Protagonist selects PN-477 an oral and injectable triple agonist peptide development candidate for obesity

Protagonist Therapeutics has selected PN-477 a novel oral peptide - PN-477o with once-daily dosing, high potency and activation of glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP) and glucagon (GCG) receptors - as a development candidate for the treatment of obesity.

The triple agonist PN-477 is designed to offer the optimal combination of total body weight loss, improved gastrointestinal (GI) tolerability and fat to lean mass ratio, with the dosing convenience of a once-daily oral agent and the added optionality of a once-weekly subcutaneous administration.

PN-477 has completed extensive preclinical evaluation including oral and metabolic stability, potency, pharmacokinetics and pharmacodynamics studies, and has demonstrated effects in preclinical models of obesity and glycaemic control. PN-477 has shown potent in vitro activity in activating the GLP-1, GIP, and GCG receptors. PN-477 also demonstrated robust preclinical proof-of-concept in various animal studies including the diet induced obesity (DIO) preclinical mouse model, normal dogs, and cynomolgus monkeys.

"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 treatments 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," said Dr Dinesh V Patel, President and CEO of Protagonist.

Overall, PN-477 has the right balance of potency, oral and in-vivo stability, and pharmacokinetic properties to enable parallel development both as a once-daily oral (PN-477o) and once-weekly injectable (PN-477sc) treatment options. IND enabling studies of PN-477 are underway and initiation of Phase 1 clinical studies is anticipated in the second quarter of 2026.

"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. We look forward to moving PN-477 into first-in human clinical Phase 1 studies in the second quarter of 2026," added Patel.