Amgen Inc. (AMGN) Earnings Call Transcript & Summary

My name is Julianne, and I will be your conference facilitator today for Amgen's Conference Call to Discuss MariTide Top Line Phase II Results and Progress on Development Program. [Operator Instructions] I would now like to introduce Justin Claeys, Vice President of Investor Relations. Mr. Claeys, you may now begin.

Thank you, Julianne. Good morning, everyone, and welcome to our call to Discuss the MariTide Phase II Top Line Results and Progress on its Development Program. Bob Bradway will lead the call and be joined by members of the management team for the discussion and Q&A session. Press release has already been made available, and we will use slides as part of the webcast call. Those slides will be posted to our website at the conclusion of our prepared remarks. We will make some forward-looking statements, which are qualified by our safe harbor statement. And please note that actual results can vary materially. Over to you, Bob.

Okay. Thank you, Justin, and let me welcome all of you to our call, and we're excited to share top line data from our MariTide Phase II study. These data underscore our confidence in MariTide's differentiated profile and the potential benefits this product can offer to patients. In a moment, our Head of Research and Development, Jay Bradner, will share details from the study. And as you will see from the considerable material that he'll review, there are some important takeaways. First, we saw robust weight loss with MariTide at 52 weeks without a weight loss plateau, indicating the potential for further weight loss. Second, we've confirmed MariTide's robust weight loss can be delivered with monthly or less-frequent dosing. Third, in terms of tolerability, a low percentage of patients in the trial discontinued treatment for any reason. Based on these data, we believe MariTide has a unique, differentiated and competitive profile, which we will explore in Phase III development. Later in the presentation, Susan Sweeney, our Executive Vice President of Obesity and Obesity-related Conditions, will provide an update on our broad Phase III plans. Looking ahead, you've heard me say many times that Amgen's manufacturing is a source of competitive advantage, and we look forward to drawing on this capability to serve patients with MariTide. Now let me turn it over to Jay to take you through the Phase II data. Jay?

