Protagonist Therapeutics has begun dosing patients in a Phase 1 clinical trial of an oral ulcerative colitis (UC) treatment candidate known as PN-10943, the company announced in a press release.
PN-10943 is a gut-restricted blocker of a protein called alpha-4-beta-7 integrin, an adhesion molecule that regulates the migration and homing of lymphocytes (immune cells) to gut-associated lymphoid tissue (GALT). The GALT contains immune T- and B-cells that protect against pathogens.
The Phase 1 trial is a randomized, double-blind, placebo-controlled study in up to 80 healthy volunteers. It contains two parts: While the first will explore single ascending doses (100, 300, 1,000, and 1,400 mg) of PN-10493, the second will involve once-daily administration of PN-10943 over 14 consecutive days in ascending dose groups.
The trial’s primary objectives are the potential therapy’s safety and tolerability. Other goals include evaluation of pharmacological parameters. According to Dinesh V. Patel, PhD, Protagonist’s president and CEO, the company expects to have top-line results in the first half of 2019. The data will be used to design a Phase 2a trial of PN-10943 in UC patients, expected to begin in the second half of 2019.
Preclinical studies have shown that PN-10943 outperformed Protagonist’s PTG-100 — also a gut-restricted blocker of alpha-4-beta-7 integrin — as measured by in vitro potency, target engagement, and efficacy in models of colitis.
Based on these data and on recent feedback from global regulatory authorities, including the U.S. Food and Drug Administration, Protagonist decided to replace PTG-100 with PN-10943 as a therapy candidate for inflammatory bowel disease (IBD).
In March, Protagonist decided to discontinue the Phase 2b PROPEL trial (NCT02895100) testing PTG-100 in people with moderate to severe UC, after an interim analysis deemed the study futile. PTG-100 was being tested in three daily doses — 150 mg, 300 mg, or 900 mg. No safety issues were found.
According to Patel, Protagonist will use the knowledge and experience acquired from the previous studies with PTG-100, which provided evidence of safety and preliminary efficacy of the compound that worked in a similar way to PN-10943.
“PN-10943 has been designed with superior potency and preclinical properties and applies the same oral, gut-restricted approach to treatment that has been validated previously by Protagonist in clinical studies in ulcerative colitis patients,” Patel said in the release.
In an earlier press release, Patel also said that replacing PTG-100 with PN-10943 “is the most efficient allocation of resources for the Company with minimal impact on overall development timelines.” It also provides the company greater financial flexibility as it ensures that operations will be funded to the end of 2020.
Protagonist recently hosted a conference call and webcast to present preclinical results of PN-10943, as well as key milestones for the company’s other investigational compounds — PTG-200, being co-developed with Janssen Biotech for moderate to severe active Crohn’s disease (also a type of IBD), and PTG-300 for the treatment of anemia in rare blood disorders such as beta-thalassemia.
A Phase 1 trial in 80 healthy volunteers showed that PTG-200 — which blocks the function of the interleukin-23 receptor, implicated in inflammatory responses — was safe and well-tolerated. According to Patel, Protagonist expects to advance PTG-200 into a Phase 2 trial.
A replay of the call is available here and will be accessible until late January. Protagonist plans to present further PN-10943 data at a future medical conference.