PTG-100, an oral α4β7 antagonist with high gastrointestinal exposure and limited systemic exposure, may show efficacy in patients with moderate to severe active ulcerative colitis (UC), according to a study in Gastroenterology.

The randomized, double-blind, placebo-controlled PROPEL study (ClinicalTrials.gov Identifier: NCT02895100) was conducted at 103 sites between January 10, 2017, and March 23, 2018.

Phase 1 included 78 healthy male volunteers to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of PTG-100. Phase 2a included patients with moderate to severe active UC who were randomly assigned to receive PTG-100 (150, 300, or 900 mg) or placebo once daily for 12 weeks. Participants underwent screening for up to 35 days and were assessed on day 1 (baseline) and at weeks 2, 4, 6, 8, and 12. Mouse studies measured biomarkers and drug concentrations in blood and tissues.


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The researchers found that PTG-100 potently and selectively blocked adhesion of cells expressing α4β7 integrin to MAdCAM-1. Oral dosing of PTG-100 in mice revealed that it was mostly limited to the gut with higher exposure levels in the gut-associated lymphoid tissues compared with plasma.

In phase 1, the mean peak plasma concentration and area under the curve (AUCt) increased as the PTG-100 dose increased, after a single dose. Additionally, a small increase was observed in half-life with the dose, ranging from 3.1 hours at 100 mg to 5.9 hours at 1000 mg. PTG-100 was well-tolerated after single- and multiple-dose administration for up to a maximum dose of 1000 mg.

Phase 2a included 98 participants (mean age, 43 years; 53.1% men; 88.8% White); 25 participants received placebo, 25 received PTG-100 150 mg, 25 received PTG-100 300 mg, and 23 received PTG-100 900 mg. A total of 58 participants (59.2%) completed the study. The trial was declared futile, and further recruitment was discontinued based on the outcome. However, after unblinding of the interim data following the futile outcome, “an unusually high placebo remission rate of 24% was observed,” commented the study authors. The data confirm that PTG-100 localizes to the lamina propria and lymphoid aggregates of colonic epithelial cells in patients with UC.

The investigators noted that the phase 2a study had a limited number of patients and initially did not meet the primary endpoint. It thus underwent a blinded re-read of endoscopy videos, and subsequently showed dose-dependent effects in PTG-100 recipients compared with those receiving placebo.

“The consistent preclinical biological and phase 2a data suggest that local gut activity of an oral α4β7-integrin antagonist, distinct from full target engagement in blood, may be important for efficacy and treatment of ulcerative colitis,” stated the researchers.

Disclosure: Protagonist Therapeutics provided funding for the research. Some of the study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.

Reference

Sandborn W, Mattheakis LC, Modi NB, et al. PTG-100, an oral α4β7 antagonist peptide: preclinical development and phase 1 and 2a studies in ulcerative colitis. Gastroenterol. Published online August 30, 2021. doi: 10.1053/j.gastro.2021.08.045