Many drugs in pipeline for itch but no magic bullet

By Michael Woodhead

22 Nov 2019

The treatment of chronic itch is entering an exciting new era as many drug candidates are close to being marketed, but there will no ‘magic bullet’ for the condition, an international expert says.

An explosion in research into the mechanisms of chronic itch has revealed many therapeutic targets, but each is specific to particular aspects of itch, according to Professor Gil Yosipovitch, a dermatologist at the University of Miami, and Director of the Miami Itch Center.

Speaking at the International Forum for the Study of Itch (IFSI) annual conference in Sydney, he said there were now many candidate drugs in development for itch, with some acting at the peripheral epidermal axis, some on immune cytokines and others working at the neuronal axis, targeting mediators such as Substance P.

“There are multiple pathways leading to chronic itch, and therefore no drug will eliminate all kinds of itch,” he said

The best drug to treat chronic itch will depend on its cause, whether it is dermatologic (eg atopic dermatitis), neuropathic, systemic (eg chronic kidney disease or cholestasis) or psychogenic.

“Targeting nerves seems to be the most effective for treating different types of itch, and targeting the itchy cytokines seem to be effective in dermatological itch,” he said.

Professor Yosipovitch said his own belief is that the long term answer may lie in targeting neural sensitisation to reduce chronic itch.

Drug candidates included molecules such as serlopitant, a drug that acts on Substance P (SP) and neurokinin 1 receptor (NK1R) receptors and which has already in shown success against psoriasis associated itch in clinical phase 2 trials, he noted

Cytokine signalling such as the JAK/STAT pathway is also a key aspect of itch, and there is potential in JAK inhibitors such as abrocitinib to reduce itch in atopic dermatitis, said Professor Yosipovitch.

Potential targets included TRPA1 ion channels, which is a master regulator of itch, required for conducting itch sensitisation.

Another important neural target is MRGPRX2 (Mas related G protein coupled receptors) in the skin and peripheral nerves immune cells, he added

But Prof Yosipovitch reminded the meeting that there were also potential for anti-itch treatment with more well-known pathways such as GABA targeted by gabapentin and the opioids.

He believed the drug that was closet to being made commercially available for itch is difelikefalin, a kappa opioid receptor agonist that has just been shown to reduce itch intensity by more than 4 points in 37% of patients in a trial published in the NEJM.

“Itch should deserve to be a disease state in its own right – it’s not just a sign, and we need to provide treatments for it,” he said.

“But I don’t think that there will be one drug that will cover all types of itch. We shouldn’t have that expectation that one day well have a billion dollar blockbuster for itch, but there will be several drugs that can address it,” he concluded.

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