Advancing the pipeline of cystic fibrosis clinical trials: a new roadmap with a global trial network perspective

Abstract

The growing use of modulator therapies aimed at restoring cystic fibrosis transmembrane conductance regulator (CFTR) protein function in people with cystic fibrosis has fundamentally altered clinical trial strategies needed to advance new therapeutics across an orphan disease population that is now divided by CFTR modulator eligibility. The development of a robust pipeline of nucleic acid-based therapies (NABTs)-initially directed towards the estimated 10% of the cystic fibrosis population who are genetically ineligible for, or intolerant of, CFTR modulators-is dependent on the optimisation of restricted trial participant resources across multiple development programmes, a challenge that will preclude the use of gold standard placebo-controlled trials. Advancement of a full pipeline of symptomatic therapies across the entire cystic fibrosis population will be challenged by smaller effect sizes and uncertainty regarding their clinical importance in a growing modulator-treated population with more mild and stable pulmonary disease. In this Series paper, we aim to lay the foundation for clinical trial strategy and community partnership that must deviate from established and familiar precedent to advance the future pipeline of cystic fibrosis therapeutics.

Figure 1.. Overview of current and near-term trial options for pwCF ineligible for CFTR modulators.

As a case example for the regional challenges of population size to fuel the trial pipeline, in the 2021 U.S. CF Foundation Patient Registry there were only 1100 of 1613 adults with CF currently genetically ineligible for modulators and who would meet initial eligibility for early phase trials (age ≥ 18 years and with ppFEV₁ ≥40% or greater and not post lung transplant). Accessibility and willingness to participate in a clinical trial is a critical factor when considering feasible trial sizes that can be successfully enrolled contemporaneously across a full pipeline, and less than 50% of these 1100 have prior documented experience in a research study and a subset of these (less than 25% overall) in a recent clinical trial (2015 – 2022). The unique perspectives of individuals identifying as BIPOC and/or of Hispanic ethnicity must also contribute to inclusive trial recruitment strategies across the entire CF population since a disproportionate number (approximately 40%) of pwCF within minoritized populations are genetically ineligible for CFTR modulators(26, 29). There are many potential paths (arrows) to re-enter the pipeline after initial trial participation with several unknowns (represented by “?”) regarding the willingness and eligibility of participants to enroll in a clinical trial after completion of a prior trial, particularly in the setting of NABTs. Trial sponsors may be hesitant to enroll subjects who have previously participated in a NABT trial since this history could confound safety monitoring and there may be the potential to develop an immune response from exposure to a prior genetic therapy that could limit potential benefit of future genetic therapies(15). Most genetic therapy trials will require long term safety follow-up studies, including up to 15 years duration for gene editing therapies(82, 83). It will be essential to enable co-enrollment in several clinical trials during this time despite potential complications with attributing safety events.

Figure 2.

The CF Global Trial Network Scientific Review Process provides a streamlined mechanism to enable joint scientific review and prioritization of the CF therapeutic pipeline. Clinical trial networks, including the CFF TDN, ECFS CTN, and the CF CanACT, participate in a unified scientific review of the sponsor protocol and then independently assess the protocol’s priority within their respective network. Following independent priority review, an internal discussion among Network leadership occurs, after which a joint communication is sent to the Sponsor outlining the priority score of each network. CFF= Cystic Fibrosis Foundation; TDN= Therapeutics Development Network; ECFS= European CF Society; CTN= Clinical Trials Network; CanACT= Canada Accelerating Clinical Trials.