Amgen Inc. (NASDAQ:AMGN) World Congress on Insulin Resistance, Diabetes and Cardiovascular Disease Conference Call December 5, 2022 8:00 AM ET
Company Participants
David Reese – Executive Vice President, Research and Development
Narimon Honarpour – Vice President, Clinical Development
Conference Call Participants
Umer Raffat – Evercore
Matthew Harrison – Morgan Stanley
Michael Yee – Jefferies
Jay Olson – Oppenheimer
Salveen Richter – Goldman Sachs
Evan Seigerman – BMO Capital
Geoff Meacham – Bank of America
Colin Bristow – UBS
Mohit Bansal – Wells Fargo
Michael Schmidt – Guggenheim Partners
David Risinger – SVB Securities
Chris Schott – JPMorgan Chase
Matt Phipps – William Blair
Trung Huynh – Credit Suisse
Colin Bristow – UBS
Operator
Hello and welcome. My name is Alex and I will be your conference facilitator today for the Amgen Analyst and Investor Conference Call from the World Congress on Insulin Resistance, Diabetes and Cardiovascular Disease Conference. [Operator Instructions] I would now like to introduce David Reese, Executive Vice President of Research and Development. Dr. Reese, you may now begin.
David Reese
Thanks, Alex and good morning everyone. Thanks for joining us for an update on the AMG 133 program in obesity and allied disorders. These are a review of data just presented at the World Congress on Insulin Resistance, Diabetes and Cardiovascular Disease.
Next slide, please. Here is our standard Safe Harbor disclaimer and I should note that these slides are up on our website now for those who wish to follow along.
Next slide, please. In terms of today’s agenda, I will provide a brief introduction to our strategy in obesity and allied disorders following which Narimon, the Head of our cardiometabolic group in clinical development – global clinical development will provide a focused review of the AMG 133 data just presented at Congress over this weekend and then we should have plenty of time for questions and answers.
Next slide, please. As you all know, obesity is one of the major public health challenges of the 21st century. It is a complex, very heterogeneous disease with underlying complex biology. There is a strong genetic component that is rooted in evolutionary pathways fixed into human evolution. This heterogeneity of the disease leads to diverse outcomes in different patient populations, cardiovascular disease, metabolic syndrome and diabetes, various respiratory disorders, mechanical complications to name just a few. Now to tackle this disorder, we have taken an integrated structured approach at Amgen.
Next slide, please. This approach first is focused on human genetics and our large capabilities in human data to understand patient populations, the heterogeneity of the disease on a biology level and to understand how we may actually arrive at a precision medicine where we match treatments to the underlying drivers of individual patients with obesity. As always, we take a biology-first, modality-next approach and anticipate over time both large molecules, small molecules, RNA-based therapeutics and perhaps other approaches. We are developing a multi-asset portfolio with both incretin and non-incretin-based approaches. Initially, we will talk more about that as we get into 2023 and over the course of that year. And all of this again is powered on insights derived from genetics and our human data capabilities. Finally, given the complexity of the disease and the multiplicity of potential targets, we believe multi-specific molecules will be important in the evolution of this field and a prime example of that is AMG 133, which really illustrates all of the principles that I have laid out on this slide.
So with that, I’d like to turn things over to Narimon who will now go through a detailed review of the AMG 133 data just presented and then we will open things up for questions. Narimon?
Narimon Honarpour
Thank you, Dave. If we may advance to the next slide please. I am pleased to share the highlights of the AMG 133 data recently presented at the WCIRDC Congress.
Next slide, please. Recall that AMG 133 is an investigational therapy being evaluated as a treatment for obesity and obesity-related illnesses. Among its distinguishing characteristics is that it’s an antibody peptide conjugate. It has an antibody backbone that blocks the GIP receptor and bound to this backbone are two GLP-1 peptides that stimulate or agonize the GLP-1 receptor. The molecule has been engineered to simultaneously inhibit one metabolic pathway, the GIP pathway, whilst stimulating the other, the GLP pathway. Rationale for this design is based on: one, the human genetic data that strongly suggests that reduced GIP receptor activity is associated with reduced body weight; and two, the existing body of knowledge and important clinical experience with GLP-1 agonists. Our preclinical experience suggests that synergistic effects with this approach on weight loss and that led to the molecule being tested in Phase 1.
Next slide, please. So this Phase 1 study was designed as a randomized, double-blind, placebo-controlled trial with both single dose cohorts as well as multiple dose cohorts. Patients that participated in the study were obese, but did not have other medical conditions. The objectives of this trial were typical of Phase 1 first-in-human studies that is they were to assess the safety, tolerability, pharmacokinetics and pharmacodynamics, for example, weight reduction, of AMG 133.
