Damian McNamara

October 20, 2016

LAS VEGAS — RPC4046, a new anti-interleukin (IL)-13 monoclonal antibody, significantly reduced eosinophilic counts in patients with eosinophilic esophagitis at 16 weeks compared with placebo, in the first phase 2 study.

"The take-home message from this study is that RPC4046 is very effective for decreasing mean esophageal eosinophil counts," said Evan Dellon, MD, from the University of North Carolina in Chapel Hill.

"It also improved secondary outcomes, including endoscopic severity, symptoms of dysphagia, and patients' and clinicians' global assessment of disease activity," Dr Dellon told Medscape Medical News.

RPC4046 is a recombinant, humanized, monoclonal antibody highly selective for IL-13. It inhibits binding to both of the IL-13 receptor sites.

IL-13 is a cytokine involved in allergic inflammation fibrosis pathways and heavily involved in the pathogenesis of chronic allergy immune-mediated eosinophilic esophagitis, explained Dr Dellon, who presented 16-week results here at the American College of Gastroenterology 2016 Annual Scientific Meeting.

IL-13 is overexpressed in the esophageal tissue of patients with eosinophilic esophagitis, it induces genes that overlap with eosinophilic esophagitis transcriptome, and it influences the expression of a number of mediators in this disease.

In the double-blind, randomized, placebo-controlled, multicenter HEROES study, about one third of the 99 patients received low-dose RPC4046 (180 mg), about one third received high-dose RPC4046 (360 mg), and about one third received placebo. When not taking anti-inflammatory therapy, all participants had histologic evidence of eosinophilic esophagitis and symptoms of dysphagia.

The participants were in their late 30s, male, and predominately white, which is consistent with an eosinophilic esophagitis population, Dr Dellon reported. Average time since diagnosis was 4 years, and those taking proton-pump inhibitors were allowed to continue that treatment during the study period.

The primary outcome was change from baseline in mean esophageal eosinophil count, measured in the five most inflamed high-power fields on esophageal biopsy.

Table. Change in Eosinophil Counts With RPC4046 vs Placebo

Eosinophil Count Low-Dose Group High-Dose Group Placebo Group P Value
Baseline mean 116.6 122.6 92.4 <.0001
Change at 16 weeks –94.8 –99.9 –4.4 <.0001

Eosinophils counts are expressed as cells/high-power field.

 

"There was a marked and significant decrease in eosinophil counts in the low-dose and high-dose arms, so the primary end point was met," Dr Dellon reported.

At baseline, "daily dysphagia scores were quite high," he said, reflecting at least 4 days of dysphagia in the 2 weeks before study entry.

Change in the frequency and severity in dysphagia symptoms, tracked in a daily symptom diary, showed a strong trend toward decreased severity in the high-dose group, but it was not significant. "There was not much difference between low-dose and placebo groups," he added.

"The most surprising aspect was that the medication had similar efficacy in the subgroup of eosinophilic esophagitis patients previously refractory to steroids," which was just less than half the cohort, Dr Dellon pointed out.

Steroid-Refractory Patients

"There seemed to be a stronger symptom response in this subgroup, which is very encouraging, because there are few effective medication options for these patients," he said.

And when the population is limited to the steroid-refractory group, "we see the same magnitude of symptom decrease in dysphagia in the high-dose arm, which does reach statistical significance," he reported. There was no corresponding change in the low-dose or placebo group.

The safety profile in the overall study "appears to be favorable," said Dr Dellon. Headache, upper respiratory tract infection, and arthralgia were among the most common adverse effects. Three serious adverse events occurred: Two patients developed acute appendicitis (one in the high-dose group and one in the placebo group), and one patient in the placebo group required hernia repair.

At 16 weeks, mean Eosinophilic Esophagitis Endoscopic Reference Scores were significantly lower with RPC4046 — both high and low doses — than with placebo (–4.8 vs –4.2 vs –0.9; P < .0004).

Participants reported a significant decrease in disease severity at 16 weeks in the high-dose group. Scores on the Investigator's Global Assessment Scale of disease severity decreased in both the high-dose and low-dose groups.

"The safety and efficacy data from this study support the continued development of RPC4046 in eosinophilic esophagitis," Dr Dellon said.

One member of the audience asked about underlying strictures in the patient population.

"About 33% of patients had strictures at baseline, but no one had a stricture severe enough that you could not pass the scope," Dr Dellon reported.

"These results are from a phase 2 study, so this medication remains experimental. The results need to be confirmed in a phase 3 study," he added.

"It looks promising," said Felice Schnoll-Sussman, MD, from the New York–Presbyterian Weill Cornell Medical Center in New York City. "This is one of the first studies to look at eosinophil counts in the eosinophilic esophagitis population, and the researchers saw a dramatic decrease."

"One would be hopeful that this therapy will have a role in the future, based on the dramatic changes," she told Medscape Medical News.

In the meantime, a 52-week open-label extension of the phase 2 HEROES study is underway.

Dr Dellon reports receiving grant and research support from Receptos, which was acquired by Celgene, the sponsor of the study. Dr Schnoll-Sussman has disclosed no relevant financial relationships.

American College of Gastroenterology (ACG) 2016 Annual Scientific Meeting. Abstract 19. Presented October 18, 2016.

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