Merck coughs up for Afferent


Spending up to $1.25bn on a developer of a chronic cough project seems a strange move for Merck & Co. The explanation could lie in Afferent Pharmaceuticals’ novel P2X3-targeting technology, which might have utility in a broad range of indications from hypertension to pain (see table below).

No other companies are developing P2X3 blockers, according to EvaluatePharma. If the mechanism works out and Merck can expand into bigger indications it might have a lucrative new drug class to itself for a while.

Let me clear my throat

For that to happen Afferent’s lead asset, AF-219, will need to prove itself in its first indication, chronic cough. The signs are good, with the first portion of a phase IIb trial showing that the agent significantly reduced cough frequency compared with placebo.

Data from the second cohort of the study are expected in the second half of this year, as well as results from a 12-week trial in chronic cough. Privately held Afferent previously said it expected to begin a phase III programme in early 2017.

Now this is Merck’s responsibility. One thing it will have to watch out for is altered taste perception, which affected 57% of patients on the lowest dose of 50mg twice-daily in the phase IIb trial. 

This might seem trivial, but one of the 29 patients dropped out because their sense of taste was deadened – and in a previous higher-dose study, 100% of patients noticed the side effect and 25% discontinued because of it.

Chronic cough, lasting for months or years, affects around 10% of Americans, with no specific therapies approved, according to Afferent – although many patients respond to treatment for an underlying condition like asthma or COPD.

Afferent is also investigating AF-219 in idiopathic pulmonary fibrosis (IPF), where it says around 80% of patients suffer from chronic cough that is not alleviated by therapies for IPF itself.

Hypertension and pain

While AF-219 could address an unmet need in chronic cough, it is Afferent’s second pipeline project, AF-130, that could bring in the big bucks. This is in development – admittedly at an early stage – in the much larger indications of hypertension and migraine.

Afferent Pharmaceuticals’ pipeline
Project Indication Status Trial details
AF-219 Chronic cough Phase IIb NCT02349425;
Idiopathic pulmonary fibrosis with cough Phase II NCT02502097
AF-130 Resistant hypertension Phase I NCT02652936
Migraine Preclinical

On the face of it, it seems unlikely that these disorders share a common cause with cough, but according to Afferent they do. The company says P2X3 receptors play a key role in the sensitisation of certain nerves – and argues that chronic cough is driven by these hyper-sensitised nerves, making it distinct from acute cough caused by infection.

As well as airway hyper-reactivity, P2X3 receptor-mediated sensitisation has been associated with various types of pain, migraine, treatment-resistant hypertension and heart failure, the group adds. This could represent a link between these seemingly unrelated diseases – or that is the bet that Merck is making, anyway.

$500m up front plus up to $750m in milestones does not seem like too big a gamble for a shot at a new drug class. But hypertension is a crowded space and pain is a tricky area for drug development. Getting a P2X3 inhibitor approved in cough will be one thing – expanding into other indications represents a higher hurdle.

To contact the writer of this story email Madeleine Armstrong in London at or follow  @medtech_ma on Twitter

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