Palatin Technologies, Inc. (0KF3) Earnings Call Transcript & Summary

Good morning, and welcome to the Palatin KOL webinar. [Operator Instructions] As a reminder, this call is being recorded, and a replay will be made available on the Palatin website following the conclusion of the event. I'd now like to turn the call over to Carl Spana, Chief Executive Officer at Palatin Technologies. Please go ahead, Carl.

Thank you, Sara. Good morning, everyone. I'd like to thank you all for participating in Palatin's conference call this morning with myself, the CEO of Palatin; and Dr. Jesse Richards, who's a Professor at the University of Oklahoma Medical Center in Tulsa. Today, as you can see, I think we have the title up, we're going to talk about the role for novel melanocortin 4 agonists in treating obesity and weight loss. Move forward here, just -- here we go. We do have forward-looking statements, so the lawyers are now happy. So -- sorry. So looking at the agenda here, I think we have a pretty good agenda here. I'll do a couple of introductory remarks, introduce Dr. Richards. I'll turn it over to Dr. Richards, and he'll go through his part of the presentation. I'll do a very brief update on the clinical trial that we'll be starting a little bit later this year, and then we'll have a question-and-answer session. So on this slide, there's a couple of points that I'd like to highlight on this slide that I think are important for how we think about melanocortin. Really, the second checkmark in is really sites that one of this landmark study showing the value of what happens when you have effective weight loss management. We take obese people, we bring their weights down. A lot of their metabolic parameters get better, cardiovascular system is better, diabetes, so on and so forth, and hypertension. And I think we're all aware of that. But if we move over to the right by 2, in order to maintain that gain, we've got to maintain the weight loss, right? So a lot of the current thought processes now and a lot of the focus has been on driving weight loss and more weight loss as we continue to think about that. And certainly melanocortin system will play a very key role there, I think, in conjunction with the current treatments that ones and other incretins that are in development. But I think we also cannot forget the importance that weight loss maintenance is going to play over the course of how the obesity treatments roll out over time. Because without the maintenance, we're not going to maintain those gains, and I think that's really what's important in the long run. And finally, on the last point that I wanted back is -- one of the key things we'd like to accomplish today is a reintroduction into melanocortin system and the key and critical role of melanocortin system plays in the regulation of body weight, body adiposity, energy storage and food intake. This is an extremely well-validated target. There are actually multiple melanocortin agonists already approved, one for rare forms of obesity, setmelanotide, which Dr. Richards will talk about today. But we have Vyleesi or bremelanotide for female sexual dysfunction, which is a Palatin-approved product, which actually was the first melanocortin product approved. We know from genetic studies that loss of function of melanocortin system, particularly MCR4 and its upstream ligand, leads to hyperphagia, obesity. So this is an extremely well-validated target. There are thousands of dose -- or tens of thousands of doses of melanocortin agonists in the commercial environment being given. So we already know that these can be given safely over a long period of time with both bremelanotide and setmelanotide. I think we're distributing, what, almost -- Steve, what are we? Somewhere around almost 10,000 doses a month for our drug. So these are already being established as safe and effective treatments. So I think the melanocortin system is going to play a very key role in both weight loss and as well as the maintenance side. With that being said, I'm going to introduce Dr. Richards. Dr. Richards is board-certified in internal medicine and obesity medicine. He's a Director of obesity medicine and the bariatric section and the Assistant Professor in internal medicine at the University of Oklahoma in Tulsa. What's interesting is as part of Dr. Richards' practice, he has a very large contingent of patients with syndromic and monogenetic obesity with setmelanotide, which is really the mutual interest that we came and why we actually got together and collaborated with Dr. Richards because he has a very strong interest in how melanocortin agonists can be used to treat obesity. So with that being said, I'm going to turn the presentation over to Dr. Richards. He'll talk about some of the interesting work that he's doing and his thoughts on how melanocortin can be used in the current environment. Dr. Richards, I'll get to your first slide.

Thank you so much, Carl. All right. One more?

Yes, here we go.

