Oral lenabasum failed to significantly reduce the frequency of pulmonary exacerbations in people with cystic fibrosis (CF) treated in a Phase 2 trial, but new analyses suggest this failure could be attributed, at least in part, to differences among the patients that confounded results.
The investigational therapy showed some evidence of benefit after these differences were accounted for, the analyses reported.
These findings were presented at the 2020 North American Cystic Fibrosis Conference in the poster, “CB2 Agonist, Lenabasum, for the Treatment of Pulmonary Exacerbations in Cystic Fibrosis.”
Lenabasum, which is being developed by Corbus Pharmaceuticals, works by activating the protein cannabinoid receptor type 2 (CB2). By binding to receptors primarily found on the surfaces of activated immune cells, the treatment aims to lower inflammation and fibrosis (scarring).
A previous Phase 2 clinical trial, CF-001 (NCT02465450), enrolled 85 CF patients and concluded in 2016. Its findings suggested that the treatment lessened the frequency of pulmonary flares (periods when lung function suddenly gets worse).
“The negative impact of recurrent pulmonary exacerbations on the health and quality of life of people with CF cannot be overstated, nor can the need to find non-immunosuppressive treatments to control the lung inflammation that causes these events,” James Chmiel, MD, a professor at Indiana University School of Medicine, said in a press release.
The recent Phase 2b trial, called CF-002 (NCT03451045), enrolled 447 people across 21 countries with CF, ages 12 and up, who were at high risk for recurrent pulmonary flares.
“This was the first interventional study in CF to select for patients who have high rates of pulmonary exacerbations and one of the largest CF studies to date,” said Chmiel, the study’s principal investigator .
Participants were assigned to one of two doses of lenabasum (5 mg or 20 mg) or to a placebo, taken twice a day.
Its primary endpoint, or main measure of efficacy, was the frequency of pulmonary exacerbations through 28 weeks of treatment. Corbus previously announced top-line results from the trial showing that this goal was not met, with no statistically significant differences in exacerbation rates seen between the lenabasum and placebo groups.
Data also show that forced expiratory volume (FEV) — a measure of lung function based on how much air a person can breathe out in a given amount of time — did not differ significantly among the treatment groups.
Lenabasum was generally safe and well-tolerated in the trial. Rates of adverse events and serious adverse events were similar among lenabasum and placebo group patients. Side effects more often reported in those given lenabasum included headache, dizziness, and fatigue.
However, post-hoc analyses — those done after the trial’s completion — found that placebo group patients from five countries in eastern Europe had substantially lower pulmonary exacerbation rates than did patients from other countries (the U.S., Canada, and western Europe). Relative to rates elsewhere, exacerbation rates among the eastern Europeans were about 85% lower, and these patients accounted for 21% of the entire study group.
“This low rate may reflect differences in what physicians in various geographies call a [pulmonary exacerbation] or would treat with [antibiotics], or may reflect improvement in care or background treatment compliance,” the researchers wrote in the poster.
Further analyses excluded patients from these five countries. They compared the remaining patients, by study group and by similarities in terms of their baseline (study start) FEV and their use of CFTR modulators.
These analyses found that lenabasum’s use lowered exacerbation rates, with the magnitude of reduction ranging from 27% to 61%, depending on the group analyzed. Their results “suggested evidence of clinical benefit,” the researchers wrote.
“While I am disappointed that the study did not achieve its primary endpoint, I am encouraged by findings of potential reduction in exacerbation rates in subjects with similar lung function and treatment with CFTR-modulators,” Chmiel said.
“I look forward to further analyses of the data, because they may confirm the initial clinical rationale to continue development of lenabasum for [the] treatment of pulmonary exacerbations in people with CF.”
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