Amgen Inc.’s most anticipated data readout of 2024 was delivered on 26 November, with maridebart cafraglutide (MariTide, formerly AMG 133) generating up to 20% weight loss in obese and overweight individuals who do not have diabetes in a Phase II clinical trial. But while these results are enough to justify taking the GLP-1 agonist/GIP antagonist into a broad Phase III program, the company’s disclosures seem to have left more questions unanswered than were resolved.
Key Takeaways
- Amgen reported up to 20% weight loss with MariTide in Phase II, but the greatest reductions were seen in overweight and obese patients without type 2 diabetes on the second-highest dose tested.
- The company reported only select topline data, primarily for its highest dose, with safety and tolerability results limited to two cohorts that implemented dose titration.
- Analysts had mixed views on MariTide’s competitive profile based on the lack of transparency, but agreed the program should move into Phase III, especially given the chance for Amgen to deliver a GLP-1 agonist delivered once-monthly versus available once-weekly options.
For example, the data that Amgen executive vice president of research and development James Bradner presented showed that the highest level of weight loss achieved in non-diabetic obese and overweight individuals occurred at the 280mg monthly dose, about 20% at 52 weeks. At the highest dose of 420mg, weight loss appears to be around 18%, but that is for four pooled cohorts in which patients received 420mg dosed monthly, every other month, monthly with four weeks of dose titration or monthly with a 12-week titration period.
Bradner said during the company’s same-day analyst call to discuss the MariTide results that efficacy across all four 420mg dose cohorts was similar, including for trial participants who injected the drug every eight weeks instead of once-monthly. He also noted that “dose escalation did not diminish weight loss efficacy” in the two 420mg arms in which trial participants titrated up to their maximum dose.
“Several questions went unanswered as the company withholds some data points for presentation at a future medical conference,” William Blair analyst Matt Phipps said in a 26 November note.
“The decision not to disclose individual 420mg arm efficacy leads investors to assume reduced efficacy when adding escalation or moving to every other month, despite management commentary that the efficacy was comparable across 420 mg arms,” Phipps said.
Among obese and overweight participants with type 2 diabetes – who received only 140mg, 280mg, 420mg of MariTide or placebo once monthly with no dose escalation period to titrate up to the maximum intended dose – efficacy was observed in a dose-dependent manner. The highest weight reduction observed in diabetic patients at 52 weeks was in those who were treated with the 420mg dose, with weight loss of 17%. Average hemoglobin A1C (HbA1c) declined by up to 2.2 percentage points at week 52 in obese and overweight patients with type 2 diabetes.
“This degree of weight loss is a very encouraging result for people with type 2 diabetes, who are typically much more resistant to weight loss interventions, especially treatment administered on a monthly basis,” Bradner said. He noted that bringing forward a once-monthly therapy has been a long-term goal for type 2 diabetes drug development.
Safety Data Limited In Initial Readout
In terms of safety, Amgen reported limited adverse event data and only from the 420mg cohorts in the non-diabetic population where dose escalation was used to titrate patients up to their maximum dose as a means of reducing gastrointestinal side effects in the early days of treatment – a common strategy for GLP-1 agonists, including the two marketed blockbusters, Novo Nordisk’s Wegovy (semaglutide) and Lilly’s Zepbound (tirzepatide).
GI side effects of nausea, vomiting and constipation were the most common adverse events associated with MariTide in the Phase II study, and most of these side effects were mild to moderate and associated with the first dose. Nausea occurred within a six-day window and vomiting occurred within a one- to two-day window in the two dose escalation arms of the study. Discontinuation rates in the dose escalation arms were 11% due to any adverse event and 8% for GI-related events.
Bradner noted that more than 90% of eligible patients from Part 1 of the Phase II trial – individuals with 15% or more weight loss in Part 1 – enrolled in Part 2, which will evaluate MariTide for 52 weeks. Part 2 will assign participants to placebo or MariTide dosed at 70mg, 140mg or 420mg once-monthly or 420mg dosed quarterly, to assess how long weight loss is maintained among patients who switch to placebo, to assess the durability of weight loss beyond 52 months in individuals who stay on MariTide, and to assess various maintenance doses, including quarterly injections.
Data Robust Enough To Move Into Phase III
Despite the murkiness of Amgen’s presentation of the Phase II Part 1 data, MariTide showed that it could deliver double-digit percentage weight loss at 52 weeks with once-monthly and potentially every-other-month injections, which could be an important selling point for consumers who only have access to once-weekly injections with Wegovy and Zepbound. The data also suggest that weight loss observed at 52 weeks may continue beyond the first year of treatment.
“Weight loss remained progressive and did not plateau at any dose, indicating the potential for further weight loss beyond 52 weeks,” Bradner said.
In addition, in both the 465 non-diabetic patients and 127 patients with type 2 diabetes, weight loss across all dose levels of MariTide led to improvements in multiple cardiovascular measures, including blood pressure, triglycerides, LDL cholesterol and high-sensitivity C-reactive protein.