All right. So I actually was very fortunate to assemble across my collaboration with Carl. I actually was Googling brain fMRI, melanocortin 4 receptor. And I found the study on this little drug called bremelanotide that as an adult internist that specializes in obesity, I had never prescribed. And I looked it up and I went, wow, this has been approved for years. How have I never heard of this? Well, I realized that when I saw the name, the trade name Vyleesi, that it looked really familiar because my wife is a OB/GYN. And every time I walked into her office, I was walking past a poster for Vyleesi, and I just never associated the actual mechanism or looked into it. So go ahead, next slide. So this, again, an ongoing discussion. We have a really large clinical population here in the Midwest, unfortunately, at the buckle of the obesity belt as it were. We're a tertiary center, and we deal with a lot of severe, severe obesity. Probably the average BMI-ICN consults is like 55 and a very large patient population, especially native and underrepresented folks. So we see tons and tons of genetics. With this, I've been doing a lot of setmelanotide therapy for my patients over the past several years. And we've noticed this really just amazing response to MCR4 agonism. So with this in our clinical population, we're combining melanocortin 4s with GLP-1s. I've seen treating patients before and after bariatric surgery. And we're really seeing this like just massive increase in efficacy and changes with combination therapy. And so this is really what's sparked a lot of my clinical interest and passion in this space because I see folks that they -- because of their defects and problems, both environmental, genetic, epigenetic, hormonal and otherwise, like one monotherapy doesn't work, but combination therapy can truly be life-changing for them. So all right, next slide. All right. So let's just talk about like, I would say, the elephant in the room, but I think that really underplays it, like the blue whale, okay? GLP-1s have taken the world by storm. They have completely redefined how we think of obesity. While the medical community has been well established and settled that obesity is a medical disease for a decade, at least in my subspecialty, the lay public really wasn't until the improvement in medical efficacy and tolerability that we saw with GLP-1s that we saw this widespread interest. The main problem with GLP-1s is not that they don't work; they do. The main problem is that they don't work for everybody and that there are a number of significant AEs, specifically the GI ones and specifically the concerns about lean mass, and that can be limitations. We have a lot of folks that do absolutely fine on low doses of semaglutide or tirzepatide. But when you try to dose increase them to a long-term maintenance dose, say, 1.7 or 2.4 for sema or get up to that 10 to 15 milligrams if folks don't respond great to low doses, they just don't tolerate because of severity of the nausea or the diarrhea or the constipation, especially if they have any sort of baseline GI issues. And this has been well validated in the clinical trials. And by and large, most folks tolerate them. But there is also a significant section of sub-responders, patients that just don't achieve a clinically relevant -- I want to differentiate. Obviously, FDA approval is 5% or more. And most folks on current generation or next-generation therapies are going to hit that. But clinically, at least here in the American Midwest, we really are talking more like 20% and then being able to maintain that long term. Unfortunately, the running joke is that BMI 31 is Oklahoma skinny. Or when I went down to Alabama recently, I was talking to some other docs, they said 300 pounds is a mobile unit. So this is areas where you have severe, severe obesity that 5% or even 10% is helpful, but it's really not moving the scale enough to get patients to a clinically resolved round. That's where we need combination therapy because, next slide, shockingly enough, the body is really, really good at not dying from starvation. Now I'm not going to go through this whole slide. I could spend 45 minutes or more just going to this slide. I know we have a lot of other stuff to cover. But I really like this one because it really shows that on the bottom left, you have all of these gut access signals. So this is the afferent signals leading from the gut, giving the brain information on the nutrition status of the body. Do we have nutrients? Are we going to starve? Do we need to go out and fight a pack of lions to get a wildebeest carcass for some nutrition? This is really like what your brain does in terms of risk-benefit analysis. And through all the signaling, which we're agonizing with peripheral incretin analogs, you then get transmission up into the brain through a complicated hypothalamic and other CNS pathway feedback system to then your brain tell your body what to do in terms of acquisition and control of metabolism. So I kind of view this as how we would treat hypertension. Obesity is actually very similar in medical, at least in my medical mental schema, to how we would do that. So we might give a medication of vasodilates. We might give a medication that controls the amount of sympathetic hormones that kidneys secrete. We might de-integrate the kidneys if we have just a severe terrible situation where there's already a vascular disease. You might go in and surgically alter the blood vessels. All of these different things can play a role in control of the thing. I view this very similar with medical and surgical treatment in the pathway of obesity. The really -- the nice thing here, though, is that while your incretins are giving you a peripheral signal in the melanocortin system by agonizing the final step in that