EXPERT ANALYSIS FROM THE EADV CONGRESS
VIENNA (FRONTLINE MEDICAL NEWS) – Help is on the way for physicians stymied in their efforts to treat patients with severe chronic itch, Sonja Ständer, MD, declared at the annual congress of the European Academy of Dermatology and Venereology.
Now working their way through the developmental pipeline are two promising novel classes of drugs designed to target the physiologic mechanisms underlying this common and challenging problem: neurokinin 1 (NK1) receptor antagonists and selective opioid receptor agonists, explained Dr. Ständer, professor of dermatology and head of the Center for Chronic Pruritus at the University of Münster (Germany).
She led a landmark study that outlined the previously unappreciated dimensions of chronic pruritus as a clinical issue. This was a cross-sectional study of nearly 12,000 German employees in various industries that demonstrated the prevalence of chronic pruritus was 16.8%. One-quarter of affected individuals had chronic pruritus for longer than 5 years. The prevalence climbed with age, from 12% in workers up to age 30 years to 20% in 61- to 70-year-olds ( Dermatology. 2010;221:229-35 ).
One in three patients who present to dermatologists’ offices have chronic pruritus, she added.
Chronic pruritus can have a multitude of different causes: not only chronic skin diseases, but incurable renal and liver diseases, psychiatric conditions, neurologic disorders, drug side effects, and various forms of cancer, with hematologic malignancies figuring prominently. The quality of life impact is huge. And even though a plethora of topical and systemic therapies are available for itchy skin, they often are ineffective in patients with severe chronic pruritus. Thus, there is a significant unmet need for new and effective therapies, Dr. Ständer continued.
NK1 receptor antagonists: Substance P is a neuropeptide which plays a major role in the induction and maintenance of pruritus. The NK1 receptor, which is abundantly expressed in the skin and CNS, is substance P’s receptor – and therefore a logical target for novel anti-itch therapy. Bind that receptor and a key signaling pathway in pruritus is disrupted.
Aprepitant is an oral NK1 receptor antagonist approved as Emend more than a decade ago for prevention of chemotherapy-induced nausea and vomiting. Dr. Ständer was lead author of an early single-arm pilot study showing aprepitant is also dramatically effective for severe refractory chronic pruritus ( PLoS One. 2010 Jun 4;5:e10968 ).
Aprepitant is approved only for 3 days of use for its licensed indication. However, Dr. Ständer said she and other dermatologists have used it off-label for as long as 4 weeks in patients with chronic pruritus and found it to be safe, with mild nonlimiting side effects and relief that is often long lasting after treatment discontinuation.
Oral aprepitant is under study in several ongoing phase II clinical trials for treatment of severe pruritus resulting from targeted biologic therapies for various cancers. In addition, Leo Pharma is developing a topical gel formulation of aprepitant for chronic pruritus which is now in phase II studies.
Serlopitant is a once-daily oral NK1 receptor antagonist under development specifically for treatment of severe chronic pruritus. In a recent as-yet unpublished multicenter, double-blind, placebo-controlled phase II clinical trial involving 257 patients with severe refractory chronic pruritus of various etiologies, 6 weeks of serlopitant at 1 or 5 mg/day was markedly more effective than placebo in reducing itch intensity. Based upon these favorable results, Menlo Therapeutics has begun two new phase II randomized, placebo-controlled studies of the drug: ATOMIK, a roughly 450-patient, 40 U.S.-site study in patients with atopic dermatitis; and AUBURN, involving roughly 150 burn patients with chronic pruritus at 20 centers.
Selective opioid receptor agonists: These agents target kappa- and/or mu-opioid receptors on peripheral pain-sensing neurons in order to inhibit itch without activating other opioid receptors linked to classic opioid side effects such as respiratory depression, constipation, and addiction. These selective agents are essentially designed to be nonnarcotic opioids.
One such agent is nalfurafine, an oral kappa-opioid receptor agonist marketed in Japan for treatment of uremic pruritus in patients with chronic kidney disease undergoing hemodialysis and for refractory pruritus in chronic liver disease. The drug is in phase II studies in the United States.
Nalbuphine, a dual kappa-opiod agonist and partial mu-opioid antagonist, is Food and Drug Administration–approved as an injectable agent, known as Nubain, for moderate to severe pain. An investigational extended-release tablet formulation has successfully completed a U.S. multicenter, double-blind, placebo-controlled phase II/III clinical trial in hemodialysis patients with severe chronic uremic pruritus and a phase II study in patients with prurigo nodularis. Because the drug was effective in two conditions having very different sources of itch, it is likely to be of benefit in many forms of severe chronic pruritus, Dr. Ständer said.
She reported having no financial conflicts of interest.