Thank you, Bob. This is an exciting day for Amgen R&D and Amgen operations. We're delighted to share the results of the MariTide Phase II chronic weight management study as well as new data from a dose-informing Phase I study of MariTide also for patients with obesity. We remain fully confident that MariTide's differentiated profile can contribute meaningfully to addressing the epidemic of obesity, the burden of type 2 diabetes and other serious obesity-related conditions. As shown in the macromolecular space-fill structure in the upper left-hand corner of this slide, MariTide is a very unique molecule designed with the benefit of human genetic insights and expertise from the highly experienced Amgen research team. MariTide is a first-of-its-kind peptide antibody conjugate, which we developed specifically for patients with obesity. It is both a GLP-1 receptor agonist and a GIP receptor antagonist. MariTide has 3 unique design attributes worth emphasizing. First, MariTide is long-lasting. MariTide has a monoclonal antibody backbone targeting the GIP receptor, confirming a long half-life with sustained and predictable exposure. Second, MariTide is intrinsically potently synergistic. Two GLP-1 receptor activating peptides are physically attached to the antibody backbone. The 4 functional arms of MariTide work together to provide a synergistic therapeutic effect. Third, MariTide inhibits the GIP receptor. Human genetics has shown that variants of the GIP receptor with less activity protect against obesity and some related diseases. So we developed a GIP receptor inhibitor. MariTide's unique characteristics provide the potential for improved efficacy, a predictable, consistent pharmacological profile and monthly or less-frequent dosing. MariTide's synergistic molecular design requires only a fraction of the peptide supply with fewer injections and fewer devices versus weekly injectable alternatives. We're delighted to share the 52-week results of our Phase II study of MariTide in chronic weight management. In this double-blind, placebo-controlled randomized Phase II clinical trial, we measured the impact of MariTide on weight loss in people living with obesity or overweight with and without type 2 diabetes. We concurrently enrolled patients with diabetes to a separate cohort as patients with diabetes are known to respond less favorably to incretin-based therapies. This study of 592 adult patients is comprehensive with 11 arms that assess a range of doses, monthly or less-frequent dosing and 2 rapid dose-escalation arms. This study was well controlled, and we are pleased with the overall conduct. Today, we will focus on the top line 52-week data that has informed our Phase III design. First, we will share the top line results arising from the treatment cohort that included people living with obesity or overweight without type 2 diabetes. This cohort enrolled 465 adult patients across 7 total arms, 6 treatment arms and a placebo arm. As seen on the slide, 3 arms studied doses of 140, 280 and 420 milligrams administered monthly by subcutaneous injection and without dose escalation to target dose. We also studied a dose of 420 milligrams administered every other month to explore the possibility of even less frequent MariTide dosing. To explore the effect of dose escalation on tolerability and efficacy, the last 2 arms of this cohort evaluated lower starting doses of 70 milligrams escalated to monthly target doses. With that 4 weeks or 12 weeks of escalation in the target dose, MariTide dose escalation allowed patients to quickly arrive at therapeutic target doses. In terms of baseline characteristics, we enrolled 63% female patients, 67% white and 22% Asian and 7% black patients. Across the study, participants had a mean weight at baseline of 107 kilograms, mean waist circumference of 115 centimeters and mean body mass index of 38 kilograms per meter squared. Starting with weight loss. On this slide, we present the 52-week dose-ranging activity of MariTide on body weight in patients with obesity or overweight without type 2 diabetes. As you can see from the graph, all doses were highly active with MariTide demonstrating up to approximately 20% average weight loss at 52 weeks. Importantly, weight loss remained progressive and did not plateau at any dose, indicating the potential for further weight loss beyond 52 weeks. For clarity, in comparing target doses, this figure shows pooled data from all of the 420-milligram dose arms. Though not shown here, it is notable dose escalation did not diminish weight loss efficacy at 52 weeks. Further, patients receiving MariTide every other month experienced comparable weight loss to those receiving 420 milligrams monthly. Across all MariTide dose arms, we observed that approximately 98% of patients lost a clinically meaningful 5% or more of their body weight. In summary, with monthly or less-frequent dosing, MariTide produced up to approximately 20% weight loss at 52 weeks without a plateau and benefited almost every patient on the trial. Beyond weight loss, MariTide delivered robust and clinically meaningful improvements in cardiometabolic parameters. The measurements displayed in this table are clinical risk factors for serious obesity-related conditions. The uniform improvement in these parameters is a strong indicator of MariTide's potential to improve outcomes even more broadly than chronic weight management. With pooled results across the 420-milligram dose arms compared to placebo control, we see clinically meaningful and statistically significant reductions from baseline in systolic blood pressure of 11 millimeters of mercury, in LDL-C of 5% and, in triglycerides, reduction of 19%. We also observed a statistically significant reduction of 53% from baseline in hs-CRP, a serum measurement of inflammation associated with inflammatory and cardiovascular conditions. Lastly, though not shown on the slide, there were no significant increases in free fatty acids with MariTide treatment versus placebo at 52 weeks. Taken together, the reduction of these cardiometabolic disease risk factors contributes favorably to the differentiated profile of MariTide. We will now present data in the cohort of patients living with obesity or overweight and type 2 diabetes, where MariTide's effect was impressive, both with respect to weight loss and reduction of hemoglobin A1c. Taking a look at this cohort, the study enrolled and randomized 127 adult patients to 3 treatment arms and a controlled placebo arm. Here, we studied 3 doses of 140, 280 and 420 milligrams, each administered monthly by subcutaneous injection and without dose escalation to target dose. Regarding baseline characteristics, this cohort enrolled 42% female patients, 68% white, 24% Asian and 7% black patients. Across the study, participants had a mean weight at baseline of 104 kilograms, mean waist circumference of 117 centimeters and mean body mass index of 36 kilograms per meter squared. All patients enrolled to this cohort were living with diabetes, and the baseline mean hemoglobin A1c was 7.9%. On this slide, we present the effect of MariTide on weight loss for patients with obesity and overweight and type 2 diabetes. As shown, MariTide delivered up to an approximately 17% average weight loss at 52 weeks. Substantial weight loss was observed across all dose arms. Again, weight loss remained progressive and did not plateau at any dose, indicating the potential for further weight loss beyond 52 weeks. 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. Importantly, we observed a greater magnitude of weight loss with the highest MariTide dose of 420 milligrams. Additionally, patients receiving MariTide in this cohort reduced their waist circumference by up to approximately 17 centimeters or about 6 inches at week 52 compared to baseline. Across all MariTide dose arms, approximately 99% of patients lost a clinically meaningful 5% or more of their body weight. Together with the weight loss data in the nondiabetic population, these results establish a foundation for a compelling Phase III program. Turning now to glycemic control. MariTide conferred a rapid, deep and sustained reduction in hemoglobin A1c in all dose arms with an impressive absolute reduction from baseline of 2.2 percentage points in the 420-milligram monthly dosing arm. Additionally, 50% of patients receiving this dose were restored to the normal range or hemoglobin A1c of less than 5.7%. Beyond the significant improvement in hemoglobin A1c, the effect of MariTide on cardiovascular risk factors was also compelling. We see clinically meaningful and statistically significant reductions in systolic blood pressure of 11 millimeters of mercury and in triglycerides with a reduction of 28% from baseline. We also observed a profound and statistically significant reduction of 72% from baseline in hs-CRP. Eliciting such significant reductions in body mass and hemoglobin A1c in patients with obesity and type 2 diabetes, MariTide has the potential to become a monthly type 2 diabetes therapy. A monthly therapy has been a long-standing goal in the field of diabetes drug development. The dedicated Phase II study of MariTide in patients with type 2 diabetes with and without obesity is currently open and enrolling. The Phase II trial has confirmed MariTide's differentiated profile as a highly efficacious treatment for obesity and overweight. We will now share top line insights into the safety and tolerability of MariTide and, in particular, the favorable contribution of dose escalation. In the Phase II study, all arms were successfully completed, the large majority of patients finished the trial and over 90% of eligible patients chose to continue on study for another year, an encouraging measure of persistency on MariTide. There were no new safety signals identified through 52 weeks in the Phase II study. We would like to specifically highlight that there were no changes in bone mineral density observed with MariTide treatment compared to placebo at 52 weeks. Additionally, changes in heart rate remained within the normal range and were consistent with approved therapies in this category. Consistent with studies of medicines that feature GLP-1 receptor agonism, the most common adverse events were GI-related, including nausea, vomiting and constipation. In the Phase II study, these events were predominantly mild to moderate and transient, and nausea and vomiting were primarily associated only with the first dose. Today, from here forward, we will focus on data from the 2 dose-escalation arms as we intend to utilize dose escalation across our broad Phase III program. Dose escalation of MariTide significantly improved the patient experience with improved GI tolerability compared to all other dose arms. Dose escalation was employed in 2 arms over 4- or 12-week periods, each with an initial dose of 70 milligrams. In the dose-escalation arms, the discontinuation rate due to GI events was less than 8% and discontinuation due to any adverse event was only 11%. The incidence of nausea and vomiting in these arms of the Phase II was roughly 70% and 40%, respectively, and these events were predominantly mild. It is also notable that MariTide's long half-life confers durable efficacy without prolonged side effects as the events of nausea and vomiting were predominantly mild and largely associated with the first dose, episodic and generally resolved within a median window of 6 days and 1 to 2 days, respectively. Importantly, repeat dosing after 1 month with target doses of MariTide was extremely well tolerated through the remainder of the 52-week study period. To illustrate the mild nature and early incidence of nausea and vomiting, here we graph the incidence of new nausea and vomiting events over time for each of the 2 dose-escalation arms. Each bar on the graph represents the number of new events that occur within the week shown. Nausea and vomiting data for the 4-week dose-escalation arm are on the left, and nausea and vomiting data for the 12-week dose-escalation arm are on the right. These analyses make clear that once patients are tolerized by a first dose of 70 milligrams of MariTide, further treatment at much higher target doses throughout the 52-week period is extremely well tolerated. Further, the predominantly green color of the bars reflects the predominantly mild nature of GI symptoms. These data demonstrate that rapid dose escalation in as few as 4 weeks with MariTide works and that a lower starting dose improves tolerability. In parallel to the Phase II chronic weight management study, we're conducting a Phase I pharmacokinetic study of alternative dose-escalation schedules, featuring even lower initial doses. This study rapidly enrolled 121 adult patients living with obesity or overweight without type 2 diabetes. As shown in the schema on Slide 23, patients were randomized to 1 of 3 dose-escalation schedules. Akin to the Phase II study, one arm evaluates 70 milligrams on days 1 and 15, followed by a target dose on day 29. The other 2 arms evaluate lower first doses of 21 or 35 milligrams, respectively. Both are then followed by a second dose of 70 milligrams on day 15 and then the target dose on day 29. A planned preliminary analysis of the ongoing study at day 43 replicated the Phase II tolerability experience observed with the 70-milligram starting dose. Day 43 is relevant because by that point, all patients have completed dose escalation and have arrived at the target dose. Notably, in the 2 arms that featured lower initial doses, we saw markedly improved tolerability, in particular, GI symptoms of nausea and vomiting. Dose escalation from lower starting doses of MariTide significantly reduced the incidence of nausea to under 50% and vomiting to under 20% at day 43. As before, GI symptoms were predominantly mild and transient. Dose escalation of MariTide contributes meaningfully to its unique and differentiated profile and provides conviction as we rapidly advance into the Phase III program, which will incorporate these findings. Returning to the Phase II study. The second part of the study, which evaluates MariTide treatment beyond 52 weeks is ongoing and progressing well. Patients who received greater than 15% body weight reduction in Part 1 were eligible to continue on for Part 2. Part 2 is a 52-week, double-blind, placebo-controlled randomized substudy. Indicative of MariTide's favorable patient experience and compelling weight loss, we're pleased to report that greater than 90% of eligible patients chose to continue into Part 2 of the study, again, a pretty remarkable sign of the MariTide persistency. As shown in the schema, patients were rerandomized to active treatment or placebo-controlled based on the dose received during Part 1. Part 2 has a unique design that explores 3 opportunities for MariTide. First, progressive weight loss beyond 52 weeks with monthly dosing of 70, 140 and 420 milligrams. Second, durable weight loss after MariTide withdrawal among those patients randomized into placebo-treated groups. And third, based on the significant and progressive weight loss observed with every-other-month dosing in Part 1 of the study, we're investigating a quarterly maintenance regimen in Part 2. Part 2 of the study is ongoing, and we will share results when available. Importantly, Part 2 is not a gating item for Phase III, but will provide important additional insights into MariTide's profile. In summary, MariTide's unique characteristics highlight a differentiated and compelling profile. MariTide demonstrated up to 20% average weight loss at 52 weeks. Importantly, weight loss did not plateau at any dose, indicating a potential for further weight loss beyond 52 weeks, which we're studying in Part 2. We have confirmed that MariTide will be delivered with monthly or less-frequent dosing, which offers an important benefit for patients. MariTide demonstrated compelling potential for patients with type 2 diabetes, delivering up to an approximately 17% average weight loss at 52 weeks. MariTide also conferred rapid, deep and sustained reduction in hemoglobin A1c in all dose arms with an impressive absolute reduction of 2.2 percentage points from baseline in the 420-milligram arm. MariTide has the potential to be the first monthly therapy for type 2 diabetes, a long-standing goal of the field. MariTide's substantial impact on cardiovascular risk factors was also compelling. The uniform improvement in these parameters is a strong indicator of MariTide's potential to improve outcomes beyond the potent effect on weight loss. MariTide is well tolerated. Over 52 weeks in the Phase II study, we had low discontinuation rates, in particular, within the dose-escalation arms where less than 8% of subjects withdrew due to GI events. We have learned that dose escalation with MariTide works without compromising efficacy. Lower starting doses substantially improved GI tolerability with rates of subject incident nausea under 50% and vomiting under 20% in a dedicated Phase I dose-escalation trial assessing lower first doses. As a doctor, I'm admittedly excited about MariTide's profile and the potential it has for patients. I would like to thank the patients and the investigators participating in our MariTide clinical program and my many Amgen colleagues around the world for their dedication to advancing this important treatment. I will now turn it over to Susan, who will discuss our Phase III plans.

