Allakos Reports Positive Results in Mid-Stage Study of Therapy for Rare GI Disorders

Allakos said its lead investigational antibody, AK002, met all the prespecified primary and secondary endpoints in a phase 2 study in patients with eosinophilic gastritis and/or eosinophilic gastroenteritis.

Eosinophilic gastritis (EG) and eosinophilic gastroenteritis (EGE) are severe orphan inflammatory diseases characterized by the presence of high levels of eosinophils in the stomach or duodenum. Common symptoms include severe abdominal pain, nausea, diarrhea, bloating, cramping, early satiety, loss of appetite, vomiting, dysphagia, and weight loss. The estimated prevalence of eosinophilic gastritis and eosinophilic gastroenteritis in the United States is approximately 50,000 patients.

AK002, targets Siglec-8, an inhibitory receptor selectively expressed on human mast cells and eosinophils. It has been shown to inhibit mast cells and deplete eosinophils, which when inappropriately activated, have been identified as key drivers in a number of severe diseases affecting the gastrointestinal tract, eyes, skin, lungs and other organs. The FDA awarded Allakos orphan drug designation for AK002 in eosinophilic gastritis and eosinophilic gastroenteritis.

“Eosinophilic gastritis, eosinophilic gastroenteritis, and eosinophilic esophagitis are severe debilitating diseases with no approved therapies,” said Evan Dellon, a principal investigator of the study and professor of gastroenterology at the University of North Carolina, Chapel Hill. “AK002 is unique in that it targets both eosinophils and mast cells, two major effector cell types that cause disease-related tissue damage.”

The randomized, double-blind, placebo-controlled phase 2 trial of AK002 enrolled patients with active, biopsy-confirmed EG and/or EGE. Patients were required to be moderately to severely symptomatic based on a patient reported symptom questionnaire and have biopsy confirmed eosinophilia of the stomach and/or duodenum. Qualifying patients were randomized two different dosages given monthly or placebo. Disease symptoms were measured daily using a patient reported symptom questionnaire that scored 8 symptoms on a scale from 0 to 10 (abdominal pain, nausea, vomiting, early satiety, loss of appetite, abdominal cramping, bloating, and diarrhea).

Endpoints were assessed per protocol in a prespecified hierarchical order using biopsies collected at the end of study and symptoms collected over the last two weeks of study prior to biopsy. The primary endpoint was the percent change from baseline in the number of tissue eosinophils obtained from gastric or duodenal biopsies. The secondary endpoints were proportion of patients with a greater than 75 percent reduction in tissue eosinophil counts from biopsies and a greater than 30 percent reduction in Total Symptom Score (TSS) from the patient reported questionnaire and the percent change from baseline in the TSS.

AK002 showed a statistically significant benefit when compared to placebo on all primary and secondary endpoints for each of the high dose, the low dose, and the combined high/low dose AK002 groups. The primary efficacy endpoint met with 95 percent reduction in gastrointestinal tissue eosinophils versus 10 percent increase on placebo. The treatment response secondary endpoint met with 69 percent of AK002 treated patients meeting the response criteria compared to 5 percent of patients on placebo. The patient reported symptom score met with 53 percent reduction compared to 24 percent on placebo.

All AK002 dose arms showed clinically meaningful and statistically significant benefits compared to placebo on all prespecified primary and secondary endpoints, including gastrointestinal tissue eosinophil counts and patient reported disease symptoms. Statistically significant differences in patient symptoms between the active and placebo groups occurred one day following AK002 administration. In addition, patients with comorbid eosinophilic esophagitis treated with AK002 experienced statistically significant decreases in esophageal eosinophil counts and substantial reductions in patient reported dysphagia symptoms.

AK002 was generally well tolerated, with mild to moderate infusion-related reactions the only treatment emergent adverse event occurring frequently. Ninety-two percent of patients in the study elected to enter a long-term AK002 extension study. Efficacy and safety results from the long-term extension study are expected in 2020.

The data demonstrate that AK002 produced histological resolution of gastrointestinal tissue eosinophilia and improved disease symptoms, and that these benefits occurred in the same individuals. Based on the results from the phase 2 study, Allakos will request an end of phase 2 meeting to discuss the design of the planned phase 3 study in EG and/or EGE and phase 2/3 study in eosinophilic esophagitis.

Photo: Evan Dellon, a principal investigator of the study and professor of gastroenterology at the University of North Carolina, Chapel Hill

Author: Rare Daily Staff