Merck’s cough success highlights pipeline hopes

Good news for patients whose cough is not caused by Covid-19: Merck’s chronic cough pill is a step closer to market. But tolerability questions remain.


Having hit in two of its suite of phase III trials, Merck & Co’s gefapixant could become the first drug approved for chronic cough. But its unpleasant side-effects mean that there will still be a chance for a more tolerable therapy. A handful of other companies are at work here, most notably the small developer Bellus Health. 

Bayer is another interested party, although it is not immediately clear whether the pharma major has any intention to move into larger studies. Other developers are smaller companies, and alongside Bellus include Nerre Therapeutics and Shionogi.

Most of the cough pipeline shares gefapixant’s mechanism. According to Merck, excessive activation of P2X3 receptors is associated with hyper-sensitisation of sensory neurons; when this occurs in the airways and lungs, triggered by injury or infection, it can cause a persistent and frequent urge to cough.

The cough-off: selected projects in mid- and late-stage development 
Company Project Mechanism Trial N Conditions Primary completion
Phase III
Merck & Co Gefapixant PX2 purinoceptor 3 antagonist NCT03449134 (Cough-1)
NCT03449147 (Cough-2)
720 & 1,290 Chronic cough Jun and Aug 2020
Phase II
Bayer/Evotec BAY 1817080 PX2 purinoceptor 3 antagonist NCT03310645 87 Chronic cough May 2019
Bayer/Evotec BAY 1902607 PX2 purinoceptor 3 antagonist NCT03535168 59 Chronic cough Sep 2019
Nerre Therapeutics Orvepitant Neurokinin 1 receptor antagonist NCT02993822 (Volcano-2) 315 Chronic refractory cough Feb 2019
Respivant Sciences RVT-1601  Unclassified NCT03864328 (Scenic) 180 Persistent cough in IPF/
chronic cough
Oct 2020
Bellus Health BLU-5937 PX2 purinoceptor 3 antagonist NCT03979638 (Relief) 68 Chronic refractory cough Apr 2020
Trevi Therapeutics Nalbuphine ER  Kappa opioid receptor agonist; Mu opioid receptor antagonist NCT04030026 (Canal) 56 IPF/cough Dec 2020
Shionogi S-600918  PX2 purinoceptor 3 antagonist NCT04110054 372 Chronic cough May 2021
Source: EvaluatePharma &

None of the other P2X3 antagonists in development has reached phase III. A phase I/IIa trial of one of Bayer’s candidates, BAY 1817080, hit its primary endpoint in July, reducing 24-hour cough count versus placebo. Bayer’s partner, Evotec, said the compound was well tolerated.

A trial of Bayer and Evotec’s other P2X3 inhibitor, BAY 1902607, reached its primary completion date last year, but no data have yet emerged. Both are still listed in Bayer’s pipeline; perhaps the German group is trying to decide which one to advance, or perhaps it was waiting to see what the Merck project looked like.

The Relief trial of Bellus’s BLU-5937, assessing the project’s effect on awake cough frequency versus placebo at several time points up to 46 days, is scheduled to conclude mid-2020. Fortunately, given the potential for the Covid-19 pandemic to delay ongoing trials, patient enrolment is complete (Clinical trial delays become reality as Covid-19 risk spreads, March 20, 2020).

This is also true of two more of gefapixant’s phase III trials, so Merck must hope either to avoid delays or to submit using data from its other three studies.

Nerre is ploughing a lone furrow by developing a neurokinin 1 receptor antagonist for cough – and its phase II data show why this mechanism has not been pursued by anyone else. In the phase IIb Volcano-2 trial 30mg daily missed the primary endpoint of awake cough frequency at three months. Nerre claimed that in a predefined subgroup of higher frequency coughers the reduction in cough frequency was “near significant”. 

Still, the Glaxo spinout is planning phase III studies. Despite orvepitant’s tolerability being described as “excellent”, though, this one has to be a long shot – not least because Nerre last raised VC funding in 2017. 


One way and another, Merck has to be the favourite to obtain the first cough approval. Last week’s topline data on gefapixant showed the 45mg twice-daily dose meeting the primary efficacy endpoints of a statistically significant decrease in average hourly cough frequency versus placebo at 12 weeks (in the Cough-1 trial) and 24 weeks (in Cough-2). 15mg twice daily missed in both trials. 

Merck has not released actual numbers from Cough-1 and 2, but said the safety and tolerability profile of gefapixant was consistent with a phase II study. This is a problem since in phase II a 50mg dose worked, but caused taste-related side-effects in 71% of patients. Six of the 63 patients in the 50mg group dropped out of the study because of the effect on taste.

Gefapixant's phase II resuts
    Gefapixant dose
  Placebo 7.5mg 20mg 50mg
Placebo-adjusted reduction from baseline in awake cough frequency (%) - 22 22 37*
Alteration in taste (dysgeusia) (%) 4.8 9.5 33.3 47.6
Reduced ability to taste (hypogeusia) (%) 1.6 0 17.5 23.8
Discontinuations due to taste-related adverse events 1 0 0 6
*Statistically significant. Source: Merck & Co.

Even if the full dataset from Cough-1 and 2 – which Merck says will be released at an upcoming medical meeting, though presumably virtually – show its side-effects to be similarly bothersome the therapy still has a shot at approval. 

Merck puts the prevalence of chronic cough at 10% of the general adult population globally, with 46% of these cases having no treatable cause. This level of unmet need could persuade regulators to be lenient. But the others will not be daunted and could still find a niche; Bellus, for one, claims that its candidate has “little to no effect on taste”.

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