Hypothesis
Ataluren would slow lung disease in people with nonsense-mutation CF; a reanalysis with more sensitive CT scoring would reveal a treatment effect on structural lung disease that the original trial's FEV1 endpoint and Brody-II scores missed.
What failed
The 48-week phase 3 trial in 238 patients had already missed its FEV1 primary endpoint. Re-scoring 391 CT scans from 210 patients with CF-CT and PRAGMA-CF showed PRAGMA-CF disease and mucus plugging progressed over 48 weeks, but progression did not differ between ataluren and placebo, regardless of tobramycin use.
Broken assumption
Ataluren's read-through of nonsense mutations restores enough CFTR function to slow structural lung damage.
Why
The abstract does not explain the lack of effect; it concludes PRAGMA-CF is sensitive enough to serve as a trial outcome.
From the published paper: Tiddens et al. PLoS ONE, 2020. ↗CC BY