfeeding are urgently needed. Finally, although the treatment and expected outcomes of CF have improved dramatically in high- and middle-income countries, lack of access in low-income countries to these life-changing medicines highlights inequity of care worldwide.

KEYWORDS:

• Cystic Fibrosis (CF)
• CFTR modulators
• long-term treatment
• effectiveness
• new therapies
• pregnancy
• affordability

Article highlights

• ‘Highly effective’ modulator therapies (HEMTs) have revolutionized cystic fibrosis treatment.

• CFTR modulators prove efficient for an increasing typology of variants.

• Development of relevant preclinical models has enabled theratyping to identify which variant responds to certain target treatments.

• The increasing use of CFTR modulators requires the determination of specific modalities for situations such as pregnancy, breastfeeding, and transplantation.

• Prescription in very young children highlights the need to define novel strategies of disease monitoring in this target population.

• Long-term use of modulators prompts real-world data studies to monitor potential resistance development.

• Inequity of access to these very costly CFTR modulator therapies according to social and economic issues needs to be solved.

Declaration of Interest

I Sermet-Gaudelus has received Vertex funding for academic research.

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

A reviewer on this manuscript has disclosed that they are co-founder and shareholder of Kither Biotech, a pharmaceutical company developing PI3K inhibitors for respiratory disease.

Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

F. Corrao has a PhD Fellowship provided by University of Palermo (Italy).