Theranostics by testing CFTR modulators in patient-derived materials: The current status and a proposal for subjects with rare CFTR mutations

Abstract

The last decade has witnessed developments in the CF drug pipeline which are both exciting and unprecedented, bringing with them previously unconsidered challenges. The Task Force group came together to consider these challenges and possible strategies to address them. Over the last 18 months, we have discussed internally and gathered views from a broad range of individuals representing patient organizations, clinical and research teams, the pharmaceutical industry and regulatory agencies. In this and the accompanying article, we discuss two main areas of focus: i) optimising trial design and delivery for speed/efficiency; ii) drug development for patients with rare CFTR mutations. We propose some strategies to tackle the challenges ahead and highlight areas where further thought is needed. We see this as the start of a process rather than the end and hope herewith to engage the wider community in seeking solutions to improved treatments for all patients with CF.

CFTR Modulators: The Changing Face of Cystic Fibrosis in the Era of Precision Medicine

“…Furthermore, clinical trials in sicker or younger patients, and those carrying rarer CFTR mutations are more challenging due to small sample size, specific inclusion/exclusion criteria, or even for some hesitation on the part of the investigators. Strategies to adapt and optimize trial design and deliver for speed and efficacy have been discussed, including the use of patient-derived specimens, power calculations to compensate for group sampling, and N-of-1 and "basket" trials (Matthes et al, 2018;Amaral et al, 2019;Davies et al, 2019b).…”

“…The use of patient-derived specimens to comparatively evaluate drug efficacies may be a feasible starting point to identify the best candidate drug(s) in vitro and predict the magnitude of therapeutic responses for following clinical testing (Strauss and Blinova, 2017;Amaral et al, 2019). In fact, a significant but variable clinical responsiveness was observed in clinical trials with CFTR modulators in patients carrying at least one G551D mutation (Ramsey et al, 2011;Rowe et al, 2014) or in F508del-homozygous patients (Boyle et al, 2014;Wainwright et al, 2015;Donaldson et al, 2018a), which suggests that patient responsiveness to a certain therapy is influenced not only by the CF genotype but also by the genetic background and/or epigenetic factors.…”

Cystic fibrosis in the year 2020: A disease with a new face

“…Their number is too low for proper clinical trials. For these patients, the development of intestinal organoids has been a major step forward . This allows quantifying CFTR function and its rescue by CFTR modulators in vitro in patient‐specific material via the forskolin‐induced swelling assay: more function equals more swelling.…”

Molecular Diagnosis and Genetic Counseling of Cystic Fibrosis and Related Disorders: New Challenges

“…Likewise, other tests may be of help, such as sweat secretion after β-adrenergic stimulation, also called evaporimetry [ 55 ]. Ex vivo assessment of CFTR function on miniaturized versions of organs called organoids, from minimally invasive rectal biopsies [ 56 ] or on bronchial or nasal cells [ 57 , 58 ], is based on sophisticated and comprehensive techniques implemented in a few expert laboratories, which help diagnose, understand mechanistic defects and better predict organ-specific drug responses [ 59 ].…”