Thank you, Jay. I appreciate all the work the Amgen R&D organization has done to develop MariTide, an important breakthrough. Having spent much of my career working on treatments for patients with cardiovascular and metabolic conditions, I can tell you firsthand, bringing MariTide to market is something I am passionate about and so proud to lead our integrated obesity team here at Amgen. Obesity remains a large and underserved market in need of multiple options for patients. Jay, as you said, MariTide is unique and differentiated. First, on efficacy, which is what patients are looking for, we've now seen up to approximately 20% average weight loss at 52 weeks without hitting a weight loss plateau. This means there is potential for even greater weight loss over time. Second, the convenience of monthly or even less-frequent dosing. In Part 1 of the Phase II trial, there was an every-other-month dosing arm showing comparable efficacy to those receiving treatment monthly, and we have a once-quarterly dosing arm in Part 2 of the Phase II trial. This will provide more information on MariTide's durability. 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. Notably, in the trial, there were very low GI-related discontinuation rates, less than 8%. And finally, substantial improvements across cardiometabolic parameters, which we know are critical for this patient population. So let's look ahead to what's next. I am excited to announce the launch of the MARITIME clinical development program, which is aimed at addressing obesity and its related conditions. The MARITIME patient website is now live and the link to it is in the press release. MariTide's unique features could greatly help people not only living with obesity, but other serious diseases. The MARITIME clinical program will focus on key areas where obesity imposes a major burden, including cardiovascular health, metabolic function and organ performance with the potential to expand into additional indications over time. Amgen's expertise in cardiovascular, metabolic and kidney disease, including our deep understanding of patient needs, uniquely positions Amgen to tackle the challenges of obesity-related conditions. Beyond MariTide, we're focused on expanding our obesity portfolio, where we are investigating both incretin and non-incretin-based mechanisms to address obesity and related diseases. MariTide truly exemplifies Amgen's commitment to innovation and serves as a foundation for our broader efforts to advance effective therapies. Now turning to supply. At Amgen, our manufacturing team's motto is supplying every patient every time. MariTide will be delivered as a single dose in a convenient, handheld, patient-friendly auto-injector device. This will be a monthly or less-frequent single injection administration. On supply readiness, MariTide fits well into our existing manufacturing network. MariTide's monoclonal antibody backbone is tailored for manufacturing on our standard platform. This allows us to efficiently produce MariTide using established facilities and processes. As additional capacity is needed, our facilities are designed for rapid scaling, and we are already advancing process development innovations to support this. Delivery of MariTide with its monthly or less-frequent dosing schedule and synergistic design that Jay spoke about earlier requires only a fraction of the peptide supply with fewer injections and fewer devices versus weekly alternatives, which is another differentiator for MariTide. With that, I'd like to hand it over to Bob for Q&A.

