Effective treatments for cough are a significant unmet clinical need and the new drug Gefapixant, moving into phase-three trials, has the potential to be the first new therapy approved in over 50 years.
Principle researcher Jacky Smith, a professor of respiratory medicine at The University of Manchester and a consultant at Wythenshawe Hospital, says new drug Gefapixant has the potential to have a significant impact on the lives of thousands of suffers. Higher doses can reduce the sense of taste, though at 50mg, the effect is much reduced, say the research team. The drug is being developed in collaboration with the pharmaceutical company MSD, who have funded the trials.
The study shows that in a 12-week trial of 253 patients – the largest of its kind – 80% of patients had a clinically significant response to a dose of 50mg. A dose of 7.5mg reduced the coughing by 52%, 20mg by 52% and 50mg by 67% from baseline. Around a quarter did not respond to the drug.
And another 16-day study describing a 57-patient trial, showed that as little as 30mg of the drug could be effective – much lower than previously thought.
Both studies were randomised and double blind, in which neither the participants nor the experimenters knew who received the treatment.
The drug is now in two larger global phase 3 trials, carried out to confirm and expand on the safety and effectiveness results from the previous research.
Chronic coughing is thought to affect between 4 and 10% of the population, some of whom cough thousands a time a day over many years.
While many patients improve with treatment of associated conditions such as asthma, gastroesophageal reflux disease and nasal disease, many do not. The condition can cause abdominal pain, urinary incontinence in women, as well as anxiety, depression and difficulty sleeping.
Smith said: “This drug has exciting prospects for patients who suffer from the often distressing condition of chronic cough. Effective treatments for cough are a significant unmet clinical need and no new therapies approved in over 50 years. Billions of pounds are spent annually on over-the-counter cough and cold medicines despite a lack of evidence to support their efficacy, concerns about the potential for abuse and risk of harm in overdose.”
Gefapixant is able to target P2X3receptors in the nerves which control coughing and the team monitored the impact of the drug using a special cough monitoring device they developed which counts coughs.
The drug was initially developed as a pain killer, until the researchers discovered it had a significant impact on chronic cough.
Some unlicensed drugs have also been shown to improve chronic cough, but their use is limited by unpleasant side effects.
It is thought a chemical called adenosine triphosphate (ATP), released as a response to inflammation in airways, may be an important mechanism for patients with chronic cough.
Smith added: “We can’t yet say when or if this drug will be available on prescription, however, if the phase 3 trial is successful then it would certainly be a major step towards everyday use. Though it’s fair to say the drug is not a cure for chronic cough, it can and often does reduce the frequency of coughing substantially. That could make a big difference to patients who often struggle with this condition which can make such a big impact on their lives.”
Background: Gefapixant is a P2X3 receptor antagonist that has shown promise for the treatment of refractory and unexplained chronic cough. The aim of this study was to evaluate the efficacy of gefapixant compared with placebo after 12 weeks of treatment for refractory chronic cough or unexplained chronic cough.
Methods: We did a 12-week, phase 2b, randomised, double-blind, placebo-controlled study in patients with refractory chronic cough or unexplained chronic cough aged 18–80 years who were recruited from 44 primarily outpatient pulmonologist or allergist sites in the UK and the USA. Eligible patients had refractory or unexplained chronic cough lasting 1 year or longer, no radiographic chest abnormality, and 40 mm or more on a 100-mm cough severity visual analogue scale at enrolment. Patients were randomly assigned to receive placebo or one of three doses (7·5 mg, 20 mg, or 50 mg) of oral gefapixant twice daily, every day, for 84 days; visits to investigative sites were on days 1, 28, 42, 56, 70, 84, and 85. The randomisation schedule was computer generated using a permuted block algorithm by Advance Research Associates (Santa Clara, CA, USA). Patients and all personnel involved in the conduct and interpretation of the study were masked to treatment assignment. The primary endpoint was placebo-adjusted change from baseline in awake cough frequency after 12 weeks, assessed in the full analysis set, which is a subset of the intention-to-treat population. Adverse events were monitored and safety was evaluated in all patients receiving one or more doses of study drug. This trial is registered with ClinicalTrials.gov, NCT02612610.
Findings: Between Dec 21, 2015, and July 26, 2016, 253 patients were randomly assigned to placebo (n=63), gefapixant 7·5 mg (n=64), gefapixant 20 mg (n=63), or gefapixant 50 mg (n=63) twice daily. The mean age of patients was 60·2 (SD 9·9) years and 193 (76%) were women. At 12 weeks, patients’ geometric mean awake cough frequency was 18·2 coughs per h (geometric SD 3·1) with placebo, and 14·5 coughs per h (3·7) with 7·5 mg, 12·0 coughs per h (4·2) with 20 mg, and 11·3 coughs per h (2·8) with 50 mg gefapixant. Estimated percentage change relative to placebo was −22·0% (−41·8 to 4·6; p=0·097) with 7·5 mg, −22·2% (−42·0 to 4·3; p=0·093) with 20 mg, and −37·0% (95% CI −53·3 to −14·9; p=0·0027) with 50 mg gefapixant. Dysgeusia was the most common adverse event, occurring in three (5%) patients given placebo, six (10%) given 7·5 mg gefapixant, 21 (33%) given 20 mg gefapixant, and 30 (48%) given 50 mg gefapixant.
Interpretation: Targeting purinergic receptor P2X3 with gefapixant at a dose of 50 mg twice daily significantly reduced cough frequency in patients with refractory chronic cough or unexplained chronic cough after 12 weeks of treatment compared with placebo. Further development of gefapixant is warranted for the treatment of chronic cough.
Jaclyn A Smith, Michael M Kitt, Alyn H Morice, Surinder S Birring, Lorcan P McGarvey, Mandel R Sher, Yu-Ping Li, Wen-Chi Wu, Zhi Jin Xu, David R Muccino, Anthony P Ford
Background: Gefapixant has previously demonstrated efficacy in the treatment refractory chronic cough at a high, daily dose.
Objectives: The current investigations explore efficacy and tolerability of gefapixant, a P2X3 receptor antagonist, for the treatment of chronic cough using a dose escalation approach.
Materials and methods: Two randomised, double-blind, placebo-controlled, crossover, dose-escalation studies recruited participants with refractory chronic cough. Patients were assigned to receive ascending doses of gefapixant (study 1: 50–200 mg, study 2: 7.5–50 mg) or placebo for 16 days, then crossed-over after washout. The primary endpoint was awake cough frequency assessed using a 24 h ambulatory cough monitor at baseline and on day 4 of each dose. Patient reported outcomes included a cough severity visual analogue scale (VAS) and Cough Severity Diary (CSD).
Results: In clinical studies, gefapixant doses ≥30 mg produced maximal improvements in cough frequency compared with placebo (p<0.05); reported cough severity measures improved at similar doses. Taste disturbance exhibited a different relationship with dose, apparently maximal at doses ≥150 mg.
Conclusions: P2X3 antagonism with gefapixant demonstrates anti-tussive efficacy and improved tolerability at lower doses than previously investigated. Longer duration studies are warranted.
Jaclyn A Smith, Michael M Kitt, Peter Butera, Steven A Smith, Yuping Li, Zhi Jin Xu, Kimberley Holt, Shilpi Sen, Mandel R Sher, Anthony P Ford