Shaping the Future: Innovations and Trends in Obesity Treatment

William Blair biotech analysts Matt Phipps and Andy Hsieh discuss Andy’s innovative scoring system for evaluating investigational agents in obesity treatment. This system, highlighted in Andy’s report “Shaping the Future: Innovations and Trends in Obesity Treatment,” considers both weight loss and gastrointestinal side effects to provide a more comprehensive clinical assessment. Tune in to hear their insights on the future of obesity therapies, upcoming industry catalysts, and more.

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Podcast Transcript

00:17
Matt P
Today is March 19, 2025. Welcome back for another episode of Biotech Breakthroughs. I’m Matt Phipps, group head of biotech research at William Blair. I'm joined today by Andy Hsieh, another analyst here on the biotech team, and we're here to dig into his latest thematic report called “Shaping the Future: Innovations and Trends in Obesity Treatment.” Andy, welcome back to the podcast.

00:37
Andy H
Happy to be here. Thanks for hosting.

00:39
Matt P
Great. Well, Andy, I think it's definitely a good time for this report, as the just extreme exuberance around the GLP-1 field and potential for these therapies, as you say, to really reshape obesity, particularly here in the United States. I'd love to walk through some of the key takeaways from your thematic report and just some of the overall trends that you are seeing in the obesity market.

You know, one thing I think is particularly interesting, is you developed a new scoring system in this thematic report, which I really haven't seen anything like this before, that tries to bring in multiple aspects of the clinical data into kind of one simple score. Trying to focus not just on the weight loss, which has obviously been a focus for many investors, but also taking into account some of the tolerability as well.

Maybe you can just kind of walk us through how you came up with this and some of the kind of key points of the scoring system.

01:45
Andy H
Yeah, I'm happy to do that. So, it's probably one of the highlights of the report. Essentially, when investors look at investigational agents, we believe that there is an overemphasis on the velocity of weight loss without also considering the frequency and severity of gastrointestinal adverse events. We also argue that keeping patients on therapy remains one of the most important unmet medical needs in the obesity space.

If you look at some of the real-world data, about 50 to 70% of the patients discontinue after one year. Obviously, not all of them were due to side effects, but that's a big component. So we're trying to get away from that. I'm sure you've seen charts basically overlaying the weight loss over time and we thought that you're losing a lot of relevant information by looking at that.

You could actually design trials to kind of game that system by titrating a little bit faster using a higher dose. So, we wanted to cut through the noise and have a simple scoring system that could capture important data points and then it could be compared among investigational agents. So briefly, there are four components in the formula.

The first one, obviously it's weight loss at 12 weeks. Second component is the most relevant gastrointestinal side effects. So vomiting, diarrhea, and nausea. There's also the third component which is a correction constant, and I'll explain why there's that. The last component it's basically a penalty factor. So I'll walk through each component and the reason and the rationale behind choosing them. So one is that we pick the weight loss at 12 weeks. There are two reasons for that. One is basically, it's kind of a practical reason. It's because of the availability of data. There's a lot of early stage, Phase I results that don't have 36 weeks or even longer. So 12 [weeks], I think it's a good medium. And also, if you look at the titration usually for incretins, there's usually titration period in the beginning. Most of the patients will be almost through the titration period, or at least well into the titration period by 12 weeks. So that's kind of again, a happy medium.

The second component is the correction constant. And the reason that we have this is we want to have a standard. So basically, anything that is more tolerable than Tirzepatide, will get bonus points. Anything that is less, and I would say that through our research, I don't think anything has shown better tolerability compared to Tirzepatide. So that's a good goal to achieve.

And then lastly, there is a penalty factor. And the reason why we want to incorporate that is because we believe that the patient's perception of tolerability is not linear. So patients can tolerate a certain amount, in terms of frequency and severity of adverse events. But once the severity and also the frequency grow, that tolerance breaks down and the perceived tolerability worsens, I think in a steeper relationship then then then linear.

So, there is a penalty factor from 1x to 4x. So all together, that is the formula. And in the report, we kind of did one example. We did one CT-388. That's a dual agonist. And then the Tirzepatide score is seven to [CT-]388. That's about five plus. And I guess going back to the stock reaction, the scoring system really reflects some of the investor perception about [CT-]388’s tolerability profile. And so I think this is really kind of showcasing if you incorporate some of the penalty factor, some of the correction constant, and incorporating some of the frequencies of these adverse events, you can actually have a pretty objective yet simple way of putting or ranking some of the investigational agents in the obesity space.

