Cystic Fibrosis Clinical Trials: The Latest in Rare Disease Therapies and Clinical Trial Design

representing Cystic Fibrosis clinical trials
representing Cystic Fibrosis clinical trials

Over 150,000 individuals worldwide are estimated to be living with cystic fibrosis (CF), a life-threatening multi-organ hereditary disorder caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. The CFTR protein is an anion transporter found across the body that is responsible for maintaining fluid equilibrium and mucus secretions in the lung tissue. In CF, this protein either isn’t made or cannot function properly, resulting in mucus build-up, bacterial infections, and death in the case of respiratory failure. Since its first description in 1938, a CF diagnosis spelled fatality in the early years of life, but advances in our understanding of the disease and CF therapies have helped extend patient life expectancy well into adulthood.

To date, CF can be treated with a combination of airway clearance techniques, surgical lung transplant, and medications like mucus thinners, bronchodilators, CFTR modulators, antibiotics, and anti-inflammatories. However, the clinical landscape of CF treatments has been continuously changing over the last few decades. As sponsors and contract research organizations (CROs) continue to expand the limitations of drug discovery and rare disease clinical trials, CF patients can expect even more treatment options to become available in the future.

Cystic Fibrosis Clinical Trial Design Considerations

Developing drugs for orphan diseases is particularly challenging because the sponsor’s or CRO’s risk of failure is higher and potential earnings are lower than that of more well-known diseases. For this reason, optimizing the design of cystic fibrosis clinical trials can go a long way in helping ensure success for companies. For one, given the availability of a wide variety of standard treatments, traditional placebo-controlled studies may not be as attractive as including an active comparator arm. A 2021 Delphi study (Dobra et al., 2021) also found that lack of time, difficulty traveling to the site, and the costs of accommodating visits were the three most important barriers to patient participation in cystic fibrosis clinical trials. Recruitment for rare disease research is a challenge as it is, but patient-centric considerations within the protocol can improve enrollment. These can include minimizing the frequency and length of visits, offering travel or childcare assistance, and incorporating study design feedback from real cystic fibrosis patients.

Today’s Landscape of Targeted Therapies

CFTR modulators are one major area of therapeutic research that has seen impressive developments in recent decades, helping address different problems caused by a variety of CF mutations. As of 2023, the following small molecule drugs have been approved for the treatment of CF, including in infants and small children: Kalydeco (ivacaftor; 2012), Orkambi (lumacaftor/ivacaftor; 2015), Symdeko (ivacaftor/tezacaftor; 2018), and most recently, Trikafta (elexacaftor/tezacaftor/ivacaftor; 2019). All four modulators help the CFTR protein maintain its shape, stay embedded in the cell membrane longer, and keep the chloride channel open to allow fluid movement. Because there is considerable heterogeneity in mutations amongst CF patients, no one modulator is applicable to everyone; however, the recent approval of Trikafta may help treat as much as 90% of this population. Still, the search for new targeted therapies continues on as scientists explore more effective drugs which can promote normal CFTR protein folding, pump chloride ions out of the cell, and improve patient symptoms.

The Promise of Gene Therapy

Despite the approval of multiple small-molecule drugs, there is still a subset of CF patients who cannot use them. To treat patients whose mutations can’t be addressed with modulators, RNA and DNA replacement approaches are currently in clinical testing, whereas gene editing is being actively explored. Biotech and gene-therapy companies are currently investigating the use of viral vectors to deliver CFTR DNA into the respiratory epithelium and modify defective CFTR gene mutations. Unlike with modulators, gene therapy holds the potential to be a single-dose ‘curative’ intervention that works regardless of the patient’s specific underlying mutation. As this strategy is developed further, researchers are increasingly understanding the changing composition of the CF population, as well as prioritizing the need to address inequity in access to care and reduce the burden of symptoms.

Vial Rare Disease CRO

Vial, a full-service CRO supporting cystic fibrosis clinical trials, recognizes the central role of technology in the future of drug development for rare diseases and is paving the way for modernized clinical research through digital innovation. Trusted by leading sponsors, our specialized teams deliver shorter study timelines, quality affordable services, and a clinical trial experience that puts you first. Contact a team member today to discover how we can help!

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