Camlipixant safe, yields improvements in refractory chronic cough
Key takeaways:
- Camlipixant is a P2X3 antagonist.
- Studied patients had a baseline awake cough frequency of at least 25 coughs per hour.
- Researchers noted favorable changes in 24-hour and awake cough frequency with camlipixant.
Adults with refractory chronic cough who received twice-daily camlipixant had decreases in cough frequency and better scores assessing cough severity and cough-related quality of life at day 28 from baseline, according to study results.
These findings on this P2X3 antagonist were published in American Journal of Respiratory and Critical Care Medicine.
“Findings from the SOOTHE phase 2b trial showed that treatment with camlipixant reduced cough frequency, improved patient-reported outcomes and showed an acceptable safety profile in patients with [refractory chronic cough] and a baseline awake cough frequency of [greater than or equal to] 25 coughs/hour,” Jaclyn A. Smith, MD, PhD, professor of respiratory medicine at the University of Manchester and honorary consultant at Manchester University NHS Foundation Trust, and colleagues wrote.
In the multicenter, randomized, placebo-controlled, double-blind, parallel-group phase 2b SOOTHE trial, Smith and colleagues assessed 249 adults with refractory chronic cough — defined as a cough lasting for at least 1 year plus a baseline awake cough frequency of at least 25 coughs per hour — to determine the impact of three different doses of twice-daily oral camlipixant (Bellus Health) vs. placebo on objective 24-hour cough frequency at day 28, as well as drug safety.
Notably, researchers credited the randomized, dose-escalation phase 2a RELIEF trial when establishing the study design of SOOTHE.
“While the RELIEF trial did not meet its primary endpoint of a statistically significant reduction in placebo-adjusted 24-hour cough frequency from baseline, a statistically significant interaction was observed between baseline cough frequency and cough frequency reduction with camlipixant, suggesting that patients with higher baseline cough frequency experienced the greatest reductions,” Smith and colleagues wrote.
Researchers randomly assigned 62 adults 12.5 mg camlipixant (mean age, 60.7 years; 77.4% women), 62 adults 50 mg camlipixant (mean age, 61.6 years; 83.9% women), 62 adults 200 mg camlipixant (mean age, 59.7 years; 88.7% women) and 63 adults the placebo dose (mean age, 61.4 years; 77.8% women) following a single-blind, 16-day placebo run-in.
Efficacy
In the set of adults receiving 50 mg camlipixant, baseline 24-hour cough frequency went down and reached significance vs. placebo at day 28 (placebo-adjusted difference, –34.4%; 95% CI, –50.5% to –13.3%), according to the study.
This outcome was also reported when researchers calculated the placebo-adjusted difference in 24-hour cough frequency between those receiving 200 mg camlipixant and those receiving placebo (–34.2%; 95% CI, –50.7% to –12.2%).
According to the study, achievement of at least 30% improvement in baseline 24-hour cough frequency at day 28 was observed in more than 50% of each camlipixant group (12.5 mg, 51.7%; 50 mg, 60.7%; 200 mg, 61.5%), whereas only 35.7% of the placebo group achieved this level of improvement.
Researchers reported a similar outcome when analyzing changes in awake cough frequency, with achievement of at least 30% improvement in baseline awake cough frequency at day 28 in more than 50% of those receiving 12.5 mg camlipixant (55.2%), 50 mg camlipixant (65.6%) and 200 mg camlipixant (71.2%). Less than 50% of patients receiving placebo achieved this level of improvement (39.3%).
In contrast to 24-hour cough frequency, decreases in baseline nighttime cough frequency found with each camlipixant dose at day 28 were not significant vs. placebo, according to the study.
Switching to Cough Severity VAS scores, researchers noted better changes to baseline scores at day 15 among those assigned a camlipixant dose vs. placebo (placebo-adjusted least squares mean difference: 12.5 mg, –12.37 mm; 95% CI, –19.88 to –4.85; 50 mg, –14 mm; 95% CI, –21.52 to –6.48; 200 mg, –16.43 mm; 95% CI, –24.06 to –8.8); however, none met the significance threshold.
“These improvements were sustained to day 29,” Smith and colleagues wrote.
When evaluating changes in baseline Leicester Cough Questionnaire scores at day 15, the study reported larger changes in each camlipixant group compared with the placebo group (least squares mean change: 12.5 mg, 1.91; 50 mg, 1.96; 200 mg, 2.33 vs. placebo, 1.07).
“At day 29, further improvements were observed with camlipixant,” Smith and colleagues wrote.
Additionally, after adjusting for placebo, researchers observed nominal significance in two camlipixant groups: 12.5 mg (least squares mean difference, 1.34; 95% CI, 0.24-2.43) and 200 mg (2.03; 95% CI, 0.9-3.15).
Safety
In terms of safety, serious treatment-emergent adverse events did not occur in any patient. Of the four study groups, the 50 mg camlipixant group had the lowest proportion of patients who experienced at least one treatment-emergent adverse event at 21%. This group was followed by the 200 mg group (30.6%), the placebo group (34.9%) and the 12.5 mg group (37.1%).
A notable adverse event experienced by a greater proportion of patients receiving camlipixant vs. placebo was taste alteration (4.8%-6.5% vs. 0%), according to the study. Of those reporting this event, mild-moderate was the frequent level of severity.
Researchers also highlighted the treatment-emergent adverse event of nausea, as 3.2% and 8.1% of patients receiving 200 mg camlipixant and 50 mg camlipixant reported this, respectively vs. 0% of patients receiving placebo and 0% of patients receiving 12.5 mg camlipixant.
“Camlipixant has the potential to be a new treatment option for patients with [refractory chronic cough] who currently have limited treatment options,” Smith and colleagues wrote. “The ongoing global, multicenter phase 3 CALM-1 (NCT05599191) and CALM-2 (NCT05600777) trials will provide further insights into the efficacy and safety of camlipixant in this underserved patient population.”
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Perspective
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In recent years, several P2X3 antagonists have been explored for their potential to treat chronic cough, including gefapixant (Merck) and eliapixant (Bayer). This specific study has trialed the latest addition to this class, camlipixant. The results align with expectations: reduced cough frequency (overall and daytime, but not nighttime), improved efficacy at higher doses for patients with severe baseline cough and taste alteration as a common side effect Two significant findings from this trial stand out.
First, researchers attempted to minimize the placebo effect by introducing a 16-day placebo run-in period prior to randomization. This is particularly important given the substantial placebo effect observed in previous cough trials, with up to 60% reduction in cough frequency in placebo arms.
Second, the adverse events were milder and less frequent compared with other P2X3 antagonists, suggesting that camlipixant is both tolerable and safe while maintaining efficacy in treating cough.
However, limitations exist. The trial’s duration was only 28 days and included approximately 300 participants. A larger-scale, longer-term phase 3 trial is necessary to confirm these findings. The authors have reportedly initiated such a trial, and the results are eagerly anticipated.
Several questions remain for future research, including optimal dosing for different patient groups, potential variations in efficacy among P2X3 antagonists for specific subgroups, strategies to further reduce adverse events and methods to address the significant placebo effect in cough drug trials.
Despite these challenges, the advancement in this field is encouraging and offers hope for chronic cough patients. As research progresses, we look forward to more effective and tailored treatments for this debilitating condition.
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