Okay. Can we open up the microphones for questions, and please remind our callers of the process for getting their questions asked.

[Operator Instructions] Our first question comes from Michael Yee from Jefferies.

Maybe I would just ask about where you see the 2 key areas of significant differentiation. I feel the market may view this as in-line efficacy, but with higher tolerability and side effects. So do you feel this is a drug that is significantly more convenient on every-other-month dosing and quarterly and also the titration totally brings the adverse event profile down? Maybe just talk about where you see the differentiation.

Yes. Why don't we just reiterate some of the clinical features that we've demonstrated in Phase II and then Susan can address the implications of that for patients and prescribers?

Yes. Thank you, Mike. This is Jay. We see a quite differentiated profile really across all [Audio Gap] of efficacy, tolerability, dosing and patient experience. To remind and to answer your question, with respect to efficacy on weight loss, all arms active, nearly every patient benefited, approximately 20% without type 2 diabetes and 17% weight loss with type 2 diabetes is strong data at 52 weeks. Not seeing a plateau on these curves suggests that there could be additional weight loss into Part 2 beyond 52 weeks and, of course, corroborating all of this is waist circumference. The cardiometabolic parameters changes are significant, LDL-C, hs-CRP. These read through to benefits beyond weight loss in serious cardiovascular diseases. And diabetes data with hemoglobin A1c of 2.2%, absolute reduction in hemoglobin A1c is very strong. And again, 17% weight loss in this population is very impressive. On tolerability, I think the differentiation with infrequent, mild, transient GI symptoms of nausea and vomiting that are principally associated with just first dosing, that improved so substantially with dose escalation, that improved further still with lower doses, and now we established with these data that dose escalation works for MariTide, even lower in the Phase I with less than 20% vomiting. Persistency is a real challenge in this class, as you know. And I think MariTide, a great sign of persistency here are the patients from Phase -- from Part 1 of the Phase II who were eligible to continue on for another year of MariTide and 90% chose to participate. Around dosing, as you mentioned, it is true. It's a simple, rapid dose escalation in as few as 4 weeks, monthly or less-frequent dosing. I mean as a doctor, I've yet to meet the patient that prefers more injections, but it also means fewer devices. It means less peptide. There's a lot to love about monthly or less-frequent dosing. In sum, I think it's a great patient experience and shaping up to be a very strong physician experience. And Susan, I'd ask you to add anything from your perspective.

Yes. I think the -- thanks, Jay. I think that now seeing approximately 20% average weight loss at 52 weeks, we didn't see a weight loss plateau there, so there is a potential for even greater weight loss over time. The other 2 pieces, Jay, that you talked about that I think are important is the administration of monthly goes beyond convenience. Certainly, it's more convenient to have a monthly injection rather than having a weekly injection, 52 injections over the time period. But also, in the data that we're seeing, in the dosing arm which we saw every other week, it could potentially be that patients have less dosing and also exploring in the Part 2 of the Phase II trial of looking at 2 12-weekly. We know that getting to weight loss is important, but also being able to maintain and keep your weight loss is just as important.

Yes. I think, Susan, it may be worth having Jay just remind of the data around durability. And Jay, to the extent you're comfortable sharing anything from the Phase II that gives us further confidence in durability, let's address that.

Yes. Thanks, Bob. This is an important point. Mike, you'll recall, we had a very interesting signal in the Phase I study, where after 3 doses, we stopped administering MariTide as intended. And for 150 days further, many patients retained the benefit of weight loss that they enjoyed from the medicine. And we've followed this finding up now in 2 ways in Part 1 of the study with 2 8-week dosing. And as I remarked, every 8-week dosing produced as much weight loss as every 4-week dosing. That's quite a contribution. But as we move into Part 2 of the study, exploring quarterly dosing, as Susan described, we'll also have a chance to see the durable effect of the year of MariTide in these placebo-treated patients. And so we're very much looking forward to sharing Part 2 of the Phase II study when the data are in hand.

And Mike, as you know, that's not a feature of the approved weeklies as one of the competitors describes it as the yo-yo effect. And that's not what we see, at least in the data that we've discussed so far with our product. We go to the next question.

Yes. And just real quick before we do that, just one small clarification. I think we might have said every other week, and that was every other month that we were talking to, of course. Sorry, every other month.

Our next question comes from Terence Flynn from Morgan Stanley.

Two-part for me. I was just wondering if you can tell us what the weight loss was in the dose-escalation cohorts. I know you gave it to us for the monthly -- the 3 monthly cohorts. But in the obesity study, just wondering what the weight loss was in the dose-escalation cohorts. And then the second question is just -- can you tell us what the go-forward dose and schedule is going to be for the Phase III obesity program?

Thank you very much, Terence. By the dose-escalation cohorts, I assume you're referring to the Phase I study, and we have...

On the Phase II.

Oh, on the Phase II?

Yes. I think he was asking within -- with diabetes. Sorry, repeat the question, Terence. We're a little...

It was -- I think there were -- you had 2 dose-escalation cohorts in the Phase II study, the obesity study. And it looks like on the weight loss curves, you gave us the 3 dosing cohorts for monthly dosing, but I don't think you disclosed the dosing escalation cohorts, like the 2 other arms. I saw 3 arms, but I didn't see the 2 other arms on that curve. And then the second question related to the go-forward dosing schedule for Phase III.