06:59
Matt P
Yeah. No, I agree with you on a lot of that. You know, we always see kind of the news article headlines touting the percent weight loss, maximum percent weight loss, and, as you mentioned, that could be not the best thing to look at across trials based on different criteria, different titration regimens. So I do I think it's nice to have this kind of incorporation of additional factors that are clearly going to be important for the long term, I guess maybe just from this scoring system, you mentioned Tirzepatide had a seven. Obviously, that must be a pretty good score given the profile of Tirzepatide and you mentioned the other dual small molecule. I guess anything else that kind of stands out on this scoring system as you've done the analysis?

07:41
Andy H
Yeah. One thing is, if you compare two doses in a certain clinical trial, if you calculate the higher dose having a lower score, that usually indicates that the drug sponsor is a little bit more aggressive on the titration front, a starting dose or the final dose. So maybe in the preceding Phase II trial or Phase IIb, maybe it's more prudent to go a little bit lower and that might really optimize the clinical profile instead of continue to push that dose. So we see several examples in the report of that. There are also examples where you have actually a dose response, not dose response, but I guess a score response. So the lower dose, lower score, higher dose, higher score, and actually looking at the Tirzepatide clinical development the two doses are actually pretty similar.

So that is one example where I think the dose selection was actually really good. Now one thing I wanted to highlight is maybe it's a good tool to compare within the same class. So maybe GLP-1/GIP dual agonists might not be super suitable when you compare a different mechanism of action.

So if you compare with some of the muscle sparing agents, it might not give you a good answer in terms of which one is the best. So I would probably confine the utility of the scoring system to within the same therapeutic modality.

09:33
Matt P
Interesting. I'd like to touch a little bit more on another point you raised, and that is, currently, I think there's been real world data showing that the number of patients who stay on therapies for nine months, 12 months, especially longer than that, gets pretty low. And, you know, whether it be discontinuation due to tolerability or maybe it's, you know, kind of access and reimbursement, clearly there's some factors that are preventing more continuous utilization of these therapies.

You know, personally, I've always had an opinion that until we kind of solve that problem, it is going to be difficult to achieve some of these real peak sales numbers that have been thrown out. Just, you know, if you're constantly cycling through new patients, it just makes it hard to ever reach kind of these, you know, 150 billion or whatever number you want to put out their numbers.

So I’m curious to get your thoughts on that and maybe what you think can help overcome that major obstacle right now.

10:38
Andy H
Yeah. That's a good question. And I agree with you. That's a big unmet medical need in the obesity space and I completely agree with you. If you really want to achieve some of the numbers have been thrown out, that durability or the duration that patients stay on therapy, that's going to be a super important metric to look at.

So far we just haven't seen encouraging durability to support that number. So obviously investors are thinking about potential improvement on that front. So I think there are clinical trials currently that is attempting to answer that question. There is a Phase II trial called ATTAIN-MAINTAIN looking at transitioning patients from Tirzepatide to orforglipron, the small molecule GLP-1 receptor agonist.

So we'll see more and more maybe innovative trial designs coming out to answer that question. The maintenance phase is very interesting because it also alleviates some of the pressures that we have seen in the obesity space. Right? So, the idea that you can just maintain the weight loss and not induce active weight loss, I think this is kind of hand-wavy from a scientific perspective, but you probably don't need that much drug in the body to achieve that.

So with lower dosages, that might alleviate some of the supply constraints that we have seen. Or, you can potentially for injected route of administration, you can have longer dosing interval from once a week to every other week or potentially once a month. So those are all interesting maybe next leg of growth for the obesity space, as in innovation continues to drive more convenience, better tolerability, and to really kind of tackle this chronic condition.

13:01
Matt P
Yeah. Very interesting. You know, again, similarly, I do think that once monthly might help with that maintenance phase. You know, we'll see. We haven't seen all the data from MariTide’s Phase II yet. I think that will be at a conference this summer. So, that might help inform if that can have a have a tolerability profile and a dosing frequency that supports maybe that some of that maintenance utilization. But yeah, we'll see.

You know, there's a lot in this report and especially looking at all the different targets that are being explored. So similarly, these kind of next waves, one might be the maintenance phase, but clearly a lot of work on other targets and other routes of administration. So I want to just kind of touch on a few of those, first being the orals. I know this is always a big talking point with physicians and investors and companies on, “Okay, can you get better compliance with an oral versus, let's just assume, the once weekly?” And then right now we have both peptide-based orals and small molecule-based orals in the clinic. So, Andy, where do you sit on how much more benefit could be provided with an oral for maybe patient convenience and maybe anything that's looking promising?

14:16
Andy H
Yeah, it's actually a tough question just because if you survey investors about potential oral penetration rate, I've heard as low as 15-20%, all the way to 75%. So, we definitely don't have a consensus on the utilization. Where I land is there's a geographic mix, I would say. I think the delineation factor is really on income levels.