Next slide, please. This is an illustration of the study schema with the single-dose cohorts shown on the left, each single dose cohort enrolled approximately 8 patients, 6 of which would have been allocated to AMG 133 and 2 to placebo per cohort. Patients received a total of one subcutaneous administration in these separate cohorts. On the right, you see the multiple dose cohorts tested that similarly had subjects randomized to either AMG 133 or placebo. Patients enrolled in these cohorts received a total of 3 subcutaneous administrations each 4 weeks apart, with the last administration just before Day 60.
And as stated in the footnote here for the multiple ascending dose cohorts, we have three other cohorts where the analysis is ongoing. Two of them were designed to assess potential dose escalation strategies and then helped inform part of our planned Phase 2 dose-ranging trial. We also had one cohort designed to provide experience with digital tools that assess things like patient activity and eating behavior. And as I mentioned, the analysis of these cohorts is still ongoing.
Next slide, please. Baseline characteristics of the patients are shown here. Notably, the BMI on average range from 32 to 34 in these cohorts and the hemoglobin A1cs as you would expect for an obese, but otherwise healthy population were in a normal range.
Next slide, please. Okay, here are the results from our single-ascending dose cohorts with AMG 133. Shown here on the left is the mean percent body weight change observed with single-ascending dose cohorts. Again, patients enrolled in these cohorts received only one administration of study drug. Dose-dependent and durable reductions in weight were observed as you can see across the variety of doses administered and persisted for many weeks after the one administration. And on the right, we show the pharmacokinetic data from these cohorts. And the key takeaway here is that the molecules will behave both predictable, dose-dependent plasma concentrations, and an extended half-life, which ranges from 14 to 25 days and is typical of molecules in an antibody-based type therapy.
Next slide, please. Alright. Here, we have the mean percent body weight changes seen in the multiple ascending dose cohorts, where patients received a total of three subcutaneous dosing administrations each 4 weeks apart with the last administration, as you can see in that red arrow just before day 60. Again, in these cohorts, we see dose-dependent and durable weight reduction. This ranged from approximately 7% weight reduction at day 85 for the 140 milligram cohort and up to approximately 14.5% reduction at day 85 for the 420 milligram cohort. Notably, no plateau effect was observed within the dosing period of 90 days, with effects persisting for several months after the last administration of drug. We continue to be encouraged by the mean percent changes in body weight, pace of weight reduction and the duration of the weight reduction observed.
Next slide, please. With regards to safety and tolerability in this study, we have not observed any notable safety concern with most treatment-emergent adverse events having been mild and transient, the more majority of which, which were associated with the initial administration of drug, that is the first administration. The types of treatment emergent adverse events observed were generally GI-related, consistent with the GLP-1 based therapies that have been approved.
Next slide, please. So to conclude, we have tested a novel approach that is to block the GIP receptor pathway whilst stimulating the GLP receptor pathway with AMG 133. The results of this Phase 1 study suggests that extended dosing intervals such as every 4 weeks are viable for further testing and we remain encouraged by the weight reduction observed, the pace of the weight reduction and the durability of the effect. And the safety assessments have been supportive of further clinical testing in Phase 2, which we are pursuing and plan to initiate in early 2023.
This concludes this part of the session today. And I’ll hand it back to you, Dave.
David Reese
Thanks, Narimon. Alex, why don’t we go ahead and open up the Q&A session? Can you remind our attendees how to ask a question?
Question-and-Answer Session
Operator
Thank you. [Operator Instructions] Our first question for today comes from Umer Raffat from Evercore. Umer, you may proceed.
Umer Raffat
Good morning, guys. Thanks for taking my question. Very interesting dataset. And maybe three quick ones, if I may. First, I couldn’t – if someone asked me what’s the exact rate of nausea and vomiting, I don’t know if I know that answer. Maybe I missed it in the poster, but I don’t recall seeing that anyway. If you could just help us clarify that, number one, especially in the multi-ascending dose? Second, have you – and I realize there is a lot of variability in small numbers, but have you been able to identify a C min, which enables you to preserve the weight loss that could be very relevant to your dosing plans? And finally, do you think – and the more I look at this data, the more I wonder, do you think a quarterly dosing is pulled on a maintenance basis once you are into the induction? Thank you.
David Reese
Great. Thanks, Umber. Good questions, all of them. First I want to comment on the rate of nausea and vomiting as well as the C min issue, I think that’s important. In terms of potential quarterly dosing, certainly, one of the things we are thinking about is more extended dosing intervals in a maintenance setting, for example, given the pharmacokinetics that we have observed and given the half-life antibody, like half-life of the molecule that opens up I think a lot of optionality and we will be exploring different dosing regimens in Phase 2 to address that question. Narimon, do you want to talk about the rate, in particular, in the MAD portion of the trial of some of the adverse events and the question around the C min?
