The equitable challenges to quality use of modulators for cystic fibrosis in Australia

Cystic fibrosis, an autosomal recessive disease, causes premature mortality with a current life expectancy of 56 years.¹ Variations in a single gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR), an anion channel, cause this multisystemic disease.² Bronchiectasis remains the most significant contributor to mortality, with other affected systems including the gastrointestinal, pancreatic, hepatobiliary, sweat glands and reproductive systems.³ Clinical manifestations of cystic fibrosis vary widely, leading to diverse phenotypic expressions.

Over 2000 CFTR variants have been described worldwide, with 719 confirmed as disease causing.⁴ These pathogenic variants are classified based on their functional consequence on the CFTR protein² (Box 1). Class II includes F508del, the most prevalent CFTR variant globally.² In Australia, about 90% of people with cystic fibrosis have at least one copy and about 50% are homozygous for the F508del allele.^{2, 5}

Therapeutic management of cystic fibrosis has evolved significantly over the past century. Aggressive early intervention with optimised nutrition, airway clearance and antibiotics, along with newborn screening and the introduction of specialist centres, increased the life expectancy from 4 to 40 years, but with a significant burden of care impacting quality of life.³ A landmark development occurred in 2011, 22 years after the CFTR gene was isolated, with the introduction of the first targeted disease modifying therapy, ivacaftor.²

Four CFTR modulators (ivacaftor, lumacaftor, tezacaftor and elexacaftor) have received approval from major regulatory bodies (Box 2). These approvals followed a development strategy with high throughput screening of 228 000 compounds, using Fischer rat thyroid (FRT) cell lines and human bronchial epithelial cells.² Drug candidates underwent animal toxicity studies and human clinical trials to ensure safety and efficacy. Ivacaftor functions as a CFTR channel potentiator.² Lumacaftor and tezacaftor, first-generation correctors, stabilise the CFTR protein to prevent premature degradation in the endoplasmic reticulum and are currently approved as dual combination medications with ivacaftor.² The latest advancement is the triple combination therapy of two correctors, elexacaftor and tezacaftor, with ivacaftor (ETI), which is approved for people with cystic fibrosis with at least one F508del-CFTR allele.⁶

The rarity of certain CFTR variants presents a challenge to large scale phase 3 clinical trials. To address this, in vitro data from FRT cell experiments were submitted to the American Food and Drugs Administration (FDA), leading to ivacaftor's extended approval and the establishment of a new precedent for drug approvals.² Since then, the FDA has expanded the number of approved CFTR variants to 97 for ivacaftor, 127 for tezacaftor–ivacaftor and 177 for ETI, based on in vitro evidence and existing clinical data. In line with these developments, the Australian Therapeutic Goods Administration (TGA) has also expanded approvals.

In Australia, the TGA evaluates new drugs for safety, quality and efficacy, whereas the Pharmaceutical Benefits Advisory Committee recommends treatment subsidisation through the Pharmaceutical Benefits Scheme (PBS) ensuring eligible patients have affordable access. The details of TGA drug approvals and PBS listings can differ, with PBS listings often being more restrictive (Box 2).

Given the rapidly evolving landscape of precision medicine, the Australian health technology assessment pathway is undergoing its first review in over three decades. We eagerly await the outcomes and hope that new pathways will address current inequities in Australian cystic fibrosis patients’ access to disease-modifying treatments. Incorporating in vitro cell models into cystic fibrosis care could identify the best therapy (in terms of CFTR rescue) for patients with multiple therapeutic options and help address inequity by providing access for patients with rare variants.

AJ is chair of the scientific and medical advisory committee of Rare Voices Australia and has received speaker payments from Vertex Pharmaceuticals. LF has been a sub-investigator on Vertex clinical trials and received sponsorship of travel costs to attend educational meetings. SW has received competitive funding sponsored by Vertex Pharmaceuticals. Vertex Pharmaceuticals had no involvement in the planning, writing or publication of this article.

Not commissioned; externally peer reviewed.