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# Why Amgen's GIP Blockade Still Trades at a Discount to Dual Agonists
- URL: https://bioweek.com/amgens-maritide-highlights-the-mounting-trade-offs-in-next-gen-incretins/
- Published: 2026-08-30T17:30:00.000Z
- Updated: 2026-08-31T08:44:12.000Z
- Description: MariTide delivered up to about 20% mean weight loss at 52 weeks without a plateau, then Amgen lost about $7 billion in market value. The remaining fight is GIP direction, first-dose gut burden, and conjugate manufacturing cost.
- Author: BioWeek
- Tags: Pipeline, Markets

When Amgen said MariTide cut body weight by as much as about 20% over 52 weeks, the clinical file looked like a late but credible obesity entry. The tape disagreed. Shares [fell](https://www.reuters.com/business/healthcare-pharmaceuticals/amgen-drug-leads-up-20-weight-loss-trial-2024-11-26/?ref=bioweek.com) 4.8%, wiping about $7 billion from the company's value, because investors had already priced a readout that would outrun weekly dual agonists rather than merely join them.

Maridebart cafraglutide, still listed as AMG 133, is a bispecific antibody-peptide conjugate given as a monthly or less frequent subcutaneous injection. In a double-blind, dose-ranging [study](https://www.amgen.com/newsroom/press-releases/2024/11/amgen-announces-robust-weight-loss-with-maritide-in-people-living-with-obesity-or-overweight-at-52-weeks-in-a-phase-2-study?ref=bioweek.com) of 592 adults living with obesity or overweight, people without type 2 diabetes lost up to about 20% of body weight on average at week 52, and the curve had not flattened. People with type 2 diabetes, who typically lose less on GLP-1 medicines, lost up to about 17% and cut average HbA1c by as much as 2.2 percentage points. Blood pressure, triglycerides, and high-sensitivity C-reactive protein improved across doses. Free fatty acids did not rise in a meaningful way.

Those figures sit next to Eli Lilly's tirzepatide (Zepbound), whose pivotal obesity program is commonly cited near 21% mean weight loss, and next to triple-agonist retatrutide, whose 48-week Phase 2 work landed near 24%. Some buyers wanted 22% to 25% or better, a bar that would have recast Amgen as the next category leader. The [trial](https://clinicaltrials.gov/study/NCT05669599?ref=bioweek.com) did not miss its own design. It missed a Street narrative built on beating Lilly outright.

### A 52-Week Curve That Was Still Falling

The study split into two cohorts: 465 adults without diabetes and 127 with type 2 diabetes. Investigators tested monthly fixed doses of 140 mg, 280 mg, and 420 mg, plus less frequent and dose-escalation arms, including bi-monthly injections. Amgen has said the roughly 20% mean loss in people without diabetes came without a plateau, which is why Part 2 is still running past one year. More than 90% of eligible patients chose to continue, a retention signal that matters if the commercial pitch is durability rather than a single-year peak.

Gastrointestinal events were the cost of getting there. Nausea, vomiting, and constipation led the adverse-event list. Nausea and vomiting were mostly mild, short-lived, and clustered around the first dose. Dose escalation cut that incidence. In the escalation arms, about 11% of participants stopped for any adverse event, and fewer than 8% stopped for gastrointestinal reasons. High starting doses made that first-week burden more visible than a weekly peptide titration typically does. For a consumer-facing obesity market, an 11% any-cause dropout in the better-tolerated arms is usable, but it is not a clean win against Zepbound and Wegovy on gut feel.

The convenience claim is clearer. Semaglutide (Wegovy) and tirzepatide are weekly. MariTide is designed as a single injection in a handheld autoinjector on a monthly or even bi-monthly cadence, and Amgen has said it plans to study quarterly maintenance.

### Two Companies Reading GIP in Opposite Directions

Tirzepatide stimulates GIP receptors as well as GLP-1 receptors. MariTide does the reverse on GIP. It agonizes the GLP-1 receptor and antagonizes the GIP receptor, a bet Amgen ties to human genetics in which GIP receptor loss-of-function appears protective against obesity. Preclinical work, the company says, found that turning GLP-1 on and GIP signaling down together produced more weight loss than hitting either pathway alone.

Phase 2 has not settled that split. Weight loss in the same neighborhood as a GIP agonist does not prove antagonism is superior, only that it can work in people. It also keeps a safety file open that weekly dual agonists have not had to answer in the same way. Physiological GIP signaling is involved in bone formation, which is why investigators watched bone mineral density after earlier Phase 1 noise. Amgen said there was no association between MariTide and BMD changes in this study. That statement will not close the question. Longer Phase 3 exposure, under FDA review, is where a bone signal would have time to appear or stay absent.

### Monthly Dosing Versus a Harder Molecule

MARITIME, Amgen's Phase 3 program in obesity and related conditions, is the next test of both the biology and the factory. An antibody-peptide conjugate is not a fully synthetic incretin. The antibody backbone comes from mammalian cell culture. The peptides are made chemically. Then they have to be conjugated. That extra step usually means higher cost of goods and a more brittle CMC path than a peptide-only weekly pen, even when Amgen can run the product through its existing biologics network. A monthly or less frequent shot can still win on adherence. It has to win by enough to offset a more expensive molecule.

Investors can hold two facts at once. A 20% mean loss that is still moving at week 52, with monthly dosing and a 2.2-point HbA1c drop in the diabetes cohort, is a serious obesity candidate. A nearly 5% share drop on the day of the data is a reminder that this market now grades on a curve set by Lilly and Novo Nordisk. MariTide has to show that GIP blockade, a slower injection schedule, and a more complex conjugate are worth choosing when the weight-loss number is close, not clearly ahead.