Narimon Honarpour
Sure thing. Thanks, Dave and thanks for the question. So in fact, if I may refer to the poster table 2b on safety, we have the number of treatment emergent adverse events listed there in general and qualitatively listed as mild, moderate and severe. And for those patients at the higher doses, so 280, 420, I would say almost all of them on a mild range were nausea and vomiting, GI-related. Now with regards to the C min and concept for identifying what is minimally required to preserve weight loss, we certainly have preliminary information from our Phase 1 experience, but we are going to continue to follow the pharmacokinetics here in Phase 2. So I think we will need to really investigate that further in the study to come. Thank you.
David Reese
Thanks, Narimon. It’s a good question, Umer and that’s something we will be addressing directly in subsequent studies. Alright, Alex, next question.
Operator
Thank you. Our next question is from Matthew Harrison of Morgan Stanley. Matthew, your line is now open and please proceed.
Matthew Harrison
Great. Good morning. Thanks for taking the question. I was hoping you could just talk a little bit more broadly on the dosing strategy you are thinking about for Phase 2 and in particular, are you looking at potentially a higher dose to have greater weight loss or are you considering some of these things around dosing frequency as more of a focus for Phase 2? Thank you.
David Reese
Yes. Thanks, Matt. Obviously, a very important question Narimon will comment in a minute here. What I would say broadly is we are designing a very robust Phase 2 trial with different doses and schedules, really to preserve optionality as we come out of Phase 2 for further development of the molecule. This is something I feel very strongly about. And so this will be a pretty hefty Phase 2 trial. Narimon, maybe you want to provide additional color on the dosing strategy we are taking.
Narimon Honarpour
Thanks, Dave. I think you summarized it well. And Matt, in summary, I would say, we want to be able to explore both in the Phase 2. We want to look at the full range of the magnitude of dose and we want to understand as deeply as we can the appropriate intervals of that dosing. So I will say what we have elected to pursue thus far because our Phase 2 study hasn’t been finalized. In other words, it’s been submitted to regulatory authorities, but we haven’t cut in the final go ahead is that the details will be on clinicaltrials.gov when we do have that final protocol ready to share, but the experience will be bracketed by what we have seen and tested in our Phase 1 study in terms of the magnitude of the dose. From a frequency perspective, we feel quite comfortable with every 4-week fixed interval dosing. We will plan to assess that in the Phase 2. We will be looking at longer intervals of dosing meaning less frequent as well. And also, we will include some dose escalation strategies into the Phase 2 to really understand the optimal experience for patients and providers. Thank you.
David Reese
Thanks. Next question, Alex.
Operator
Thank you, Matthew. Our next question comes from the line of Michael Yee from Jefferies. Michael, your line is now open.
Michael Yee
Good morning. Thanks for the update and thanks for this call. We had a two-part question, but they are related. Based on the human genetics or at least animal tox data, what can you say about long-term safety of GIPR antagonism and specifically as it relates to what you would predict with diabetes effects since I know there is no diabetes patients here? So just comment on what you would expect for HbA1C and whether you will even look at diabetes patients and/or go after that population? Thank you.
David Reese
Thanks. I will take the second part and then Narimon can summarize some of our human genetics work, which has been quite extensive here and potential long-term safety, in particular, related to the GIP receptor. In Phase 2, we do plan on studying both patients with type 2 diabetes as well as those who are normal glycemic. So we will get a look at both of those populations. Narimon, do you want to comment on the genetics?
Narimon Honarpour
Absolutely. Thank you for the question. We have worked closely with our colleagues at deCODE Genetics and understanding this question. In over 500 different disease phenotypes that are included in their analyses and there are many – there are hundreds of thousands of patients, if not more that they include in their databases, in looking at the variety of GIPR variants, there have been no particular safety signals or concerns that have come out of that analysis. So we feel quite comfortable with our approach in terms of antagonizing the GIP receptor. And we will continue to do the standard monitoring for safety in our clinical trials to come. Thank you.
David Reese
Thanks. Great. Next question, Alex.
Michael Yee
Thank you.
Operator
Thank you, Michael. The next question comes from the line of Jay Olson from Oppenheimer. Jay, you may proceed.
Jay Olson
Hey, congrats on these early results, and thank you for the update. Given the innovative design of this conjugate, could you talk about the relative contribution of the GIPR antibody and the GLP-1 peptides to the substantial weight loss that you’re showing in this study? And then how are you thinking about the other assets in your obesity portfolio beyond 133 in terms of any other targets or modalities you may consider? Thank you.