So I think in the US, where [there is] access to the high potency drugs, people will tend to want to have the SubQ option just to really get that velocity of weight loss achieving the maximal weight loss. Whereas middle- or lower-income countries, where access to refrigeration, for example, and pens, small molecules could be a very attractive option.

And you can make literally metric tons of those. So in a bottle versus injector pens per week, that is it is very attractive. So, I think for maybe middle- or lower-income countries, the utilization for oral small molecule drugs could be between 70-80%, but that number might be completely flipped for the US market, for example.

Now you mentioned about the maintenance. This is where I really struggle. I really don't know how patients might feel because if you have experienced a year of weight loss on an injected drug, maybe you want to stay on that. You can potentially benefit from a longer dosing interval, but it's the same drug. The biggest risk is really switching drugs, right? If you have like a Tirzepatide to an orforglipron, I think there's a theoretical risk that you might not be tolerating the second maintenance drug. It'll be much better if you can just transition from one drug, maybe injected to an oral, you know, later on. Maybe through a different formulation.

So that's kind of how I think about that. Obviously there's, you know, once orforglipron goes on the market I think we'll definitely see better clarity there.

16:40
Matt P
Interesting. Okay. So again, some more development stage. Let's call them some targets. One, I think that’s made some waves recently and some news is amylin. Maybe you can just tell us a little bit about this target and kind of where maybe some molecules are in development there.

16:58
Andy H
Yeah. So, it's not a new target. I mean, there's already an approved precedent before. Not well adopted, just because of the tolerability profile. I think some improvements are made for the second generation one. For example, the incorporation of the calcitonin receptor agonism to make it even more potent basically elevated the status of this asset.

So it's very interesting. I think there's a lot of development going on. This is where I actually am curious about your take since you're probably closer to that part of the story, the kind of recent development. I'm curious about your thoughts on that big pharma that recently entered into the space.

17:45
Matt P
Yeah. No, I think it was interesting to see another larger pharmaceutical company step into the obesity landscape with the in-licensing of the GUBamy molecule. It's in earlier stages of development. But I do think, personally, it kind of symbols like, okay, if you're going to want to step in with an amylin molecule , it probably signals that you have interest beyond just that molecule given everything that's going on in the obesity landscape here. Whether or not you feel you need a GLP-1 I guess is a question, but it seems like you're going to want to be able to explore combinations. Again, maybe it's the amylin in the maintenance setting or for patients who don't tolerate the GLP-1 specific side effects very well.

But I think it's good to see more companies getting into this space. You know, again, it's so large it seems like more will need to have some exposure. Whether that be through, again, trying to fast follow with the GLP-1 or maybe completely going after novel targets like amylin. So you know, I thought it was a decent deal. And again, the target does look interesting, particularly given just some of the differential activity and safety and just on target of adverse events compared to the GLP-1 class. So we’ll see where it goes.

19:06
Andy H
Yeah, for sure. I was actually very enthusiastic about amylin’s activity in the population where patients are living with obesity and also type two diabetes. Unfortunately, I think the recent CagriSema data, REDEFINE 2, did not show that. I was really surprised. And I was completely wrong in my thesis that, you know, the amylin’s differentiation in that higher risk population. So, yeah. We'll see hopefully full data will be released soon and we could really dig into the data once it's available.

19:40
Matt P
Yeah. Okay. So what about then another target, glucagon. And again, these are being developed in combinations I think primarily. What are some of the advantages and disadvantages of adding glucagon on to some of these other mechanisms?

19:55
Andy H
Yeah, so most of the sponsors looking at glucagon has a liver focus. It's expressed in on hepatocytes . So you know, maybe liver associated diseases that is also concurrently happening with the metabolic syndrome or insulin resistance. So those are kind of the applications there. And we've seen some data in the MASH field. So, basically the inflammatory fatty liver disease. So, I think that's the role of the glucagon is anything that has a liver application, that's where it could fit.

00:20:43
Matt P
I know some of that MASH is probably talk for another day but definitely been some interesting developments there and what was a major unmet medical need. So hopefully it continues to be the case. I think another kind of interesting one that also has a bit of a history is the cannabinoid type one receptor modulator target that had been previously been explored, you know, years ago, I guess.

And now coming back into focus, maybe what's the goal of these newer agents to try to avoid some of the side effects of the previous molecules?

00:21:14
Andy H
Yeah. The goal here is really to make it more peripheral, so no CNS access. That's the goal. Data has been mixed regarding the next generation CB1 modulators out there. So I think investors are still on the fence about whether, from a small molecule standpoint, can you really design a small molecule that can have limited penetration into the brain or the CNS compartment?

