Retatrutide

iStock, Talaj 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 pro 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.

iStock, Yutthana Gaetgeaw Eli Lilly’s tirzepatide is expected to be worth $62 billion annually by 2030, according to Evaluate. That valuation would be three times larger than what AbbVie’s blockbuster Humira ever achieved. Total prescription drug sales are expected to grow to $1.75 trillion by 2030, at which point GLP-1 therapies will make up 9% of total prescriptions, according to a new report from Evaluate. The weight loss and diabetes mega-blockbusters are expected to grow 20% between 2024 and 2030. “They are in a class of their own,” Evaluate said in the World Preview report , published Tuesday. Eli Lilly’s tirzepatide, marketed as Mounjaro for diabetes and Zepbound for weight loss, is expected to rake in $62 billion a year by 2030, according to Evaluate. That valuation would be three times larger than what AbbVie’s blockbuster Humira—long considered the best-selling drug in the world —achieved. It’s double the 2024 sales of Merck’s Keytruda. The broader category of GLP-1 drugs are “projected to reach hitherto unseen sales peaks,” according to Evaluate. This class of drugs is expected to have five of the top 10 slots on the best-sellers list by 2030 and will be four of the most promising candidates in the pipeline. But Lilly appears to be clearly leading the way. “Lilly’s supremacy in this battle is already apparent,” Evaluate wrote. Mounjaro and Zepbound are expected to be the best- and third-best selling drugs by the end of the decade. Lilly’s main competitor is Novo Nordisk, whose semaglutide is marketed as Wegovy for diabetes and Ozempic for weight loss. Those drugs sit at sixth and fifth, respectively. “First-mover Novo Nordisk lost ground due to its sluggish response to manufacturing shortages of Wegovy (semaglutide), which led to a flood of compounded (pharmacy-mixed) drug,” according to the report. Novo has acknowledged some stumbles, even ousting CEO Lars Fruergaard Jørgensen in May in a surprise move. Evaluate did say that Novo’s pipeline asset CagriSema, which combines semaglutide with an amylin agonist, is the most promising asset in R&D at the moment, with peak sales projections of $80 billion. But the drug has stumbled in the clinic, falling short of expectations and forcing Novo to launch a longer-duration trial to test different dosing. “If it doesn’t improve, CagriSema will only match Zepbound in efficacy, yet is more complex to manufacture,” Evaluate said. The Rest of the Best Immuno-inflammatory drugs will also continue to lead, with AbbVie’s Skyrizi and Sanofi/Regeneron’s Dupixent in the forefront and on track to make over $25 billion each in 2030. Oncology, too, will have a story to tell in 2030, with Johnson & Johnson’s Genmab-partnered blood cancer drug Darzalex meeting Merck’s falling star Keytruda as its patent expires in 2028 . The current best-selling immuno-oncology drug will fall to seventh place by 2030. “Keytruda’s 2028 expiry puts Merck at the top of the most exposed companies to patent-related sales losses over the rest of the decade—and is the only top ten drug with negative growth,” Evaluate wrote. But Merck is hoping to patch some of the holes in its Keytruda losses with a subcutaneous formulation that Evaluate named as one of the most valuable pipeline drugs by net present value. “It’s a shining case study in life-cycle management,” the analysis firm said, and one that the forthcoming GLP-1 combos and formulations may be able to copy as pipeline assets like oral GLP-1 orforglipron and triple-G agonist retatrutide are expected to take the market by storm . Pfizer has taken one of the biggest tumbles on Evaluate’s rankings, falling from the number one slot in the pandemic years to last place in the list of top 10 companies with the most drug sales expected in 2030. Novartis is also expected to be stuck in the bottom half as it lacks a standout blockbuster. Sanofi, on the other hand, is the “most impressive” non-GLP-1 company rising up the list, according to Evaluate. The French pharma is rising thanks to Dupixent, which is expected to grow by 10%.