David Reese
Yes. Thanks, Jay. Let me just address briefly the second part of your question, and then I’ll ask Narimon to comment in particular on our pre-clinical data regarding the relative contributions of the GIP receptor and GLP-1. As I mentioned, we’re taking an approach rooted in genetics and human data. We expect both incretin-based and non-incretin-based therapies, or targets. We are interested in particular in molecules that have orthogonal mechanisms of action to currently available therapies or novel mechanism of action that may be complementary to existing therapies. And over the course of 2023, as I noted, we will start talking about some of those approaches as we get ready to move forward. But it’s a pretty comprehensive approach, but the foundation here is really our human genetics and human data work. Narimon, do you want to talk about the relative contribution of these two signaling pathways?
Narimon Honarpour
Thanks, Dave. I would say that in a summary, there are contributions from both, but the real power from this approach comes from having both happen at the same time. From our pre-clinical data, there was a cystic effect observed in having both simultaneous antagonism of the GIP receptor with stimulation or agonism with the GLP-1 receptor. So we believe both components of the way this molecule had been designed are important and the effects that we’re observing. Thank you.
David Reese
Next question, Alex.
Jay Olson
Thank you.
Operator
Thank you, Jay. Our next question comes from Salveen Richter of Goldman Sachs. Your line is now open. You may proceed.
Salveen Richter
Good morning. Thanks for taking my question. Two from me here. What do you think the peak body percentage weight change would be if you were able to maintain the every 4-week dosing since the 60-day period? And secondly, apart from the potential benefit of less frequent dosing, you’ve spoken to differentiating via the population study. So looking at obesity associated with cardiovascular or metabolic disease, how do you study that in the Phase 2?
David Reese
Yes. Thanks. Yes. In terms of the potential peak reduction, certainly at the higher dose, there was no plateau observed. And so obviously, that’s one of the key endpoints for the Phase 2 trial, understanding just what that peak may be with prolonged dosing. The durability that we’re seeing also, I think, is quite important in this regard with a lack of relative rebound. One of the explanations for that relative smoothing out of the peaks and troughs of exposure to the molecule that may occur with molecules that require less frequent administration, for example, weekly. Narimon, let me get you to comment on the second part in terms of additional indications. But obviously, as I mentioned earlier, Salveen, preserving optionality so that we may then tackle specific indications going forward is one of the things we want to see coming out of Phase 2. Narimon?
Narimon Honarpour
Thank you. Well, I want to just begin by saying that a Phase 2 study in and of itself is not likely to be able to address all the questions with regards to a patient population as heterogeneous as obesity. So it becomes very important to put that type of data in the context of broader data resources that we have available to us like those that we work with deCODE genetics on. So I would say the first point that would be useful to make is that we will be looking at the Phase 2 data in the context of broader data sets. The other piece that I think is important to consider is the depths of data that we will be collecting in the Phase 2. So we won’t just be looking at the anthropomorphic measures such as weight reduction, which are important, but also relatively high level with regards to understanding the mechanism of how AMG 133 works in particular. So we will have a variety of assessments, including deep phenotyping that we believe in deep characterization that we believe will be important in getting biomarkers from these patients, etcetera, and again, putting it into the context of that larger patient population data that we have access to. Thank you.
Salveen Richter
Great.
David Reese
Thanks. Alex, next question.
Operator
The next question comes from the line of Evan Seigerman from BMO Capital. You may proceed.
Evan Seigerman
Hi, guys. Good morning, and thank you for the presentation of the data. So two from my perspective. I would love to talk about kind of the potential weight loss in terms of lean muscle versus adipose tissue. What are you seeing for AMG 133 so far? And how – do you have any idea how fast too fast is that when it comes to weight loss? Any feedback from FDA kind of on this extended release approach? Thank you.
David Reese
Yes. I’ll let Narimon address both of these questions. Obviously, the question about lean body weight versus changes in lean body weight versus changes in adipose mass are quite important, Phase 1 is relatively small and hard to get a handle on that. But this is a very specific question going forward. Narimon, if you could maybe tackle that as well as the second part of the question here.
Narimon Honarpour
Sure thing. Thanks, Dave. So at a high level, I think we could say what we expect are similar impact is what one sees from the existing increasing class of medicines that have been put to market. There are effects on both types of weight, lean and adiposity. But in these patients, in particular, with high atoposity, high-body mass index, you see a lot of the reduction happening in the reduction in fat mass. So we haven’t formally assessed that in our Phase 1 data at this point. It is going to be limited given the small number of patients. So it’ll be hard to be too definitive about what we observe. Importantly, we will be looking at this question in the context of our Phase 2 trial, where we will be making those assessments formally. There was a question that was asked with regards to have we received any feedback on whether there is such a thing as too fast of weight reduction. We haven’t received that type of feedback. What I will say is what we understand from our Phase 1 study is that this pace of weight reduction that we observed seems to be well tolerated and safe. we will be continuing to monitor things in the context of our Phase 2. Thank you.