Yes. Sorry, Terence. I do understand your question now. That is right. We presented pooled data for the 420-milligram monthly dosing arms and 2 of those arms are dose-escalation arms with MariTide. Largely, the arms behaved comparably to each other with 420 milligrams, whether it was given monthly or every 8 weeks.

And with respect to dosing escalation, Terence, as we said earlier, we did not see any difference in efficacy. And then with respect to Phase III program going forward, go ahead.

Yes. So we really have all guidance needed for the Phase III firmly in hand. Dose escalation with lower starting doses will be employed. And we're currently in discussions with regulators to rapidly advance into Phase III, and so there will be more to follow.

Our next question comes from Umer Raffat from Evercore.

I just wanted to spend a quick second on the dose response or lack thereof between your diabetes and the obesity cohorts. So specifically, when I look at the obesity cohort, obviously, it looks like 280 looks like the best dose. But then on the diabetes side, 280 looks just like 140, but 420 looks a lot better. So just wanted to understand that dynamic. But also ask is there a -- because I realize 420 is shown on a pooled basis. Is there a subset of the 420, which looked a lot better than the 18% peak weight loss? And my follow-up also is -- I noticed the stats methodology you guys used was the efficacy estimand. How did these weight loss? what a peak 20% weight loss look on the treatment policy estimand?

Thanks, Umer, for the questions. So all arms were active, as I shared. These are Phase II data, and you're used to looking at Phase II data. We have many more 420-milligram arms than we do 280-milligram arms, and I would not read anything into the appearance of the data for 280 versus 420. We look at these data and see all 3 doses as quite active. Now in the type 2 diabetes cohort, we are struck by the improved performance of 420 milligrams versus 280 milligrams in that more treatment-resistant population and take some of this guidance into Phase III clinical investigation. You asked about the efficacy estimand. As is commonplace in this field, we report these efficacy numbers today with the efficacy estimand. And we will share more thorough data in a poster -- in a public presentation in the new year.

Our next question comes from Salveen Richter from Goldman Sachs.

Just given you have continued weight loss post 52 weeks and you're investigating more dose-escalation arms, can you help us understand how this informs the go-forward for Phase III with regard to the Phase III doses and the starting dose as well as the length of follow-up here as you look to kind of understand the plateau here on weight loss and maybe that time frame to kind of understand over when that occurs?

Yes. Well, thanks for the question. It is striking that the weight loss curves for all 3 doses in the patients with obesity or overweight without type 2 diabetes continue to decline right up to the 52-week data endpoint of Part 1 of the study. And so we're quite looking forward to the data from Part 2 to understand just how much benefit MariTide can contribute. We do not need to wait for these data. This is not gating to enter into Phase III clinical investigation. As I shared, we are in discussions with regulators to rapidly advance into Phase III. But we know that monthly or less-frequent dosing can work. We intend to invoke dose escalation with lower starting doses in the Phase III. And as you point out, regarding the date or time on study, we have the luxury -- a lot of choices there with substantial weight loss at 52 weeks that looks from the shape of the curves with and without diabetes to be continuing through week 52. And so more to follow there.

Our next question comes from Chris Schott from JPMorgan.

Can you just elaborate on the duration of the GI events here? I think the press release mentioned 6 days for nausea, 1 to 2 days for vomiting. I guess do you expect that duration could change at all with the lower titration doses that you may be exploring in the Phase III based on some of that Phase I data you have?

Yes. Thanks, Chris, for the question. It's important to note that the GI events observed with MariTide to date are quite mild. They're quite transient, and that's really what you're getting at with the question around duration. And that they're primarily associated with the first dose, that after the first dose, patients are on study for 51 weeks and have really sparing experience of nausea and vomiting. And so thinking then about the duration of when nausea and vomiting is observed, there's a reliable window within 6 days with upfront dosing of 70 milligrams as seen on the Phase II where these symptoms were reported in the subset of patients that did experience those symptoms. That is for nausea. For vomiting, it's a window of about 1 to 2 days. This does not mean that patients were nauseous for 6 days or that they were vomiting for 1 to 2 days. Those are the windows during which these symptoms were reported, again, quite mild, quite transient, primarily associated with the first dose. The data collected on the Phase I were again at day 43, which is quite informative, given the pattern of upfront nausea and vomiting experience, is quite reassuring. There'll be more to say about the durability in the fullness of time, but also looking extremely transient with lower doses.

And Chris, I might just elaborate there because there were a fair amount of questions leading into the Phase II study about whether a long-acting agent like this might travel with long-acting side effects, and of course, that is not what the data show. What the data show is the long-acting efficacy and short duration side effect profile. Furthermore, there was a question whether those side effect profiles would be reintroduced with subsequent injections, and again, that is not what the data show. The data show, as Jay said, that patients enter the study may experience some side effects in the first dose and then may go another 51 weeks without any events of nausea and vomiting. So 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 in the study agreed to do that and part of what gives us confidence as well about a different tolerability profile for this medicine versus the weeklies and the potential benefit of persistency as a result. But again, the good news is that also paves the way for the efficacy that we're seeing. And again, the fact that people continue to get benefit after 52 weeks or seem to be getting benefit after 52 weeks and are taking a medicine that they're prepared to stay on is an important finding for us.

Our next question comes from Yaron Werber from TD Cowen.

Great. So I have a 2-part question. And maybe the first one, just to follow up, Jay, on Terence's question. So can you give us what the weight loss was in the Phase I PK studies on those 121 patients? And then secondly, we're getting a lot of questions. I'm just -- if you can clarify the dropouts of 11%, that's not an average, right? That's the highest dropout that we've seen is 11% and less than 8%. And is it dose proportional?

Yes. Thank you, Yaron. Appreciate the question. The data from the Phase I are, to remind, just 43 days on treatment, but I can say that the efficacy is in line with our expectations based on the Phase II. The dropout rate of 11% is the discontinuation of the investigational product for the pooled data between the dose-escalation arms, and 8% of this absolute number relates to GI events. Yaron, one more thing that occurs to me is as we contextualize the dropout rate, it is a very well-conducted study, and we did not have challenge with dropout really throughout the whole of the study. And notably, the highest discontinuation of investigational product was on placebo, which is always a good sign.

