New painkiller on horizon

C&I Issue 4, 2019

A completely new class of pain medication is to be developed through a collaboration between King’s College London, UK, and the pharma company Merck & Co. Under the agreement, King’s and UK science funding organisation Wellcome are eligible to pocket up to $340m in development and sales, as well as royalties if a drug comes to market.

Merck & Co. will carry out optimisation, preclinical development and clinical trials, while funding further research into the biological mechanism of pain by the research group of Peter McNaughton, professor of pharmacology at King’s. A 2011 discovery by McNaughton and colleagues, while at the University of Cambridge, identified the importance of the protein HCN2 in chronic pain (Science, 2011, 333, 1462). Deletion of the HCN2 gene greatly reduced pain caused by inflammation or neuropathic injury associated with nerve damage in mice. Neuropathic pain can often continue in the absence of obvious injury.

‘It was clear this discovery could have huge implications for the development of novel analgesics,’ says Edward Emory, a lead researcher in this research at Cambridge and now at University College London. He is not involved in the Merck collaboration. ‘What made the discovery so exciting was the observation that normal (acute) pain responses were seemingly unaffected by HCN2 deletion, meaning that the ability to protect against damage was still intact,’ Emory explains. It is important for patients to sense damaging stimuli to protect themselves from harm.

It turned out that HCN2 can cause a continuous sensation of pain through the initiation of electrical signals in pain-sensitive nerve fibres. Research at King’s showed that blocking HCN2 activity could deliver pain relief without side effects (Science Translational Medicine, doi: 10.1126/scitranslmed.aam6072). Specifically, ivabradine, an HCN inhibitor used for treating heart conditions, reduced chronic pain in mice with diabetes.

‘[By] targeting the molecular causes of pain we have developed new molecules that we believe can avoid the major side effects that come with current painkillers,’ McNaughton says. One in four people with diabetes suffers from neuropathic pain. ‘The range of therapeutics used for treating neuropathic pain is incredibly broad,’ comments Emory. ‘[They] are often repurposed from other conditions such as epilepsy, anxiety disorders and depression, with few individuals managing to achieve complete pain relief.’

Since 2012, Wellcome has pumped £4.5m in funding to advance McNaughton’s research towards a candidate drug for blocking HCN2.

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