David Reese
Great. Thanks. Alex, next question.
Operator
Thank you. The next question comes from the line of Geoff Meacham from Bank of America. You may proceed.
Geoff Meacham
Hey, guys. Thanks so much for the question. Just had two quick ones. So you guys when you look at the weight rebound at the last administration, at the high and low dose, it looks like it did rebound and it took maybe a few months, but the middle dose there, it didn’t. Was there something unusual on that cohort? Any sort of common themes with there? And then I know the question has been asked on A1C at baseline, but can you talk a little bit about how you guys are thinking about that as that trend as maybe an indicator of your plans to move into a formal diabetes indication? And maybe what are the steps there? Thank you.
David Reese
Hi, I’ll take the second part of that question and then ask Narimon to talk about the kinetics of weight rebound. As we mentioned, these patients in Phase 1 were normal glycemic by definition, per protocol entry criteria. One wouldn’t expect a very big change, if any, at all in hemoglobin A1C consequently. Again, we’re going to enrolling type 2 diabetes patients in the Phase 2 trial, specifically and we will, of course, be tracking all of the metabolic parameters that are typically followed in that population in the clinical trial setting. Narimon, do you want to talk about the question regarding weight rebound?
Narimon Honarpour
Sure. So I’ll speak to what I believe the question was oriented towards the multiple ascending dose scores that were looked at, and specifically with regards to the middle dose 280 milligrams where it looks like there was steady maintenance of weight over the dosing interval – I’m sorry, post dosing interval. There was nothing in particular about those patients in terms of their characteristics that would lead one to believe that they had some known reason why their weight stayed relatively flat. I think it is important to remain humble about Phase 1 data given the small number of patients. You do expect to see some variability. It might be that the apparent differences that we’re seeing here between the cohorts is just due to that, the small numbers and variability that you would expect rather than it be driven by a particular foundational element or driver. Thank you.
David Reese
Thanks. Next question, Alex.
Operator
Thank you. The next question comes from the line of Colin Bristow from UBS. You may proceed.
Colin Bristow
Hey, good morning. And congrats on the data, and I appreciate you guys hosting this. Could you give us a little more detail on these three cohorts, which are ongoing and yet to be disclosed. Can you tell us what doses are being tested? And any other – anything else that would be helpful? When should we expect any disclosure on these cohorts? And I’m curious, do you need to wait for them to reach completion in order for you to move to Phase 2? And then just a housekeeping one really, just within the data on the MAD cohorts, there were two patients who were replaced. Could you just qualify what was happening there? Thank you.
David Reese
Yes. Sure. I’ll ask Narimon to address both of these both in terms of some of the specifics on the ongoing cohorts, which is is not slowing us down in terms of Phase 2, Colin, I will say that. And then in addition to the ongoing cohorts that speak to the specifics of the replacement patients also. Narimon?
Narimon Honarpour
Thank you. So you are spot on, Dave the completion of these additional cohorts is not slowing us down and progressing towards Phase 2. In terms of the details on what those cohorts were in particular, for those in the dose escalation, we have two low dose administrations at 70 milligrams that are administered 1 week apart. And then we go to the highest dose that 420 milligrams within that cohort afterwards for two subsequent administrations each 4 weeks apart. For the second one, we have again four – this time, four low dose administrations each 1 week apart at 70 milligrams then hitting that target high dose at 420 milligrams, again, given for two doses approximately 4 weeks apart. So these patients, we were looking primarily at the dose escalation strategies that could work that might make the experience for patients a bit easier, if it would attenuate or change any of the mild nausea and vomiting symptoms that they may have had. They aren’t intended to examine things like the weight reduction that we would expect from these doses as we’ve qualified and characterized in the earlier multiple ascending dose cohorts that we have studied. We do have one cohort also open that is assessing the use of digital tools. Those patients have completed their experience, but the analysis of these is ongoing. And in terms of digital tools, we’re talking about things like wearables that assess actigraphy, sleep quality, that also record their dietary habits. This is very exploratory in its nature, but as an innovative company, we’re interested in understanding the utility of these tools and how we may apply them in our trial experiences. So we thought that would be a good thing to try out as well.
There was a question asked about patients that had been replaced in the 420-milligram cohort, and I want to be sure to address that question. So for the two patients that were replaced, they were replaced because they had withdrew from – withdrawn from the study early on, so within the first month. And in order to understand the full characteristics of the drug at the high dose, we needed to maintain our specified cohort size. So with two subjects having stopped their participation in the study rather early, we needed to replace them with two other subjects. So that’s the rationale there, and we don’t expect that, that would have impacted the overall assessments that we have at the 420 milligram cohort. Thank you.
