“End of the antihistamine era” as new strategies target neural mechanisms

by Charles Bankhead, Senior Editor, MedPage TodayOctober 18, 2019

LAS VEGAS — More options than ever exist for atopic itch conditions, offering the potential for better control but also increasing the complexity of patient management, a long-time itch research and clinician said here.

“The most important thing to know, and you have to prepare yourself for it, is that it is the end of the antihistamine era,” Gil Yosipovitch, MD, of the University of Miami, said at the Fall Clinical Dermatology Conference. “Each one of them is limited in chronic care. We have new options for treatment and some others that are going to be rising in the next couple of years. The field has grown exponentially.”

These advances have come from better understanding of the biologic basis of itch. But more treatment options also make clinical management more complex, challenging, and costly, he said.

Each new patient should be viewed from the perspective that chronic itch is a disease state in its own right. Chronic itch can arise from multiple causes, which are not always clear, he said. Dermatologic conditions remain the most obvious source of chronic itch, but consideration of neuropathic, systemic, and psychogenic causes may warrant consideration when the cause is less obvious.

In some instances, no clear cause of itch can be found, a clinical circumstance that has its own name: chronic pruritus of unknown origin. The condition is most prevalent among older patients, said Yosipovitch.

Topical agents remain first-line treatment for dermatologic conditions that cause itch, including atopic dermatitis, psoriasis, contact dermatitis, and urticaria. Among new options for chronic itch, the PDE4 inhibitor crisaborole (Eucrisa) provides rapid and significant itch relief, including difficult-to-treat conditions, such as hand and dyshidrotic eczema, psoriasiform atopic eczema, and flexures of the arms and thighs.

Multiple new targeted therapies have proven effective for “itchy dermatoses,” such as atopic dermatitis and psoriasis, and some have shown efficacy in idiopathic itch, said Yosipovitch. These include the IL-4/IL-13 receptor inhibitor dupilumab (Dupixent), the IL-17 inhibitors secukinumab (Cosentyx) and ixekizumab (Taltz), and the JAK/STAT inhibitors.

The IL-31 receptor inhibitor nemolizumab could soon join the lineup of targeted therapies for itch. The investigational, first-in-class monoclonal antibody provided “rapid and sustained improvements” in pruritus and inflammation in a randomized trial of adults with atopic dermatitis. Earlier this month at the European Academy of Dermatology and Venereology congress, Yosipovitch and colleagues reported that nemolizumab had significant activity in prurigo nodularis. Nemolizumab is a “powerful drug” that provides “very meaningful reductions” in chronic itch.

Several different JAK/STAT inhibitors have proven efficacy for reducing itch associated with atopic dermatitis.

“They have been approved for psoriasis and are also effective against itch in atopic dermatitis, but I think their effects go well beyond these conditions,” said Yosipovitch.

No discussion of itch treatment can omit the role of the neural system, he continued. Numerous neural inputs contribute to chronic itch, and therapies that target the inputs have proven effective for multiple forms of chronic itch.

Dermatologists see patients with neuropathic itch more often than previously recognized. Yosipovitch said his weekly patient visits include at least three or four cases of neuropathic itch. Currently available options comprise mechanical barriers (primarily occlusive bandages), topical therapies, and systemic agents.

Topical therapies include a compounded product containing ketamine, amitryptiline, and lidocaine, all in concentrations that affect ion channels involved in itch but do not have neurotropic effects in the brain. In one recent study, the solution had a significant antipruritic effect in patients with neuropathic and idiopathic itch. Relief lasted as long as 7 hours in some patients.

Capsaicin patches also are available and effectively relieve neuropathic pain and itch. However, the high cost and need to apply the patches in clinic have limited their popularity, particularly in the U.S., said Yosipovitch.

Currently, gabapentinoids are perhaps the most practical treatment for neuropathic itch. Widely used to treat neuropathic pain, the agents also effectively relieve neuropathic itch. The availability of generic pregabalin has made the drug class less expensive to use for neuropathic itch, although the medication is still a bit pricey, said Yosipovitch. Pregabalin is administered twice daily, as opposed to three or four times a day for gabapentin.

Low-dose mirtazapine, a tetracyclic antidepressant, has accumulated evidence of efficacy in atopic dermatitis, neuropathic itch, psychogenic itch, and idiopathic itch. When the drug works, it works quickly and is not addictive in low doses.

Chronic itch has found its way into the discussion of opioids as a result of the observation that many forms of chronic itch involve an imbalance between mu- and kappa-opioid receptor activity. The observation led to the development of the kappa-opioid receptor agonist nalfurafine — which is approved in Japan for treatment of pruritus associated with end-stage renal disease (ESRD), and is used for other types of chronic itch — as well as nalbuphine in the U.S.

The investigational agent CR845 is the first peripherally acting kappa-opioid receptor agonist and is highly selective for the kappa receptor, said Yosipovitch. Preliminary clinical studies have demonstrated clinically meaningful reductions in itch intensity after 8 weeks in patients requiring hemodialysis for ESRD.

Butorphanol, an inhaled kappa agonist and mu antagonist, has FDA approval for migraine but has proven effective in treating various types of intractable chronic itch. Butorphanol is a controlled substance; that, in its inhaler formulation, might limit dermatologists’ enthusiasm for it as a treatment for itch — but not Yosipovitch.

“I’ve prescribed this for hundreds of patients with chronic itch,” he said. “The [district attorney] came to monitor my clinic one day because I was the number one prescriber of kappa opioids in the country for itch.”

Recent evidence of the involvement of substance P and neurokinin (NK)-1 in chronic itch provided a rationale for evaluating drugs that target those molecules. In separate placebo-controlled trials, the substance P/NK-1 antagonist serlopitant significantly reduced topical- and steroid-resistant pruritus and pruritus associated with prurigo nodularis.

“Chronic itch is complex, and there are a lot of challenges,” Yosipovitch said in conclusion. “The costs sometimes are very high, using some the drugs currently available in the market. But I am very hopeful that this is a new era and that there will be new drugs focused for our patients. A word of caution: Don’t expect there will be one drug that will cover all types of chronic itch. The mechanisms are quite complex and I’m sure we will see several drugs with different indications.”

Yosipovitch disclosed relationships with Trevi, Menlo, Sienna, Pfizer, Sanofi, Regeneron, Novartis, UCB, Galderma, Kiniksa, Sun Pharma, and LEO.