Discussion
taste disorder, hypogeusia, such disturbances, ageusia, cough, taste disturbances, dysgeusia, acute cough
TASTE DISORDER, ADVERSE EVENT
Treatment with ascending doses of filapixant (80, 150, and 250 mg BID for 4 days each) was associated with a statistically significant, dose-dependent reduction in objective cough frequency and subjective cough severity, and an improvement in the patient-reported health-related quality of life in comparison to placebo. Consistent improvements of these endpoints were seen for dosages ≥ 80 mg BID with maximum effects on cough frequency and severity at the highest dosage, 250 mg filapixant BID—but without a clear plateau for either variable. The probability of experiencing a > 30% reduction in 24-h cough frequency—which can be regarded as a clinically meaningful cut-off point for a positive response according to Schelfhout et al. [The absolute reduction in 24-h and awake cough frequency observed after 250 mg filapixant (approximately 40%) was similar to that observed after 750 mg eliapixant [The reduction in subjective cough severity VAS at the highest dose level (25 mm reduction from baseline) exceeded the threshold of ≥ 17 mm described in the literature as the minimal clinically important difference in patients with acute cough [The observed decrease in LCQ total scores, on the other hand, well exceeded the 1.3 points determined by Raj et al. as the minimal important difference for the LCQ total score [No safety issues were observed during the short therapeutic intervention and the tolerability of the drug was good at all dose levels with no AEs reported that were severe, serious, or led to discontinuation of treatment. However, the adverse event data collected in this study suggest that filapixant, like gefapixant, influences the perception of taste although the incidence rates of taste changes might have been overestimated in our “cumulative” analysis, which was intended as a “worst-case analysis”.Overall, the number of patients with taste-related AEs (ageusia, hypogeusia, dysgeusia, and taste disorder without further specification) was much higher in our study than in the above-mentioned study with eliapixant [Incident rates of > 50% for taste-related AEs are not unexpected for unselective P2X3 antagonists, as such rates and also an association between dose and incidence rates of taste disturbances have been reported for gefapixant [Our study was designed as an exploratory study in a modest number of subjects and with very short treatment duration at each dose step. Thus, it has its obvious limitations. A larger study will have to follow to assess the long-term safety and tolerability of filapixant. For this proof-of-concept study, however, a 4-day treatment period was sufficient as previous studies with gefapixant [The occasional, concomitant use of antitussives, in particular opioids, might be regarded as another problem of the study. A look at the data, however, shows that only one patient occasionally used opioids during the filapixant period (and also during the placebo period), while four patients occasionally used opioids during the placebo period. Thus, any impact on the study results in favor of filapixant seems unlikely. A third problem might be that the occurrence of taste disturbances might have led to a partial unmasking of the treatment allocation. Knowledge of the nature of the treatment received might have influenced the patient’s treatment response. Smith et al. have observed more substantial improvement in cough frequency in patients with taste disturbances than in patients without such disturbances [