Our next question comes from Gregory Renza from RBC Capital Markets.

Great. Maybe for Jay. Just in light of the data and the patient population, just curious if you can comment about what you think this means about that GIPR antagonism and how potentially that may read through to Amgen's desire to maybe broaden the portfolio across this mechanism? And then just lastly, on the MariTide development program and as you look at other potential indications, just curious if you could help us maybe prioritize how you're viewing those additional indications that you've laid out today as prospects for the broad program.

Thanks, Gregory. Susan, why don't I take GIPR antagonism and invite you to reflect on the priority of indications. So as I started at the top of the presentation, MariTide is a unique molecule because it's built for synergy. I mean there's a very strong genetic basis to select inhibition of GIPR where experiments of nature, human variation of the GIPR gene have taught us that humans born with less active GIP receptors are more protected from obesity as well as some of the serious cardiovascular diseases that associate with obesity. And where available, genetic evidence is very strong evidence. And so on efficacy, we're thrilled with the selection of GIP receptor inhibition as well with tolerability. MariTide is built for synergy. We have conducted and we have published the results of very thorough preclinical data that look at what it means to activate the GLP-1 receptor and the GIP receptor using separate therapeutic entities, and it's quite additive. But when positioning the GLP-1 peptides at a very specific location on the GIP receptor antagonist antibody, we realized significant synergy at the cell and at the tissue and at the organismal level. Well, now we're in the clinic. And so it is impossible with a medicine built with both functions to ascribe the benefits of efficacy and the excellent tolerability to one function or the other. But together, we're observing synergistic benefit with the molecules, delivering both GIP receptor inhibition and GLP-1 agonism. And now with this dose-escalation data, excellent tolerability. Susan, what are your thoughts around the priority indications?

Yes. So we're excited about the potential other indications. And as we've stated, we're currently in our Phase II trial for type 2 diabetes and are progressing quickly on all of the indications indicated on the MARITIME slide and in discussion with regulators on some of them. One thing that I -- to point out is that we were very encouraged by the cardiometabolic parameters that we saw in the Phase II trial, that'll convey benefit to patients with these obesity-related conditions. And the other one is -- to note is in these conditions, in many cases, monthly or less-frequent options are not available in those diseases. And so we're also excited about the differentiation that can provide for patients that have obesity and disease-related conditions. Lastly, I'll say is that we're exploring other studies beyond what we have noted on the MARITIME slide and more to come.

Our next question comes from Mohit Bansal from Wells Fargo.

Great. I have 2-part question. One is that, do you think -- given the profile of this drug and, obviously, the competition in obesity, do you think diabetes is probably where this drug could actually shine a lot more than obesity? That's number one. And number two, what kind of target safety profile or discontinuation profile you are looking at with -- or you could expect to achieve with a better dosing dose-escalation mechanism?

Thank you for the question. I'll start with the first question on type 2 diabetes. I mean we're really encouraged by the data that we saw with the obesity -- patients living with obesity and type 2 diabetes, both in the efficacy of 17% in weight loss in a population in which weight loss is a bit more difficult, but also 2.2 percentage drop in HbA1c at the first monthly. Certainly, there is a large opportunity for MariTide in this patient population. But I think there's as large of an opportunity for MariTide in other indications based on what we're seeing in the profile and the cardiometabolic parameters that we also saw in the Phase II program.

Mohit, again, it's been an objective in the field for some time to have a truly long-acting therapy in diabetes where the short and weeklies have been available for some time now. But just as the market evolves there to favor and to long for a longer-acting therapy like our once-monthly or less-frequent dosing intentions, we expect the same will happen in obesity. So there are a lot of attributes that we've outlined and that were characterized by these Phase II data that give us encouragement about the role we can play in the huge market for chronic weight management. And again, this is -- these are still very, very early days in reaching the hundreds of millions of people around the world who would benefit from chronic weight management therapy. And having a convenient way to rapidly reach target dose and maintain it over a long period of time, we think, is going to be a very attractive option in the marketplace.

Yes. Thanks, Mohit. For your question around the safety profile, we expect to have and we have a competitive safety profile. Dose escalation for this medicine works. Lower first doses are producing a much better patient experience with the first dosing of MariTide, less than 20% vomiting, a very low discontinuation rate. Again, 90% of patients from Part 1 who are eligible chose to stay on the medicine for another year. These are chronic illnesses. And so keeping people on the medicine for a long time deriving benefit is really, really important. 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 6 months to titrate. Here, we have dose-escalation schemes that are 2 injections, and at 1 month, you're at target dose. And we've shown in the Phase II that there is no compromise on efficacy with dose escalation. We continue to remain interested in dose escalation. Our type 2 diabetes Phase II study features lower starting dose escalation, and we will have a wealth of patient data and experience with dose escalation before launch.

Our next question comes from Jay Olson from Oppenheimer.

Congrats on all the progress. Can you talk about any hypothesis about why there's no weight loss plateau at week 52? Is that related to MariTide's ADC modality or the GIPR antagonism mechanism? And also, where would you project to see a plateau? And what level of ultimate weight loss do you think MariTide can achieve?

Thanks, Jay. I couldn't speculate on where these curves will plateau if indeed they do. Hypothesis around a weight loss plateau, I would say the reason that we -- well, the hypothesis I have about why we don't see a weight loss plateau is it's just a very synergistic and very active medicine. Between what we know about downregulated GIPR signaling from human genetics and what medicines like semaglutide have taught us about GLP-1 agonism, what we've observed preclinically and we've physically attached the peptides to the antibody, MariTide is behaving as we expected already at 20% at 52 weeks. I suspect that with this pharmacologic profile of constant tonic exposure and a long half-life, which are unique characteristics of this antibody scaffold, that we can and do expect further weight loss beyond the 52-week window in Part 2 of the study.

Our next question comes from Chris Raymond from Piper Sandler.

Just on this initial vomiting rate and nausea rate that you guys have been talking about, there's a lot of discussion around dose escalation and MariTide specific steps to alleviate this. But maybe what I haven't heard you guys talk about is any concomitant meds you could employ either with exploratory studies or Phase III to sort of help mitigate this effect. Can you guys maybe talk about any options that you've sort of mulled over internally?

