Amgen’s dog in the obesity drug race, MariTide, stimulates weight loss in animals and people without major side effects, new data from the company show. And, unlike its competitors, it may only need to be taken once a month and perhaps not for life.
In a paper published in Nature Metabolism on Feb. 5, Amgen shared preclinical study results showing that a single injection of MariTide reduced weight and improved metabolic markers in obese mice and monkeys. In a similar human study, the company reported that participants in a phase 1 clinical trial also lost weight and kept it off for up to about five months after their last dose.
“In conclusion, the safety and tolerability profiles, the longer half-life of AMG 133 allowed for extended dosing intervals and the magnitude and durability of weight loss support continued evaluation of [MariTide] in a phase 2 setting,” the researchers wrote in the paper. Amgen expects 52-week data from a 592-patient phase 2 trial by late 2024, Executive Vice President of R&D and Chief Scientific Officer Jay Bradner, M.D., said during a Feb. 6 earnings call.
The phase 1 study of MariTide involved 75 obese, non-diabetic subjects who received either a single dose or multiple doses of the drug over the study period. Doses for the single-dose arm received a single dose on the first day of between 21 mg to 840 mg, while participants in the multiple dose arm received 140 mg, 280 mg or 420 mg every 30 days for three months.
The participants in the single dose arm who received the lowest dose lost an average of about 2.4% of their body weight by Day 29 and had gained it back by Day 120. Those who received the highest dose had lost an average of 8.2% at Day 92; this group maintained their loss until the end of the 150-day study period. For comparison, subjects in the placebo group gained 1.7% of their body weight by Day 92.
In the multiple dose arm, participants who received a 140-mg dose of MariTide lost an average of 7.4% of their body weight by Day 78, after three doses had been given. Those in the 420-mg group lost an average of nearly 5% by Day 7 and 14.5% percent by Day 85. Participants in all three dosing groups maintained some degree of weight loss through Day 70, after their last dose, with a retention of as much as 11.2% in the group that received the highest dose.
As for safety, the drug was generally well tolerated by participants, according to the report. As seen with other obesity drugs, gastrointestinal symptoms like mild nausea and vomiting topped the list of side effects. In both the single and multiple dose arms, one patient each who received a 140-mg dose had elevated enzymes associated with pancreatic damage, though these resolved without clinical issues. Four participants in the 420-mg cohort of the multiple dose arm withdrew from the study following the first dose after reporting mild GI side effects, the report said.
The findings in human subjects reflect what Amgen saw in preclinical studies. In experiments on prediabetic, obese mice, animals that were given a single injection of either a low or relatively high dose of a surrogate drug for MariTide lost more than 15% of their body weight at the end of the 18-day study period. They began losing weight within 24 hours and continued losing it throughout the experiment.
Amgen saw similar results in obese monkeys that had received any dose of the drug. They began losing weight within a week after an injection and kept on losing it until Day 43, when they had lost between 11% and 15% of their baseline weight. Though they gained some back during the four-week washout phase following the initial treatment period, they still ended the experiment having lost around 10% of their original weight and with lower cholesterol levels. During the treatment period, when the effects of the initial injection were still active, they also had lower triglycerides and insulin levels.
Like Eli Lilly’s obesity drug Zepbound, MariTide modulates appetite and insulin secretion by targeting the receptors for the hormones GLP-1 and GIP. But, while the drugs are both agonists of the GLP-1 receptor—the target of Novo Nordisk’s hit weight loss drug Wegovy—Zepbound and MariTide differ in how they act on the GIP receptor. Zepbound is a dual agonist of the GLP-1 and GIP receptors, meaning it increases their activity, while MariTide is a monoclonal antibody linked to a pair of peptides that increase GLP-1 receptor activity while tamping down on the receptor for GIP.
These seemingly opposing mechanisms reflect a paradox that has shown up in research on the relationship between GIP and weight, as Duke researcher Jonathan Campbell, Ph.D., describes in a 2020 review. One hypothesis to reconcile the apparent disconnect suggests that agonizing the GIP receptor, as Zepbound does, might ultimately desensitize it and decrease GIP activity overall. Meanwhile, there could be a “compensatory relationship” between GLP-1 and GIP, as Campbell puts it, such that antagonizing GIP increases the activity of GLP-1.
Even if the details are still unclear, the new data validate that both mechanisms are a path to weight loss in the presence of a GLP-1 receptor agonist. It also suggests that MariTide might be better at helping people maintain weight loss than its competitors thanks to a longer half-life, even though it’s given less frequently. Zepbound and Wegovy are both taken weekly.
The Big Pharma expects to gain clarity through the ongoing phase 2, which includes 11 dosing cohorts, especially after tacking on a second part to the study to allow Amgen to assess weight loss durability beyond 52 weeks, Bradner said during yesterday’s Q&A portion of the call.
“And so these phase 2 data, even by end of year, will be strongly instructive as to finding a safe and tolerated and efficacious dose to carry into phase 3 clinical investigation,” Bradner said.
As for further obesity programs beyond MariTide, Amgen currently has one other clinical candidate—an early-stage med dubbed AMG 786—and then additional preclinical assets.