Hello, my name is Dr Harold Bays, Medical Director and President of the Louisville Metabolic and Atheroscosis Research Centre located in Louisville, Kentucky. I'm a clinical trialist and I've had the privilege of being an investigator in the MariTide development programme.

Could you tell us about the mechanism of action behind MariTide and the importance behind the study?

Yes, these are really important questions. So we call it AMG 133 but otherwise known as MariTide. It's a combination of a fully monoclonal antibody to the glucose-dependent insulinotropic polypeptide, where you also have attached the glucagon-like peptide-1 receptor agonist.

When we talk about MariTide or maridebart cafraglutide, what we're talking about is the tide, which is the GLP-1 receptor agonist which is the peptide. And then when we talk about the bart, we're talking about that antibody to the GIP.

What was the study design and patient population?

This was a study. It's been published in New England Journal of Medicine. It's a phase two double-blind randomised, placebo-controlled, dose-ranging study. 592 patients with obesity and patients with the type 2 diabetes mellitus.

What were the key findings and how can they be used to identify patients who would benefit most from MariTide?

So I'm going to answer that question, but I want everyone to understand that this is a phase two study, which any of our phase two studies help us in learnings, help us in teachings, help inform how it is we're going to conduct the phase three development programme.

But to answer your question, MariTide at the top dose of four hundred and twenty milligrammes every four weeks among those with obesity who did not have the diabetes, if you look at the placebo-corrected weight reductions, around 17% weight reduction, so robust weight reduction among those patients with obesity who did not have the diabetes mellitus. At the top dose of 420 milligrammes every four weeks among those with obesity and who had the type 2 diabetes mellitus, there was a placebo corrected at around 15% weight reduction.

And the reason that's important is because often we find in our clinical trials that those with the diabetes mellitus often do not respond as well as those who do not have the diabetes. So those with the diabetes often respond less well than those who do not have the diabetes. But here that gap was not as great.

The other thing to know is that among the patients with the type 2 diabetes mellitus, there was a 2.2% reduction in haemoglobin A1C. Less than one third of the weight reduction was lean body mass. A lot of people have an interest in that. What also is very important in this phase two programme and phase two study is the fact that the side effects were frequent and mostly gastrointestinal in nature.

Okay. That said, what I really want to get across is that among many of the patients who participated in this trial, and certainly in the patient population that had the type 2 diabetes mellitus, there was no dose escalation. The patient just got started on whatever dose they were assigned. And you know, it's not typical in these types of drugs and the newer types of obesity management medications. Usually we have dose escalation, but we didn't do that in this case because we didn't know if it was required or not. That's why you do the study.

What are the take-home messages for practice?

The take-home message for medical practise would be we have this investigational product, this investigational obesity management medication. In the phase 2 trial, the efficacy as far as weight reduction looks really good. It's once a month as opposed to once a week or once a day. And among those patients with the diabetes mellitus, it again has robust weight reduction, also robust reduction in haemoglobin A1C.

So that's all great, but I think what's also clinically important is we got to do something about these side effects because that needs to be improved. So I think the take-home message for clinicians would be this: let's see what happens when we advance in the phase three programme and see if a study design can be altered, can be informed by the data that we had with the phase two study.

And let's see if we can come up with a dose escalation strategy that can mitigate some of these side effects that we see with regard to gastrointestinal adverse events. So I think that's the main take-home message.

Efficacy looks really good. Need to do something about the tolerability and hopefully the phase three clinical trials will help guide us as to how that might be improved.

What further research is needed in this area?

Yes, I think the area in need of most research is exactly what I talked about before, which is I don't know that any kind of alternative dosing strategy is going to diminish the potential effectiveness of this once monthly, subcutaneous, injectable, therapeutic agent.

So I don't know if the dose escalation in the phase three trial is going to diminish that. But what I am hopeful is that further research is going to determine if we can come up with a dose escalation strategy so we can mitigate some of these gastrointestinal side effects.