Protagonist Advances Oral and Injectable PN-477, A Triple Agonist Obesity Drug; Phase 1 Trials Planned For 2026

Protagonist Therapeutics has announced PN-477 as its newest development candidate for obesity treatment. PN-477 is a triple agonist peptide that simultaneously targets GLP-1, GIP, and glucagon (GCG) receptors, key hormonal pathways involved in weight regulation and metabolism. The drug candidate is being developed in two formats: a once-daily oral option (PN-477o) and a once-weekly injectable version (PN-477sc), offering flexibility and convenience for patients.

"We are very pleased to nominate development candidate PN-477, a promising potential best-in-class oral GLP-1, GIP, GCG receptor tri-agonist peptide which has demonstrated optimal absolute and relative activity against all three hormone receptors in preclinical testing. PN-477 is specifically engineered to be orally stable with attention to the relative balance of potencies against the three receptors to potentially leverage their beneficial effects on weight loss and optimal body composition while mitigating their adverse effects. As with our previous drug candidates and late-stage assets, PN-477 is a testament to the power of our peptide technology platform, including the ability to deliver first- and best-in-class targeted oral and injectable peptide therapeutics," said Dinesh V. Patel, PhD, President and CEO of Protagonist. 

The compound has completed extensive preclinical studies demonstrating metabolic and pharmacologic benefits in animal models of obesity and glycemic control. PN-477 showed strong in vitro activation of its three target receptors and delivered encouraging proof-of-concept results in multiple preclinical models, including diet-induced obesity (DIO) in mice, normal dogs, and cynomolgus monkeys. The company highlights PN-477’s potential to balance efficacy with gastrointestinal tolerability and favorable effects on fat-to-lean mass ratios.

Dr. Patel continued, "While GLP-1 agonists have dominated the market thus far, there remains a broad opportunity for novel therapeutics with better body weight loss, higher ratio of fat to lean mass loss, tolerability and additional beneficial effects in obesity-related comorbidities. A triple GLP-1, GIP, GCG receptor agonist peptide that offers weight loss on par with the best injectable treatment options, as well as the optionality provided by both oral and injectable routes of administration, would be an important therapeutic breakthrough and represents another potential blockbuster drug opportunity for Protagonist. We look forward to moving PN-477 into first-in-human clinical Phase 1 studies in the second quarter of 2026."

With Investigational New Drug (IND)-enabling studies currently underway, Protagonist anticipates launching Phase 1 clinical trials in the second quarter of 2026. The development of PN-477 aims to position the candidate as a best-in-class obesity therapy, leveraging dual delivery routes and a comprehensive mechanism of action to compete in the growing weight loss therapeutics market.