Protagonist Therapeutics Joins Obesity Drug Race with Novel Triple-G Agonist

Protagonist Therapeutics has announced its entry into the competitive obesity treatment market with PN-477, a novel "triple-G" agonist targeting the GLP-1, GIP, and glucagon receptors. The California-based biotech is positioning its candidate as a potential game-changer, offering both oral and injectable formulations to address the growing demand for effective weight loss therapies.

A New Contender in the Obesity Market

PN-477 represents Protagonist's bid to carve out a niche in the increasingly crowded obesity treatment landscape. The company has nominated the compound for development, with plans to initiate first-in-human Phase I studies in the second quarter of 2026. This move places Protagonist in direct competition with industry giants like Eli Lilly and Novo Nordisk, who are already advancing their own triple-G agonists.

The flexibility of PN-477's dosing profile sets it apart from competitors. Protagonist is developing the drug as a daily oral treatment with the option for once-weekly subcutaneous injection, a feature that analysts at BMO Capital Markets described as "interesting." This versatility could potentially address different patient preferences and treatment regimens, enhancing its market appeal.

Preclinical Promise and Investor Outlook

While PN-477 is still in its early stages, preclinical data have shown promise. In vitro studies demonstrate the compound's ability to activate all three target receptors, and animal model studies, including those in mice with diet-induced obesity, have provided initial proof-of-concept. Protagonist claims these findings indicate that PN-477 has the "right balance of potency, oral and in-vivo stability, and pharmacokinetic properties."

However, analysts remain cautious about the asset's potential at this early stage. BMO analysts noted that Protagonist "is unlikely to get any meaningful credit for the asset given the stage of development." Similarly, Truist Securities analysts acknowledged the preclinical findings but emphasized the need for clinical validation.

Despite this cautious outlook, both BMO and Truist see PN-477 as a validation of Protagonist's oral peptide approach, suggesting that it could make the company an attractive target for potential partners or acquirers.

Competitive Landscape and Industry Trends

Protagonist's entry into the obesity market comes at a time of intense competition and rapid development in the field. Eli Lilly is currently advancing retatrutide, another triple-G agonist, in Phase II trials. Recent data showed that retatrutide could elicit up to 24% weight loss at 48 weeks, setting a high bar for newcomers in the space.

Novo Nordisk, another leader in the obesity treatment market, has also recognized the potential of triple-G agonists. In March, the company partnered with Chinese biotech United Laboratories, paying $200 million upfront with the promise of up to $1.8 billion in milestones for the development of UBT251, a subcutaneous triple-G agonist currently in early-stage studies for obesity and type 2 diabetes.

As Protagonist prepares to enter clinical trials with PN-477, the company will need to demonstrate significant efficacy and safety to compete with established players and justify its late entry into the obesity treatment arena. The potential for oral administration could be a key differentiator, but the long road to market approval means that Protagonist will need to navigate a rapidly evolving competitive landscape in the years to come.