Yes. These studies are not written with any requirement for the use of concomitant antiemetic medication. And as we transition from Phase II into Phase III, we take these and other guidances as how we expect to perhaps even have improved tolerability in the Phase III study. We are already seeing less than 20% of vomiting without a requirement for use of concomitant antiemetic medication. And so through design, decreased ascertainment bias, perhaps coaching and other best practices, we hope to see even better data as we progress from Phase II to Phase III.

Our next question comes from Courtney Breen from Bernstein.

Two-part question. The first is just on kind of continuing on the nausea and vomiting at the beginning. As you think about kind of what good looks like in Phase III, can you talk about kind of what bar would you be looking to meet by being able to kind of further titrate that dose? And then the second part of that question about the Phase III trial design. Can you talk a little bit about what you've learned so far from the industry in advancing kind of Phase III anti-obesity and kind of outcomes -- cardiometabolic outcomes-related trial designs that have informed kind of how you're approaching the Phase III?

Thanks, Courtney. I'll start, and Susan, I invite you to weigh in, if you like, on the Phase III program. MariTide is a very well-tolerated medicine. And with this medicine, dose escalation works, as shared. The experience with MariTide on the Phase II study is very mild symptoms of nausea and vomiting were experienced with dose escalation in the Phase I, dedicated Phase I. We've now shown that even lower doses of MariTide can further reduce the experience of nausea and vomiting. And as I try to depict visually on this Manhattan plot, the incidence of nausea and vomiting, there's a lot of white space in the following 51 weeks. And so really thinking about treating patients for a long time and how well tolerated this medicine is in a maintenance-like approach, I think that we have now an understanding as to why there was such a low discontinuation rate due to GI events of only 8%, why there was such a high proportion of patients, 90% of patients, electing to go on to Part 2 of the study. These are signs worth really paying attention to. And all of this in the background of extremely good efficacy with a 20% weight loss in the nondiabetic population and 17% in that typically resistant or refractory diabetic population. I won't share today a target for the Phase III clinical trial. I just said a moment ago that we expect to do better with the transition from Phase II into Phase III. And we have all the data and guidance needed from the more than 800 patients we've treated with MariTide to date for the Phase III design that's in discussion presently with regulators. I appreciate the question around the design of our cardiovascular and other outcomes trials. We'll surely share this in the fullness of time. But for,, in part, competitive reasons, but most importantly, because these are the subject of ongoing interactions with regulators, we won't do that today.

Yes. And the only other thing to add to that, Jay, is that Amgen has experience in conducting these large cardiovascular outcome trials and large trials in these patient populations. And so we're both learning from what the competitors have done and published in their area, but also taking from our own learnings in treating patients with kidney disease and cardiovascular disease for many years.

Our next question comes from Matt Phipps from William Blair.

I was wondering if you could give us a discontinuation rate for the 420 mg monthly dose in the type 2 diabetes cohort, given that's kind of important with the efficacy estimand utilization. And then also, I was wondering on the 420 mg every-other-month arm, did you see a similar pattern with the occurrence of nausea and vomiting only in the first dose or so. Just wondering if a 2-month or longer window for treatment reduces any of that tolerizing effect on subsequent doses.

Matt, these are great questions. MariTide was well tolerated across the Phase II study. We focused on the dose-escalation arms because we intend to go forward with dose escalation into the Phase III study. The fine details around the individual dosing arms will be presented in a future [ colleague ] presentation.

Our next question comes from James Shin from Deutsche Bank.

The nature of the pooled data is somewhat making apples-to-apples comparisons somewhat muddy for us. Can you break out the weight loss for the 420-milligram arms or maybe just provide the weight loss for the every-other-month arm? And then secondly, as you think ahead to the Phase III studies, are head-to-head studies against semaglutide, which is likely exposed to higher inclusion, and possibly even tirzepatide plans to definitively demonstrate MariTide's differentiation?

For your second question, I'd say potentially. And for the first, the weight loss observed between the arms of the 420-milligram monthly data that were pooled, they're very similar.

Our next question comes from Gary Nachman from Raymond James.

So with the various dose-escalation strategies you're exploring, I just want to clarify, is it just 4-week or also 12-week dose escalation that you're looking at in Phase III? So will it definitely be very rapid to the target dose that you want to achieve? That's first. And then just quickly, were there certain subgroups or patient populations that potentially saw even better than the 17%, 20% average weight loss where you went up to those levels? And is that something you'll be exploring in the Phase III in both the type 2 diabetic and also nondiabetic groups?

Yes. Thank you. I'll take your second question first, your first question second. There are many patients on study that went well beyond 20% weight loss. and we are exploring what characteristics define their experience and their outsized benefit, so very interested in that question as well. We really aren't going to get into the fine details of the Phase III program right now because we're in discussions with regulators. We have had a very good experience with both 4- and 12-week dose escalation. We focused on 4-week dose escalation in the dedicated Phase I study and saw very strong tolerability with, again, less than 20% vomiting, invoking lower first doses. And really importantly, thinking about the 4 and the 12-week dose escalation arms, we did not see any impact on efficacy with either approach to dose escalation. So we have good options going into Phase III.

Yes. And just to add to that, we also have our Phase II trial ongoing for the type 2 diabetes patients, and we have different -- we have the dose-escalation arms that are within the 4-week period in there. And as well, we know from the marketplace that current titration schedules that are very long can be a burden for patients. Certainly, they're in place to make sure that you're managing tolerability, but you also have patients having to get multiple prescriptions written as each time they're changing that dose as they go through that slow dose-escalation process.

Our next question comes from Michael Schmidt from Guggenheim Securities.

Just a more practical question. Can you just comment on what the volume is of the 420-milligram dose? And how long does it take to complete the injection? And then just another clarification on this 11% discontinuation rate. I think you said this was pooled for the study. Does that include the placebo arm? Or is it just pooled for the treatment arms?

