With PN-477, Protagonist is directly going up against Eli Lilly, which is advancing retatrutide, also a triple-G agonist, in a Phase II trial.
Despite coming late to the obesity party, Protagonist Therapeutics is looking to stand out in an increasingly competitive space by offering a novel “triple-G” agonist with a flexible dosing profile.
The California-based biotech on Monday nominated PN-477, a triple agonist of the GLP-1, GIP and glucagon receptors, for treating obesity. PN-477 is being developed as a daily oral treatment but comes with the option of being administered as a once-weekly subcutaneous injection. Protagonist expects to launch first-in-human Phase I studies for PN-477 in the second quarter of 2026.
Writing to investors on Monday evening, analysts at BMO Capital Markets called this dosing flexibility “interesting,” noting that the asset underscores Protagonist’s profile as a differentiated developer of peptide therapies. “This is not another me-too GLP-1 mono-agonist and could present as an interesting opportunity for a strategic acquirer or partner,” the analysts wrote.
Still, PN-477 remains a very immature candidate, with only preclinical data to back it up. Protagonist on Monday announced that based on in vitro data, PN-477 has demonstrated the ability to activate all three of its target receptors. Animal model studies, including those in mice with diet-induced obesity, also provided early proof-of-concept for the candidate.
These early findings, according to Protagonist, indicate that PN-477 has the “right balance of potency, oral and in-vivo stability, and pharmacokinetic properties,” according to its Monday announcement.
In this regard, however, analysts took a wait-and-see approach. “Protagonist is unlikely to get any meaningful credit for the asset given the stage of development,” BMO wrote.
Analysts at Truist Securities agreed in a note to investors on Monday, conceding that the preclinical findings underscore PN-477’s “potential to be differentiated on weight loss,” however qualifying that the asset “needs clinical validation.” As in the case of BMO, Truist likewise sees PN-477 as “validation” of Protagonist’s oral peptide approach, which “is likely to be attractive to a potential partner.”
With PN-477, Protagonist is directly going up against Eli Lilly, which is advancing retatrutide, also a triple-G agonist. Phase II data in June 2023 showed that retatrutide could elicit up to 24% weight loss at 48 weeks. Lilly has since pushed retatrutide into late-stage development.
Meanwhile, fellow obesity leader Novo Nordisk has also hopped on the triple-G train, partnering with Chinese biotech United Laboratories in March for the subcutaneous drug UBT251, which is currently in early-stage studies for obesity and type 2 diabetes. Novo paid $200 million upfront and promised up to $1.8 billion in milestones.
