PN-477 and Retatrutide represent two of the most promising triple-agonist therapies for obesity in recent years. While Retatrutide has already made headlines due to Eli Lilly’s robust clinical trials, PN-477—developed by Protagonist Therapeutics—has emerged as a novel challenger. This article breaks down the differences between the two compounds in terms of mechanism, clinical data, delivery format, and potential impact.
What Are Triple Agonists?
Triple agonists are peptide-based drugs that activate three key receptors involved in metabolic regulation: GLP-1 (glucagon-like peptide-1), GIP (glucose-dependent insulinotropic polypeptide), and GCGR (glucagon receptor). These hormones work synergistically to suppress appetite, improve insulin sensitivity, and increase energy expenditure.
Both PN-477 and Retatrutide fall under this category, making them part of a new generation of obesity medications that aim to go beyond GLP-1-only drugs like Semaglutide (Ozempic) or Tirzepatide (Mounjaro).
Overview of PN-477
PN-477 is Protagonist Therapeutics’ lead triple agonist candidate, announced as a development candidate in June 2025. While it is still in the preclinical phase, PN-477 is already gaining attention due to its dual-delivery strategy:
- PN-477sc: A subcutaneous injection, expected to be administered once weekly
- PN-477o: A daily oral tablet — potentially a game-changer for patients who dislike injections
Preclinical models have shown promising outcomes in terms of body weight loss and metabolic health. The oral version particularly sets it apart, as current triple agonists are exclusively injectable.
Overview of Retatrutide
Retatrutide is an injectable triple agonist developed by Eli Lilly. The drug completed successful Phase 2 trials and demonstrated up to 24% average body weight reduction in obese patients after 48 weeks. These numbers are among the highest ever seen in an anti-obesity drug trial.
Unlike PN-477, Retatrutide is administered only via injection, which can be a barrier for some patients. However, its established efficacy and Lilly’s global resources give it a strong foothold in the market.
Key Differences
| Feature | PN-477 | Retatrutide |
|---|---|---|
| Developer | Protagonist Therapeutics | Eli Lilly |
| Status | Preclinical (Phase 1 in 2026) | Phase 3-ready |
| Receptors Targeted | GLP-1 / GIP / GCGR | GLP-1 / GIP / GCGR |
| Delivery Method | Oral & Injectable | Injectable Only |
| Weight Loss Potential | Unknown (Preclinical models positive) | Up to 24% in Phase 2 trials |
| Branding | Not Yet Released | In Development |
Potential Advantages of PN-477
While Retatrutide is clearly ahead in terms of clinical progress, PN-477 has some key differentiators:
- Oral Delivery: If PN-477o succeeds, it will be the first triple agonist available as a daily pill
- Patient Compliance: Easier administration could mean higher adoption rates
- Smaller Biotech Agility: Protagonist may move quicker on formulation improvements or licensing
Challenges PN-477 Must Overcome
Despite the excitement, PN-477 still faces hurdles:
- Clinical Validation: No human trials have been conducted as of mid-2025
- Time to Market: First patient dosing isn’t expected until mid-2026
- Competition: Retatrutide may already be approved or close to launch when PN-477 enters trials
Which One is Better?
Right now, Retatrutide leads due to strong human data. However, if PN-477 can demonstrate comparable efficacy and prove its oral formulation works well in humans, it could radically shift the landscape.
For patients who are averse to needles, PN-477o would be the preferred option. For now, Retatrutide remains the gold standard — but that could change within the next 2–3 years.
Conclusion
Both Retatrutide and PN-477 are on the frontier of obesity therapy. Retatrutide has set a high benchmark, but PN-477's oral delivery innovation could give it a major edge in accessibility and user preference. As clinical trials begin in 2026, the medical community will be watching closely.
Stay tuned as we track updates from both developers, and break down trial results as they emerge.