“Based on these data, we believe MariTide has a unique, differentiated and competitive profile, which we will explore in Phase III development,” CEO Robert Bradway told the company’s call.
Amgen is planning a broad Phase III clinical trial program, starting with the MARITIME trials in obesity but with the intention of also testing MariTide in type 2 diabetes, kidney disease, cardiovascular disease, obstructive sleep apnea, heart failure and potentially other indications. A Phase II trial is under way in type 2 diabetes with results anticipated next year. The company also is completing a Phase I study to assess various dose escalation regimens to inform titration plans for the Phase III program.
Amgen did not disclose what dose or doses and what duration of titration period it will assess in Phase III, but said it is discussing its Phase III trial designs with regulators with plans to start its MARITIME studies in obesity as soon as possible next year. Bradner did confirm, however, that some period of dose titration will be implemented in the pivotal program.
Investors Respond To Lack Of Transparency
Without further clarity on the Phase III MARITIME trial designs and given the lack of transparency about how each dosing cohort performed on efficacy and safety, Amgen closed down 4.8% at $280.01 per share on 26 November, recovering some losses from earlier in the day when the stock fell by as much as 12.5%. Analysts noted that up to 20% weight loss was a strong result, but perhaps not as high as investors were hoping to see in the Phase II MariTide results.
Mizuho Securities analyst Salim Syed said in a same-day note that the weight loss reported in the Phase II study came in “on the low end of expectations” but in line with other incretin therapies.
“Investors were looking for a minimum 20% weight loss at the highest dose since Zepbound crosses this bar and also newer injectable treatments such as [Novo’s Phase III] CagriSema and [Lilly’s Phase III] retatrutide are expected to be at 25% or higher weight loss,” Wells Fargo analyst Mohit Bansal said in a 26 November note. “However, it seems AMGN’s topline number includes ‘efficacy estimand,’ which is likely not including discontinued patients and non-per-protocol patients. This could potentially mean <20% weight loss among [intention to treat (ITT)] patients.”
Bansal noted that the 11% discontinuation rate and 8% GI-related discontinuation for MariTide in the Phase II 420mg cohorts with dose titration is higher than the 7% discontinuation rate and 4.3% GI-related discontinuation rate seen in Phase III trials for Lilly’s Zepbound. However, he said, the 2.2% HbA1c reduction in patients with type 2 diabetes and the effects on cardiovascular metrics in non-diabetic and diabetic patients appear to be competitive with other GLP-1 agonists.
Bernstein analyst Courtney Breen said in a 26 November note that weight loss of up to 20% for MariTide in Phase II was in line with physician goals for obese and overweight patients, but added that, “for the given weight loss, the discontinuation rate for MariTide is … slightly higher than we would have hoped, albeit a substantial improvement on the Phase Ib data.”
Even so, Breen said, “we like the commercial potential for MariTide based on this data, this provides another GLP-1 option for a very large very heterogeneous obesity and diabetes population. Monthly dosing and ongoing weight loss (beyond 52 weeks) may help to extend the duration of therapy for patients over the long term.”
Despite questions about how each dose level of MariTide performed in the Phase II trial, William Blair’s Phipps agreed that the drug is differentiated, but primarily due to its once-monthly dosing.
Amgen Insists Efficacy, Tolerability Are Differentiated
Susan Sweeney, Amgen’s executive vice president for obesity and related conditions, told the call that MariTide is differentiated from other GLP-1 agonists for obesity, which she described as “a large and underserved market in need of multiple options for patients.”
The up to 20% average weight loss at 52 weeks without hitting a weight loss plateau means MariTide has the potential to deliver even greater weight loss over time and do so with the convenience of monthly or less frequent dosing, Sweeney noted.
“And importantly, for patients with type 2 diabetes, MariTide has the potential for the first and only monthly treatment with up to 17% average weight loss at 52 weeks, again without a plateau and a reduction in average HbA1c up to 2.2 percentage points. This is meaningful for patients living with obesity and type 2 diabetes,” she said, adding that the “substantial improvement across cardiometabolic parameters” is critical for obese and overweight patients.
Bradway indicated that Amgen believes its safety and tolerability profile is differentiated from its competitors, because “patients enter the study, may experience some side effects on the first dose, and then may go another 51 weeks without any events of nausea and vomiting.”
“This is different from what patients report from other medicines in the field and, perhaps, one of the reasons why we saw 90-plus percent of the people who were eligible to roll into another 52 weeks on the study agreed to do that” in Part 2 of the Phase II trial, the CEO added.
Sweeney noted that “other things that I think will contribute favorably around safety with the dose escalation is it’s a rapid path to target dose. Some of the medicines right now in this segment are 20 to 24 injections until you get to target dose. It can take six months to titrate. Here we have dose escalation schemes that are two injections and at one month you’re at target dose.”