David Reese
Thanks. I mentioned that’s a very standard approach to Phase 1 studies of this sort. Alex, next question.
Operator
Thank you. Our next question comes from Mohit Bansal from Wells Fargo. You may proceed.
Mohit Bansal
Great. Thanks for taking my question. And thank you very much for showing these data. Maybe mechanistically, when you look at the data, and based on your pre-clinical models, what do you think – so do you think there could be any difference if we give antagonism versus agonism in terms of durability of effect? We know with agonism, the weight reduction continues for at least a year. So do you – should we expect similar results for longer duration? Or is there any reason to believe something different at this point? Thank you.
David Reese
Mohit, I’ll tackle that. We can speak to our data as well aware. Again, we chose the antagonistic approach for the GIP receptor based on the very powerful human genetic data that suggests that variance that associate with reduced signaling through that pathway or associated with lower weight. I think the durability we’re observing here is very encouraging. And obviously, the durability will be really something we examine quite closely in the expanded experience in Phase 2. But I’d say I’m quite optimistic on that front right now. Alex, next question.
Mohit Bansal
Super helpful. Thank you.
Operator
Thank you. Our next question comes from the line of Michael Schmidt from Guggenheim Partners. You may proceed.
Michael Schmidt
Hi, guys. Good morning. Thanks for taking my question. Just another one on the potential safety of antagonizing GIPR, I guess specifically in your pre-clinical models, have you looked bone density and is something that you might be – that you’re confident in that there is no impact? And the second question is in your Phase 2 study, are you confident enough in the tolerability profile to look at exclusively the flat dosing schedule or are you still planning to evaluate a step-up dosing in Phase 2 as well? Thanks so much.
David Reese
Thanks Michael. I can tackle both of those and then ask Narimon to provide some color, i.e., will be looking at flat dosing approaches in Phase 2 as well as dose escalation or titration scheme. So, again, we want to preserve optionality there and really optimize both the clinical effects as well as the experience for patients. In terms of the pre-clinical models, and your question related to bone density, I believe this is rooted in a paper that’s 7 years or 8 years old that suggested that variance associated with the GIP receptor pathway could associate with lower bone mineral density, specifically inhibition of that pathway. We have looked at a much larger number of individuals with our colleagues in Iceland. We find no such association on bone mineral density at all, a finding that we are actually quite confident in. And thus far, that has not emerged as an issue in the program. Pre-clinically, we will be looking at this specifically in Phase 2 to address the question. But I can say with, I think some confidence here that the genetics here are not pointing us towards any specific concern in terms of bone mineral density. Thanks. Next question Alex.
Operator
Thank you. Our next question comes from the line of David Risinger from SVB Securities. You may proceed.
David Risinger
Yes. Thanks very much. Just to follow-up on that last question and your response. What was the duration of treatment of non-human primates when you looked at BMD in non-human primates? And second, with respect to Phase 2, I know that you haven’t finalized plan. Tell us about the planned duration of treatment in Phase 2? Thank you.
David Reese
Sure. I will ask Narimon to address the question. I don’t remember off the top of my head in the duration of therapy in the non-human primate study. Certainly, we can get that information to you. Narimon, if you know that off the top of your head, of course, feel free to weigh in. And then if you want to talk about duration of therapy in Phase 2.
Narimon Honarpour
Thanks Dave. I do not remember the duration of therapy for the non-human primate toxicology study. We certainly can follow-up. But your responses before were spot on. There were not particular observations of a concern from that study and the human genetic studies that we have looked at, which were extensive and managed by our deCODE colleagues showed no evidence of bone signal. I think the important point also for me to add is that we did assess DEXA scans in our Phase 1, and insofar as that data is concerned, we saw no notable signal for reduction in bone mineral density in the context of our Phase 1, the same study that we are seeing the pharmacodynamic effects in assessing safety and tolerability. As you pointed out, we will be looking at this out of an abundance of caution in our Phase 2 trial. In terms of the duration of the study for Phase 2, it will as expected be much longer than our Phase 1 study and include patients that are obese. You have mentioned that they will be inclusive of patients with diabetes as well, which is absolutely correct. And we will be targeting a duration of therapy for approximately 1 year. Thank you.
David Reese
Alright. Thanks. Next question, Alex.
Operator
Thank you. Our next question comes from the line of Chris Schott from JPMorgan Chase. You may proceed.
