Advancing clinical development pathways for new CFTR modulators in cystic fibrosis

Abstract

Cystic fibrosis (CF) is a life-shortening genetic disease affecting approximately 70,000 individuals worldwide. Until recently, drug development efforts have emphasised therapies treating downstream signs and symptoms resulting from the underlying CF biological defect: reduced function of the CF transmembrane conductance regulator (CFTR) protein. The current CF drug development landscape has expanded to include therapies that enhance CFTR function by either restoring wild-type CFTR protein expression or increasing (modulating) the function of mutant CFTR proteins in cells. To date, two systemic small-molecule CFTR modulators have been evaluated in pivotal clinical trials in individuals with CF and specific mutant CFTR genotypes that have led to regulatory review and/or approval. Advances in the discovery of CFTR modulators as a promising new class of therapies have been impressive, yet work remains to develop highly effective, disease-modifying modulators for individuals of all CF genotypes. The objectives of this review are to outline the challenges and opportunities in drug development created by systemic genotype-specific CFTR modulators, highlight the advantages of sweat chloride as an established biomarker of CFTR activity to streamline early-phase development and summarise options for later phase clinical trial designs that respond to the adoption of approved genotype-specific modulators into standard of care. An optimal development framework will be needed to move the most promising therapies efficiently through the drug development pipeline and ultimately deliver efficacious and safe therapies to all individuals with CF.

Keywords: Cystic Fibrosis; Rare lung diseases.

Figure 1

Distributions of genotypes containing the 20 most prevalent mutant cystic fibrosis transmembrane conductance regulator (CFTR) alleles among individuals in the US with CF. Genotypes (each consisting of two CFTR alleles) are shown for individuals with CF followed in the 2012 US CF Foundation Patient Registry (CFFPR). The 20 most prevalent mutant CFTR alleles are shown in the same order on each axis with each possible genotype represented by only one bar and homozygous genotypes found on the front diagonal. The most prevalent genotype is F508del/F508del (far left). F508del compound heterozygotes are the remainder of bars along the first CFTR allele ‘wall’. Those genotypes for which there is currently an approved CFTR modulator are highlighted with dark bars. The same data are depicted in (A and B), but with the Y-axis shown as linear in (A) and log₁₀ scale in (B).

Figure 2

Mean treatment-associated changes in sweat chloride concentration observed in three trials of cystic fibrosis transmembrane conductance regulator (CFTR) modulators. Modulators and CF genotypes studied are identified above observed values. Studies (A) and (B) were blinded, randomised and placebo-controlled. Study (C) was observational. Bars around point estimates represent 95% CIs.

Figure 3

Possible pivotal trial study designs for a candidate cystic fibrosis transmembrane conductance regulator (CFTR) modulator as influenced by genotype target, the existing modulator landscape and anticipated clinical efficacy. For any candidate modulator and CFTR genotype pairing, a series of queries (white boxes) and responses (black boxes) will inform which of five study designs (grey boxes) might be considered.

Figure 4

One-month washout design for a second-generation modulator studied in a population with access to a robust approved modulator. Subjects receiving the approved modulator are randomised 1:1 to receive the candidate modulator or placebo. Subjects can be optionally rolled over to active modulator for additional information.