Yes. Thank you very much. MariTide will ultimately be delivered as a single dose in a convenient, handheld patient-friendly auto-injector device. I mean as we've shared with monthly or even less-frequent dosing, it will be a single injection administration and further details beyond that will be provided in the fullness of time. The 11% discontinuation rate is pooled data.

And Michael, if you were wondering whether this is on-body slow injection, the answer is no. We try to be clear, this is a handheld straightforward single injection.

Our next question comes from Kripa Devarakonda from Truist Securities.

I had a question about the reductions you saw in blood pressures, LDL, CRP, to differing levels. First, just wondering if there was a difference in the depth of those reductions you saw between the type 2 diabetes patients versus the non-type 2 diabetes patients because I thought I saw the CRP lowering seem more profound for the type 2 diabetes patients. And do you think the reduction in CRP was anticipated from the weight loss? Or do you see any potential for anti-inflammatory effect of MariTide?

Yes. Thanks for the question. We're very excited about the impact that this medicine is having on these and more cardiometabolic parameters. I think the impact on blood pressure is very impressive at 11 millimeters of mercury. This is, of course, not an antihypertensive, and so it reflects the new net benefit to cardiac output and vascular health associated with the central effects leading to weight loss, but also the peripheral effects on other tissues. The LDL-C is directionally expected. The hs-CRP is quite provocative, and so thank you for highlighting this. We had hoped that this medicine with its impact on obesity, it's the changes in diet, the direct effect on tissues, such as adipocytes that contribute to inflammatory pathways, we had hoped that this would be significant, and indeed, it was. The magnitude of 53% versus more than 70%, I don't have too much insight into that. And I would rather wait to see what we see in a larger population of patients in Phase III, because as you must know, the hs-CRP is really an aggregate measure of several different inflammatory pathways in the bloodstream. It can be quite variable in patients. But actually, because it can be quite variable, to see such a signal in a Phase II is rather exciting. And so we look forward to following that up. So I wouldn't read too much into the 53% versus the 70% without or with diabetes, respectively. But rather, what I'm taking away is just that there is a strong anti-inflammatory effect of this medicine and how patients respond to it.

Julianne, we're getting close here to market time. So we're going to take a few more questions and then thank our participants and make sure they get back to work before the market opens.

Our next question comes from Evan Seigerman from BMO Capital Markets.

Matt McManaman on for Evan. Wanted to ask you -- I appreciate the attention you're giving for use in the maintenance setting. Wanted to ask, how are you thinking about establishing a foothold in this setting specifically? How could it differ from a weight management label? And any nuances for the clinical path for approval in this setting?

Yes. So on the -- thanks for the question for Evan. The -- on the weight maintenance side of it, the -- we'll be -- again, for the overall obesity program, we'll be looking at establishing MariTide as an important agent for helping patients with obesity, not only getting to their weight goal, but being able to maintain their weight goal. And so the option then will be as we continue exploring the Part 2 and the Phase II of understanding what 2 12-weekly looks like in that setting. I should also say in that second part as well, we are looking at a number of different arms in that study to look at what maintenance could look like for these patients, which is very different than what's in the marketplace. In that study, we do have patients that we do randomize to placebo. So we'll understand if we see the same outcomes that we did in the Phase I study, as when patients come off therapy, how long their weight is maintained. We also have patients rerandomized to lower doses to understand, from a maintenance standpoint, can you move down to a lower dose. And then lastly, we have patients also remaining on therapy to see the impact of how weight continues to progress and then as well on the quarterly view.

Our next question comes from Brian Skorney from Baird.

I know you said on the bone mineral density side of things, you didn't see an effect. I'm just wondering have you gotten a chance to look into subgroups at all, in particular, if you looked at menopausal or perimenopausal women because I know there's that 2014 paper showing GIPR deficiency in about 1,700 women leads to a 50% increase in fractures. So just wondering if you've got any chance to look at subgroup data there.

Yes. Thank you, Brian. We see no effect of MariTide administration on bone mineral density. In this patient population by age and proportion of women, postmenopausal women are presumed to be well represented in this. And we will continue to follow this into -- through Phase II clinical investigation. No fractures. We see no effect of MariTide administration on bone mineral density.

And you can imagine, Brian, as the world's leader in bone health scenario, that we pay close attention to.

Our last question comes from Geoff Meacham from Citigroup.

I guess the question is when you look at the extensions to quarterly dosing on maybe the 120 or 280 mg dose, like how strategically important is it to have a quarterly dosing when you look at versus how you guys look at monthly? And then I guess given the mechanism, what are the unique challenges in having such an infrequent dose administration?

So I think that we're excited to see the readout of the Part 2 data to understand how MariTide performs on the quarterly dosing. And as we've seen in the every-other-month dosing in the Part 1 of the study, patients had a significant weight loss on that dosing. I think the real benefit that we're looking to is for what it means for patients who have to stay on therapy long term, being able to have a dosing at a less frequent amount is something that is optimal for patients in being able to maintain their weight loss. And the other thing that I mentioned before is I also think in the other diseases that we're examining, having the ability to look at different dosing schedules is going to be important to be able to ensure that patients are able to maintain their weight so that they maintain the benefits in those other disease areas that we're studying.

Thanks, Susan. I'd just add that as I shared in the presentation, patients receiving every 8-week or every-other-month dosing lost just as much weight as those receiving monthly dosing. And we obviously like what we saw in that data or we wouldn't have put every 3 months or quarterly dosing into Part 2. And so this, I think, all contributes to the unique and differentiated and competitive profile that's building around MariTide.

And I think -- Geoff, I think a lot of the commentators that you all have invited to assess the field have spoken about the importance and potential value of something that's even less frequent than monthly. So we're excited to have the every-other-month data here, and we look forward to being able to share the quarterly data when they're mature. But again, I think we need to wrap up so we can let you all get back to work. But let me thank you all for joining the call today. As you can tell, we're excited about the results that we've shared here, and I know we've shared quite a bit of data. So as always, feel free to reach out if there are more questions still in your mind. But we look forward to moving this program quickly into Phase III, and we'll keep you abreast of developments as we go forward. Thank you.

This concludes our Amgen Conference Call to Discuss MariTide Top Line Phase II Results and Progress on Development Program. You may now disconnect.