(168) Results from APPLAUD Phase 2 Study with Pro-Resolution Drug Candidate LAU-7b in Adults with Cystic Fibrosis

Background: LAU-7b (oral fenretinide) is a novel drug candidate acting on membrane lipids to modulate inflammation signaling and protein trafficking. Membrane lipid imbalance is believed to play a role in aberrant pulmonary inflammation in individuals with cystic fibrosis (CF), leading to irreversible lung damage over time. Fenretinide was shown to correct the levels of certain membrane phospholipids and sphingolipids in multiple in vitro and in vivo models of CF, resulting in improved resolution of inflammation and increase in functional CFTR expression, even under cellular stress conditions. A Phase 2 clinical trial (APPLAUD) was conducted in adults with CF to evaluate the safety of LAU-7b and its effect on the preservation of lung function, by reducing inflammation and restoration of homeostasis.

Methods: APPLAUD was a double-blind, placebo-controlled study in adults with CF, randomized (1:1) to either LAU-7b or placebo for 6 consecutive treatment cycles of 21 days, spaced by 7-day drug-free periods. Eligible subjects had a FEV1 percent predicted (ppFEV1) between 40% and 100% at screening, and had at least one pulmonary exacerbation (PEx) in the prior year. The study drug was administered orally once daily, in addition to standard of care. The primary efficacy endpoint was the absolute change from baseline in ppFEV1 at 24 weeks. Secondary endpoints included parameters related to pulmonary exacerbations, quality of life, systemic inflammatory and lipidomic biomarkers, among others.

Results: A total of 166 subjects were randomized at 40 sites in the USA, Canada and Australia. Preliminary results showed that the absolute change of ppFEV1 at 24 weeks was 0.8 points in favor of LAU-7b (-0.8 ppFEV1 change from baseline in the LAU-7b arm, n=83, versus -1.6 ppFEV1 in the placebo arm, n=83; p=0.435). Planned stratification factor analysis showed that subjects with ppFEV1≥70 at baseline were better responders, resulting in a treatment difference of 3.0 points in ppFEV1 at 24 weeks favoring LAU-7b (-0.9 ppFEV1 change from baseline in the LAU-7b arm, n=29, versus -3.9 ppFEV1 in the placebo arm, n=27; p=0.058). Although the number of subjects was small, similar positive trends were noted in subjects already treated with CFTR modulators, including TRIKAFTA®. PEx incidence and the number of days of IV antibiotics were numerically lower in the LAU-7b arm compared to placebo. The safety profile of LAU-7b treatment was consistent with the safety profile observed in previous clinical studies with fenretinide. Serious adverse events, severity, and relationship distribution were similar between the two treatment arms, with no SUSAR or deaths reported.

Conclusions: Compared to placebo, LAU-7b treatment exerted a 50% reduction in the loss of lung function at 24 weeks in the overall subject population, and a 77% reduction in the subgroup of subjects with mild lung disease (ppFEV1≥70), suggesting a potential benefit on the loss of lung function over 24 weeks. LAU-7b was well tolerated and exhibited a favorable safety profile, similar to previously obtained data. The final efficacy data, including inflammation biomarker analyses, will be presented at the NACFC.

Acknowledgements: This work was supported by Laurent Pharmaceuticals Inc. and the Cystic Fibrosis Foundation.

References: