Protagonist Therapeutics has announced the selection of PN-477, a potential best-in-class triple agonist peptide, as a development candidate for obesity treatment, positioning the company in direct competition with Eli Lilly's experimental drug retatrutide. The novel therapeutic targets the same three hormone receptors—GLP-1, GIP, and GCG—to address weight loss and metabolic control.
Novel Triple-Receptor Approach
PN-477 represents a significant advancement in obesity treatment by simultaneously activating glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), and glucagon (GCG) receptors. According to Protagonist CEO Dinesh V. Patel, the drug "has demonstrated optimal absolute and relative activity against all three hormone receptors in preclinical testing."
The company has engineered PN-477 to be orally stable with careful attention to the relative balance of potencies against the three receptors. This design aims to "potentially leverage their beneficial effects on weight loss and optimal body composition while mitigating their adverse effects," Patel explained.
Dual Administration Options
Unlike current market leaders, PN-477 offers flexibility in administration routes. The company plans to develop both an oral formulation (PN-477o) for once-daily dosing and a subcutaneous version (PN-477sc) for once-weekly injection. This dual approach addresses different patient preferences and could provide a competitive advantage in the crowded obesity market.
The drug has demonstrated robust preclinical proof-of-concept across various animal studies, including diet-induced obesity mouse models, normal dogs, and cynomolgus monkeys. These studies have shown the compound has "the right balance of potency, oral and in-vivo stability, and pharmacokinetic properties" to enable parallel development of both formulations.
Market Positioning and Competition
The obesity treatment landscape is currently dominated by Novo Nordisk's Wegovy, which targets GLP-1, and Eli Lilly's Zepbound, which targets both GLP-1 and GIP receptors. However, no triple-targeting drugs are currently available on the market.
"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," Patel noted.
The competitive landscape includes multiple pharmaceutical giants developing obesity treatments. Companies such as Roche, AstraZeneca, Pfizer, and Merck are working on daily pills, while Viking Therapeutics and Amgen are pursuing dual approaches with their respective candidates.
Development Timeline and Clinical Plans
Protagonist expects to initiate Phase 1 clinical studies of PN-477 in the second quarter of 2026, with IND-enabling studies currently underway. This timeline puts the company behind Eli Lilly, which expects to complete its Phase 3 study of retatrutide for obesity treatment in April 2026.
The company's peptide technology platform has previously generated two novel peptides currently in advanced Phase 3 clinical development, with potential New Drug Application submissions to the FDA in 2025. This track record supports the company's confidence in advancing PN-477 through clinical development.
Therapeutic Potential
Patel emphasized that "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."
The company's approach focuses on achieving optimal total body weight loss while improving gastrointestinal tolerability and fat-to-lean mass ratio compared to existing treatments. This comprehensive approach to obesity management could address current limitations in available therapies and provide significant clinical benefits for patients struggling with obesity and related comorbidities.
