Maridebart Cafraglutide, AMG 133
Evidence Grade E — Very limited evidence. 5 published studies. 11 registered clinical trials.
MariTide is a large antibody-peptide hybrid from Amgen that takes the opposite approach to tirzepatide: where tirzepatide activates the GIP receptor, MariTide blocks it, while simultaneously activating GLP-1 receptors. Its most notable feature is monthly dosing — the longest interval of any obesity treatment in development. Weight loss appeared to continue beyond 52 weeks without plateauing.
5 published studies: 3 human, 1 animal, 0 in-vitro, 3 reviews
MariTide is in Phase II/III development (not yet approved). Phase II results (592 patients, 52 weeks) showed 16–20% weight loss across doses. Body composition analysis showed 26–37% fat mass reduction with 8–13% lean mass reduction. Notably, weight loss appeared to continue beyond the 52-week treatment period without plateau.
MariTide's monthly dosing would be a significant convenience advantage if efficacy is confirmed in Phase III. The ongoing weight loss trajectory without plateau is particularly interesting and distinguishes it from some GLP-1 agonists where weight loss plateaus. Amgen is conducting Phase III trials.
MariTide simultaneously activates GLP-1 receptors (via two attached peptides) while blocking GIP receptors (via the antibody component). This is the opposite GIP approach from tirzepatide, which activates GIP. Human genetic data support both approaches — GIP receptor loss-of-function variants are associated with lower BMI — but they may work through different metabolic mechanisms. The antibody backbone provides a long half-life enabling monthly dosing.
Phase II results (592 patients, 52 weeks) showed 16-20% weight loss with monthly injections. Body composition analysis showed 26-37% fat mass reduction while limiting lean mass loss to 9-12% — a favourable ratio. The ongoing weight loss trajectory without plateau is particularly interesting and distinguishes MariTide from some GLP-1 drugs where weight loss levels off. Phase III trials (the MARITIME programme) have been initiated, with results expected around 2027. Additional trials are planned for cardiovascular disease, heart failure, and sleep apnoea. The once-monthly dosing is a meaningful convenience advantage, but the large molecule size requires cold-chain distribution. Whether GIP receptor blockade versus activation produces different long-term outcomes is a fundamental question that only head-to-head data against tirzepatide could answer.
Maridebart Cafraglutide Versus Placebo in Adult Participants With Obstructive Sleep Apnea on Positive Airway Pressure Therapy
A Trial to Compare the Extent to Which Maridebart Cafraglutide (AMG 133) is Made Available in the Body When Administered Using Two Subcutaneous Presentations
Maridebart Cafraglutide Versus Placebo in Adult Participants With Obstructive Sleep Apnea Not on Positive Airway Pressure (PAP) Therapy
Comparing the Extent to Which Maridebart Cafraglutide (AMG 133) is Made Available in the Body When Administered Using Two Subcutaneous (SC) Presentations
Evaluating the Impact of Maridebart Cafraglutide on Cardiovascular Outcomes in Participants With Atherosclerotic Cardiovascular Disease and Overweight or Obesity
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Liraglutide is marketed as Victoza for type 2 diabetes (approved 2010) and Saxenda for weight management (approved 2014). The LEADER trial, involving over 9,300 patients followed for nearly four years, established that liraglutide reduced the risk of major cardiovascular events by 13% — a landmark finding that helped establish GLP-1 treatments as a class with heart benefits. Saxenda is also approved for adolescents aged 12 and older. While historically significant, liraglutide has been substantially surpassed by newer agents. In a direct comparison, semaglutide achieved 15.8% weight loss compared to liraglutide's 6.4%. Liraglutide remains relevant as a lower-intensity option and as a benchmark against which newer treatments are measured. It has over a decade of real-world safety data, making it one of the best-understood medications in this class.
Setmelanotide is marketed as Imcivree (Rhythm Pharmaceuticals; approved November 2020 for POMC, PCSK1, or LEPR deficiency; June 2022 for Bardet-Biedl syndrome; December 2024 expanded to patients aged 2 years and older). Genetic testing confirming an eligible mutation is required before treatment. In patients with POMC or PCSK1 deficiency, approximately 80% achieved at least 10% weight loss in clinical trials. In Bardet-Biedl syndrome, 32.3% achieved the same threshold. The most common side effects are injection-site reactions and skin darkening (due to the melanocortin pathway's connection to pigmentation). Setmelanotide exemplifies precision medicine — it is highly effective in the specific genetic populations it targets but is not indicated for common obesity.
HGH Fragment 176-191 has no marketing authorisation. A Phase IIa trial in obesity (approximately 300 patients) failed to demonstrate statistically significant weight loss at any dose tested. The clinical development programme was discontinued. The disconnect between animal data (which showed significant fat reduction in obese mice) and the failed human trial is the defining feature of this compound's development history. Products available through unregulated channels lack pharmaceutical quality assurance. The failed Phase II trial represents the highest level of clinical evidence available.