Chris Schott
Great. Thanks so much. Just a couple of follow-ons on prior questions. I think you have mentioned a couple of times on the call kind of a robust Phase 2 program. Help us just a little bit on timelines about when we can think about data from that program and when you could make kind of a Phase 3 decision. Is that something that’s reasonable to think about in 2024? I am just trying to get hands around when the next update we should think about here would be. And then my second one was just coming back to GI tolerability. I know the signals you are seeing here were highlighted as mild and kind of dissipating fairly quickly. But is your base case this drug is going to require dose titration like we see with some of the existing agents, or is your base case that you think you can get there just with a kind of single kind of therapeutic dose from day one? I just would appreciate – I know you wait for some more data, but just based on what you are seeing in the Phase 1, is there – are you kind of leaning one direction or the other? Thank you.
David Reese
Yes. Thanks Chris. In terms of the timeline, as Phase 2 gets up enrolling next year, you will provide guidance in terms of expected data availability, but sometime in ‘24, I think is a reasonable expectation. And we will get more specific on that in terms of – once we see enrollment. In terms of GI tolerability, as I have said, we want to preserve optionality. I think it’s quite possible that fixed dosing may be a regimen that goes forward or some form of dose titration. I don’t know that I would heavily lean or be biased to one approach or another right now. And of course, that’s something that we are going to prosecute quite carefully in Phase 2. Thank you. Next question, Alex.
Operator
Thank you. Our next question comes from the line of Matt Phipps from William Blair. You may proceed.
Matt Phipps
Good morning. Thanks for taking my questions. In the poster, you break down the difference between the intact and total AMG 133. And I guess do you think there is any impact of this naked or maybe un-conjugated AMG 133 given it does seem to have a longer half-life? And then did you look at all – or do you think that GIPR antagonism has an impact on glucagon secretion?
David Reese
Yes. Let me ask Narimon to tackle those questions. First is related to the pharmacokinetics of both the intact in total. And this is a reflection of the design of the molecule itself and then the GIP question. Narimon?
Narimon Honarpour
Thank you. In terms of the pharmacokinetics and the intact and total molecules, so just keep in mind that total is inclusive of intact. So, there is a lot of similarity there in terms of the amount of circulating drug. A lot of it is going to be intact. The total is inclusive of the, what I would call the naked antibody portion as well. So, over time, the GLP-1 peptides can be clipped off and they are relatively quickly metabolized as they are peptides. And so we don’t expect those GLP-1 peptides to, once they are clipped, to be contributing to the prolonged effects that we see with AMG 133. As we mentioned earlier, we believe both activities are important to the full complement of effect that we see because it was a synergistic effect that was observed with simultaneous GIP receptor antagonism and GLP-1 agonism. In our pre-clinical models, there may be some mechanistic rationale for the GIP receptor antibody mediating some additional effect with the chronic dosing interval. But again, we believe most of this effect is coming from the intact molecule, and both mechanisms being important in the data that we observe with weight reduction. It’s too early to give a view on the glucagon levels, and frankly, many of the other biomarker assessments from our Phase 1 experience, it is a small cohort of patients that we have. So, there is going to be some variability, but this is a very good and important question. We will continue to assess it in our Phase 2 trial. Thank you.
David Reese
Thank you. Next question.
Operator
Thank you. Our next question comes from Yaron Werber from Cowen. Your line is open. You may proceed.
Unidentified Analyst
Hi. It’s Brendan on for Yaron. Congrats to the team on the data. Just a quick one from us kind of building on some of the earlier questions. Obviously, safety, tolerability, is pretty solid so far. But is there really anything in particular we should watch for in terms of safety signals from either of the two mechanisms here that may be more of a concern as you move into some of these patient populations with other comorbidities? I know you addressed some of this in diabetes for the Phase 2. I guess really just wondering is there anything in particular you are watching for us, maybe especially from GIPR as you move into patients like with CBD or AFib, even COPD? And I guess in that same vein, assuming you will continue to measure this moving forward, but do you have any reason to think that maybe the difference in intact versus total AMG 133 might change at all across some of these other comorbidities? Thanks.
David Reese
Yes. I can address the second part here. There is no – reason biochemically, Yaron, to think that intact versus total will vary in the different disease states. Obviously, that’s something that we will measure and compare between different cohorts, in particular, those with type 2 diabetes and those who are normal glycemic. Also I would say that there is nothing that stands out now in terms of any sort of heightened safety concern related to specific populations, and obviously, we will break down safety across different cohorts as we do in a standard fashion. Narimon, I don’t know if there is anything you would like to add to that?
Narimon Honarpour
I don’t have anything else to add to that. Dave, you summarized it well. Thank you.
David Reese
Thanks. Next question, Alex.
Operator
Thank you. Our next question comes from Robyn Karnauskas from Truist Securities. You may proceed.
Unidentified Analyst
Hey. Good morning. This is Nicole on for Robyn. Can you talk about – or actually, has gastric been evaluated? And can you talk about any potential impact on brown versus white adipose tissue based on the mechanism?
