Transforming the lives of people with cystic fibrosis: CF modulator therapies, from trial to patient.

Cystic fibrosis (CF) is a rare genetic disease caused by mutations in the CFTR gene, that affects around 10,000 people in the UK. Manchester Clinical Research Facility (MCRF) has been involved in CF clinical trials for almost 10 years and played a key role during a period that has seen rapid evolution of life-changing therapies. Dr Alexander Horsley, MCRF Director, is a CF specialist and the academic lead at the Manchester Adult Cystic Fibrosis Centre (MAFC). Researchers from MACFC have served as national and global leads on several pivotal studies.

MCRF has hosted a range of clinical trials of different modulator therapies from several industry partners, including those from the successful Vertex range of compounds. Early dual-therapy combinations, such as Ivacaftor/tezacaftor (symkevi) were trialled at MCRF, and later licensed and funded in the UK (November 2019).

MCRF has been at the forefront of trials of the most recent and most powerful triple combination therapies. These compounds have progressed along our translational pathway from Phase 1 (with SME, Medicines Evaluation Unit), to Phases 2 and 3 in the MCRF, which continue to be supported through MCRF infrastructure, including experienced research nurses and staff from laboratory services and physiology.

The Phase 3 studies continued during the COVID-19 pandemic with patient safety the primary driver; MACFC and MCRF staff conducted study visits at alternative clinical sites, and the use of home spirometry was increased to reduce patient visits to the MCRF. Participants continued to be provided with-highly effective CFTR modulators that were only available as part of the trial.

MAFC was the highest recruiting UK centre to these trials in 2019 and 2020.

These trials included the Vertex triple combination therapy, Kaftrio – a breakthrough therapy that has been shown to be effective in 90 per cent of CF patients with an average improvement in lung function of over 20%. MCRF has been central to the development of these therapies, with Dr Horsley and Dr Peter Barry, Consultant Respiratory Physician (MACFC), playing leading roles as Chief and Principal Investigators. Dr Horsley has also been critical in other trials and protocol designs for compounds that have been part of the ground-breaking modulator development.

Following the trials at MCRF, the novel therapies were rapidly rolled out to more than 280 adult CF patients across Manchester, the first in Europe to receive these transformative medications. This has resulted in life-changing improvements, including eight patients who no longer require long-term oxygen support, and eight patients who are now considered well enough to no longer require a lung transplant.

MCRF continues to support new developments in CF therapies, including the next generation of triple therapy studies. Dr Horsley was Chief Investigator for the phase 2 Vx121 study, with MCRF as the lead and highest recruiting site – the study is now progressing to Phase 3.

MACFC is also a European CF Society Clinical Trials site and will be playing a key role in delivery of NIHR supported initiatives, including the i CF-STORM study and the NIHR Rare Diseases Bioresource.