So jury's still out but if you kind of use a different modality, for example, in an antibody, maybe there is a way to kind of get the best out of both worlds. Right? You can have the CB1 blockade , which is validated, but also no CNS exposure. So again, we'll see. Data is coming in the second quarter of this year.

So, yeah. So that could answer a lot of questions about bio distribution.

00:22:08
Matt P
You mentioned, I guess both CagriSema and maybe the monlunabant, if I pronounce that correctly. Kind of maybe both disappointing, I guess. Is this a case of just investor expectations being too high? Or did they really not show that they maybe have a role to play in the landscape?

00:22:28
Andy H
Yeah, I think it's a mix between maybe management’s setting expectations and Tirzepatide being the free effective drug. So, it's rare to see that. I think usually when you add efficacy, you are also carrying concurrent penalty on the side effect front. We did not see that with Tirzepatide. So there's this hypothesis that maybe the GIP receptor agonism could maybe counteract some of the lower GI side effects. And that's really, really unique. And that creates a really hard bar for follow-ons to really beat, both on the efficacy perspective and also on the safety perspective. So that might be just a higher bar, I would say.

00:23:17
Matt P
Say maybe last topic to touch on is the muscle boosting targets. There's been I know a lot of press on how the GLP-1 class can lead to reduced muscle mass. You know, that is just part of losing a significant amount of weight, but it does create some concerns, particularly if a patient stops therapy and then rebounds and now has a lower metabolic baseline because of the lower muscle mass. It might take longer to come back.

So, a number of companies here looking to try to maintain or boost muscle mass while on a GLP-1. What's your thoughts on those approaches?

00:23:55
Andy H
Yeah, I am a little also on the fence about that. So the FDA recently put out a guidance that kind of talks specifically about that. They still are putting the most weight on BMI as a biomarker. And, you know, these measurements on lean body mass, DEXA scan , for example, it could be added to the data package, but it's not going to be super informative from a regulatory perspective.

So we will have to see how these agents will gain approval. What types of data is required? I think the consensus on the street is you probably need some sort of functional results or functional improvement. So it's interesting I think, at least for me right now, it's mostly a cosmetic argument unless you see really functional or outcomes-based endpoints. I'm waiting for more data to kind of formulate a more solid opinion on that front.

00:24:56
Matt P
Yeah, I agree with you there. Again, the drugs targeting myostatin and have been around for a while. We've all maybe, or a lot of us, have seen pictures of the myostatin cows and things like that, that are very muscular. But so far, it's been very difficult to show functional improvement with those therapies.

And in addition, you know, there's some companies when I cover that, you know, maybe if you go after activin plus myostatin , you could get even greater effect, particularly in humans. But the targeting of activin brings about the risk of lowering certain hormones in women that could make it tough to conceive, get pregnant. So obviously you come off therapy, it's not a permanent thing, but still, having that on the label, especially for, like you mentioned, something that might be more cosmetic, I think could be a major hindrance for the dual activin/myostatin combos . But, you know, we'll see. I know there's a number of companies running these trials, including the major acquisition of bimagrumab. Combining that with Tirzepatide, that'll be very informative when we see the results of that. And again, maybe get a little more regulatory feedback on what the FDA wants to see.

All right. Any other maybe targets or clinical readouts you're looking for in the in the coming 3 to 6 months, Andy?

00:26:15
Andy H
Yeah. I think the ADA conference that's in June in Chicago. I think that's going to be a big conference. We're probably going to see some CagriSema data. You probably know this way better than I do, with MariTide data, you know, so those are all from a conference disclosure perspective.

But we're also going to see some Tirzepatide cardiovascular outcome studies. That's one I am very much looking forward to really answering the question if GIP receptor agonism could lead to cardiovascular outcomes benefit. So that's going to be kind of the big event. So those are maybe in the short term that I'm looking forward to.

00:27:03
Matt P
Yeah. That they will be very important. Obviously Tirzepatide has had a great commercial launch and able to really kind of overtake semaglutide in some settings. And, you know, it shows even better outcomes that might just catapult that further. But for MariTide, there are outstanding questions on whether their increased titration or step-up can actually provide benefit or reduce the GI-related side effects.

And then also seeing hopefully a little bit more breakout of the efficacy across some of these different titration regimens and all that. So yeah, hopefully we see some more data and get a better get our view on the differentiation of that molecule.

All right. Well with that I think we'll wrap up this podcast. As Andy mentioned, lots of clinical readouts to come in a highly evolving landscape. So I'm sure we'll have you back, not too long, to maybe go over some of those updates.

00:28:01
Andy H
Yeah. For sure. Thanks for hosting, Matt.