David Reese
Thanks Nicole. Let me ask Narimon to address that question as to whether we evaluated it in the Phase 1 experience.
Narimon Honarpour
We have explored gastric emptying. The data is rather small and variable. So, it’s difficult to draw any conclusions. I think that’s what we can say. There is obviously pre-clinical and – data, and what is expected from the general body of knowledge from the incretin class and you do expect there to be some effect on gastric emptying. But it would be too much for me to say that we have clinical evidence of that at this stage. So, there was a second question, I believe, on the contributions of weight reduction for brown and white adipose tissue changes. We haven’t looked at that specifically. This is work that we can continue to explore primarily in the context of pre-clinical models. But I think it’s important to consider the context here for the addressable patient population, which will have a large excess of white adipose tissue. So, certainly, there is going to be an expectation on reduction of white adipose tissue, but proportionality versus brown is something that we will just have to explore in the future. Thank you.
David Reese
Great. Thanks. I think we have a couple of questions left, Alex?
Operator
Thank you. Our next question is from Trung Huynh from Credit Suisse. Your line is open. You may proceed.
Trung Huynh
Hi guys. It’s Trung Huynh from Credit Suisse. Thanks for taking my questions. Two, if I may. So, there was an 8-kilogram difference in baseline weight of the 420 mg dose versus the lower doses. I was just wondering if tissue penetration is easier, and efficacy tends to be better if you have a lower baseline weight versus a higher baseline weight, does it work that way? And then just secondly, on the two replaced patients, and I might have missed it, but why did they withdraw from the study? Thanks very much.
David Reese
Great. I will ask Narimon to comment on both why the two replacement individuals withdrew from the study, and then the question of tissue penetration. The short answer there is that we don’t expect significant differences in tissue temp penetration, distribution based on baseline weight. I suspect biochemically that’s probably not relevant. But Narimon, let me have you go ahead and weigh in here as well.
Narimon Honarpour
Thanks Dave. I will start with the two patients that were placed in the 420 mg. So, they withdrew from the study relatively early. There was no clear reason why they chose to stop the study. There was no clear association with adverse events or anything of that nature. To the best of our knowledge, they just decided they didn’t want to continue participating in a clinical trial. With regards to the question on the degree of adiposity of patients and baseline weight and effectiveness. I think the key points to keep in mind are, given the pharmacology of this drug, the target coverage that we have modeled with the doses we have selected, remember, we do have SAD data, or single dose data at the higher doses and in patients with higher weight and we saw observed weight reductions there. Our conclusion is that the effects that we are seeing are driven by the higher dose, and we are not seeing a particular sensitivity at this point in time with regards to differences in baseline body weight. We will of course, learn more in the context of our Phase 2. And I want to be humble and saying we can’t exclude the possibility, but we certainly don’t see any signals at this point in time. Thank you.
David Reese
Great. And I think we have a final question here, Alex. Go ahead and tee it up.
Operator
Thank you. Our next question comes from Colin Bristow from UBS. You may proceed.
Colin Bristow
Hey. Thanks for the second lap. Just wanted to quickly follow-up on just your response to my first question in that you – these two discontinuations, and then you are pursuing a dose titration strategy up to the high dose – well, the 420 milligram dose, which – for which all AEs were mild. I am just curious, was that borne out of concern over adverse events? I am just trying to understand this and like the fact that you are talking about exploring higher doses in Phase 2. Thanks.
David Reese
Yes. I will ask Narimon again to comment here, of course. But of course, in Phase 1, the number of potential approaches here is very large. And so we want to get some experience with dose escalation, chose a lower dose and then going to the higher dose to sort of bracket that experience. And the lower dose titration was really designed to see if you could even further optimize the tolerability of the agent, which appears to be quite good so far. Narimon, anything you want to add to this?
Narimon Honarpour
I think you have hit it spot on, Dave. The issue, I think at the root of exploring any dose escalation strategy is if we can make the path easier for patients and more optimized. And from the safety that we have shared and articulated, patients do have mild complaints of GI tolerability at the higher and highest doses. So, if there is an opportunity to make the experience better for patients and not have those mild complaints, then why not explore that in the context of our Phase 1, which we did and carried that over as a learning into our Phase 2 study, which we are pursuing. Thank you.
David Reese
Great. Well, I really want to thank Narimon here, who as you can see, knows the data inside and out. And we are very excited to be moving into Phase 2. I want to thank everyone for joining. As always, our Investor Relations team will be standing by for additional questions. If you have got them, please feel free to send those in. Thank you and I will providing – I will provide guidance as we get into the first part of next year on Phase 2 launch and then expected timelines and further development over time. Thanks everyone and have a good day.
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