GENEVA (FRONTLINE MEDICAL NEWS) – Serlopitant, a novel once-daily oral neurokinin-1 receptor antagonist, brought significant improvement for patients with treatment-resistant chronic pruritus as early as day 2, in a phase 2 randomized trial, Paul Kwon, MD, reported at the annual congress of the European Academy of Dermatology and Venereology.

In a separate phase 2 study presented at the congress, serlopitant showed strong efficacy in patients with prurigo nodularis.

Serlopitant is an oral small molecule with high selectivity for the neurokinin-1 receptor (NK1R). At the 5-mg dose, the drug occupies more than 90% of CNS NK1Rs. The NK1R is the primary receptor for substance P, and thus plays an important role in pruritus signaling.

Serlopitant, acting as an NK1R antagonist, disrupts the itch signal that’s ordinarily transmitted along the substance P-NK1R axis to stimulate central and peripheral neurons, fibroblasts, keratinocytes, mast cells, and basophils, explained Dr. Kwon, chief medical officer at Menlo Therapeutics, Menlo Park, Calif., which is developing the drug.

Chronic pruritus is an often-debilitating condition that can have a multitude of causes. It’s associated with increased rates of anxiety, depression, and sleep deprivation. Existing treatments often fail to provide adequate relief from the severe chronic itching, or they are associated with safety or tolerability issues.

“Chronic pruritus can disrupt quality of life to a level comparable to chronic pain,” the dermatologist observed. “I think we in the medical community are hearing more and more about treatment for chronic pruritus as being a major unmet medical need.”

Dr. Kwon noted that investigators at Emory University in Atlanta have found that the quality of life disruption imposed by chronic pruritus is comparable to that of chronic pain ( Arch Dermatol. 2011 Oct;147[10]:1153-6 ).

The phase 2, randomized, double-blind, placebo-controlled, 6-week trial comprised 257 patients with chronic pruritus at 25 U.S. centers. All were non- or inadequate responders to topical corticosteroids or oral antihistamines. This was essentially an all-comers study that was not restricted to patients with any particular specific cause of their chronic itch. They had to have severe chronic pruritus, as defined by a baseline self-rated pruritus visual analogue score of at least 7 on a 0-10 scale. Patients were randomized to once-daily oral serlopitant at 0.25 mg, 1 mg, or 5 mg, or to placebo.

The primary endpoint was change in mean visual analogue score from baseline to week 6. The serlopitant 1-mg and 5-mg groups reported mean 41.4% and 42.5% reductions, respectively, which were significantly better than the 28.3% reduction in controls.

“It seems that the drug is working in a broad set of subjects,” Dr. Kwon said. “It is not entirely shutting off itch in significant numbers, but the majority of patients appear to be deriving benefit from serlopitant.”

He highlighted the rapidity with which chronic pruritus responded to serlopitant. The first dose was taken on the evening of day 1. The next day, the 1-mg serlopitant group already showed a significantly greater improvement than did placebo-treated controls. The day after that, so did the 5-mg group. Those between-group differences grew steadily larger throughout the 6-week study period.

That rapid response is clinically highly relevant, because numerous studies have demonstrated that fast onset of therapeutic effect improves patient satisfaction, quality of life, and compliance with treatment for a variety of medical conditions, he said.

Dr. Kwon characterized the safety profile of serlopitant in the trial as “fairly robust,” with only mild or moderate treatment-emergent adverse events being seen. Diarrhea and somnolence were the only adverse events more common with serlopitant than placebo, and their incidence was in the mid single digits.

“We have not uncovered any significant safety signal in this study,” Dr. Kwon declared.

Also at the EADV Congress, Sonja Ständer, MD, presented a phase 2 study of serlopitant in patients with prurigo nodularis. The randomized, double-blind, 8-week, 127-patient trial was conducted at 15 sites in Germany, where patients were randomized to once-daily serlopitant at 5 mg or placebo. All participants had a baseline pruritus VAS of 7 or more. Thirty percent of patients had more than a 10-year history of prurigo nodularis, and 24% had the condition for 5-10 years.

The primary endpoint was the difference from baseline to weeks 4 and 8 in the average pruritus VAS over the previous 24 hours. The baseline score was 7.9. The serlopitant group averaged a 1.0-point greater reduction, compared with controls, at week 4, and a 1.7-point greater decrease at week 8.

Multiple other measures of pruritus serving as secondary endpoints consistently showed significantly greater improvement in the serlopitant group. For example, at the week 8 assessment, 54% of serlopitant-treated patients reported no or only mild itch, compared with 29% of controls. And two-thirds of the serlopitant group reported some degree of improvement in the severity of their eruptive papulonodular lesions at week 8, versus 40% of controls, according to Dr. Ständer, professor of dermatology and neurodermatology and head of the Center for Chronic Pruritus at the University of Münster (Germany).

Of note, nasopharyngitis occurred in 17.2% of the serlopitant group and in 3.2% of controls. Diarrhea was also more common in the serlopitant group, by a margin of 10.9% versus 4.8%.

Dr. Kwon said additional phase 2 as well as phase 3 randomized trials of serlopitant are in the works for both chronic pruritus and prurigo nodularis. The drug is also under study for chronic itch due to other specific etiologies, as well as for refractory chronic cough.

Menlo Therapeutics sponsored the study. Dr. Kwon is a Menlo Therapeutics officer. Dr. Ständer, who was also principal investigator in the chronic pruritus trial, reported having no financial conflicts of interest.