Orvepitant successful in decreasing symptoms of chronic cough

A randomised controlled trial studied the effect of the neurokinin-1 receptor antagonist orvepitant on cough frequency and found a meaningful reduction in high-frequency coughers [1].

Refractory or unexplained chronic cough is an incapacitating and widespread disease with a negative influence on quality of life that is often challenging to treat [2]. Currently, there are no proven therapies for this condition, which is often treated off-label with first-generation antihistamines, antidepressants, and opioids – with mixed results. The phase 2b, multicentre, double-blind, randomised controlled VOLCANO-2 trial involved 315 patients from 55 sites all over North America and the United Kingdom [1]. Every study subject had a chronic or unexplained chronic cough. Prerequisite for study inclusion was ≥1 year of cough of unclear origin and/or no treatment response, with an awake frequency of ≥10 coughs per hour [1].

The orvepitant group received either 10 mg, 20 mg, or 30 mg per day for 12 weeks. Evaluations for cough frequency were done at weeks 2, 4, and 12, and patient-reported outcomes were measured at weeks 2, 4, 8, and 12. Primary endpoint was change in cough frequency at week 12 measured by a VitaloJAK® ambulatory cough monitor. Subgroups for high and low cough rates were pre-specified, knowing that statistical power was only present for a full analysis set. In addition, patient-reported outcomes, the Leicester Cough Questionnaire, cough severity and urge to cough (in VAS, 0-100 mm scale), and global ratings of change were assessed. Participants’ demographics featured a very high rate of Caucasians (94.6%) and females (80.3%). Mean awake cough frequency for the full analysis set was 43 per hour, day-time cough severity had a mean of 67.6 mm (out of 100 mm) on VAS, the urge to cough was 70.4 mm.

The primary endpoint was not met in the full analysis set. However, in a pre-defined subgroup of higher cough-frequency subjects, the higher orvepitant dose was superior to placebo (see Figure). In addition, all patient-reported outcomes were in favour of orvepitant at all dosages, though most significantly when 30 mg of the drug was taken. Cough severity decreased by 9 mm (P=0.046) and the urge to cough by 11.8 mm (P=0.005). The researchers explained the lack of efficacy in the lower cough group by a greater variance in cough frequency within this group.

Figure: Awake cough frequency responder analysis in higher frequency cough group with the 30 mg dose of orvepitant: a greater proportion of subjects in the orvepitant group respond by at least 30% (70% vs 43.8%, P=0.009) [1]



Adverse events were reported by 68.4% of placebo-treated patients and 66.7–72.2% of the orvepitant groups. In those taking 30 mg of orvepitant some adverse events were more common than with placebo, e.g. headache 8.9% versus 5.1% and dizziness 6.3% versus 1.3%, respectively. Overall, the results were found encouraging enough to promote further testing of the drug.

1. 
   
   1. Smith J, et al. PA600, ERS 2019, 29 Sept-2 Oct, Madrid, Spain.
   2. Chung KF. Pulm Pharmacol Ther. 2011;24(3):267-71.

 



Posted on 28 November 201917 March 2021