pathway, you skip over the potential for any sort of genetic, epigenetic or other neurohormonal abnormalities to prevent the signal coming back out of the brain to the periphery of the body. So especially our melanocortin 4 agonists have lots of downstream effects on the body, both in terms of body composition, neurohormonal modulation and other protective things, especially in a weight-reduce setting. So that's kind of the mental schema that I use when treating these folks. Okay, next slide. So all right, we already know, as Carl alluded to, that bremelanotide has been shown in prospective studies to actually spontaneously drive or reduce the calorie intake. So we have a short-term weight loss there in human. And then in setmelanotide, we actually have safety data from the multiple ascending doses and the weekly depot formulations showing that there is, in just healthy volunteers, a signal towards body weight improvement. Now it's not as much as the patients that have a dysfunctional melanocortin 4 pathway, either a syndromic BBS or with monogenic homozygous knockout, and this makes sense. If you have an insulin deficiency, type 1 diabetes, you might need 10 units of insulin. Whereas if you have a relative insulin resistance because of all sorts of other things going on in your body, 10 units of insulin will lower your blood sugar a little bit, but you might need 50 or 60 or 70 units. So all of this absolutely matches our neurohormonal understanding from other areas. Next slide. So in our clinic, we have lots of patients that are on combination therapy because, unfortunately, one of the complications from Bardet-Biedl syndrome is diabetes. It's actually one of the diagnostic criteria. So the large percentage of our patients have diabetes and are being treated for blood sugar control and cardiovascular protection with GLP-1s. And we actually looked at patients that were on combination therapy. They were seeing our dietitian. They were getting lifestyle, as you would expect, in our sort of multidisciplinary clinic. And then they were put on setmelanotide after being diagnosed with syndromic BBS and then were put on tirzepatide for glycemic control for cardiovascular improvements. And we saw just radical, radical improvements in body weight. So as you can see here, 26% of total body weight in 34 weeks; 30% of total body weight in 52 weeks. And that sounds great, but the kicker here is that these people were on 2.5 milligrams of tirzepatide. They never dose escalated. In fact, patient 2 here, she tried to dose escalate to 5 for a couple of weeks, okay? She reported so much appetite suppression that she just really didn't feel like eating and actually asked to go back down to 2.5 milligrams because she felt very comfortable there with her rapid but effective weight loss. So this is something where we know from the global hypertension organizations guidelines that you can give someone 1/4 of the dose of Losartan and get 40% to 50% of the efficacy for blood pressure lowering. And you give them the next 75% of the drug dose and you're going to have higher rates of AEs, and you're really only going to get an additional 40% to 60% response. That last 50% only has about 25% of the blood pressure lowering efficacy. So standard of care in both cardiovascular treatment and in [ hyperphagia ] treatment is to do lower doses of multiple mechanisms of action. And I think this is a great analogy for patients that have a -- it's peripheral to CNS effect from the GLP/GIP signaling and then have a CNS back out to periphery effect from the MCR4 agonist and, therefore, because it's a lower dose, tolerate very well. But we see, instead of sort of like a reciprocal inhibition, some sort of reciprocal almost potentiation. All right, next slide. So the other thing that we've found fascinating because as you might imagine, I deal with low SES patients and a lot of them lose insurance or change insurance, and so they might be on tirzepatide for diabetes and then they lose their insurance. Well, when you lose your insurance, you're not going to stay on tirzepatide for diabetes. You can get switched to another med or you're just going to have to control it with a non-GLP-1 medication because of cost. Well, we see rebound off of these meds all the time. And we'll just over and over again try anything and everything we can do up to and including talking people into bariatric surgery because they just don't want to be hungry anymore and want to be able to maintain their health off of long-term medications. And the really interesting thing we found is this was one -- actually, a follow-up of the patient I mentioned above. She lost tirzepatide coverage, unfortunately, with just insurance changes and policy rules and everything else, no longer had that. And you would expect after seeing a patient go from a BMI of 76 to a BMI of 53 on a GLP that when you stop the GLP, they would regain weight. Well, she was able to continue setmelanotide. And actually instead of rebounding, her weight -- her rate of weight loss slowed down, as we know, about 10% a year in patients with BBS, although there doesn't seem to quite be the same plateau in those folks. But instead of rebounding, she continued to just slowly trend along and lose medications. The really interesting thing here is that we know that with GLPs, we have multiyear data and long-term studies are ongoing right now in the 3-, 5-year time range and even longer that if you maintain the dose, you maintain the weight loss. But because of coverage and all of these other things, there is a lot of interest in alternative options, especially if people develop intolerances or, because of other reasons, can't stay on the medication for alternative mechanisms to help maintain weight in a weight-reduced state. The body is really good at adjusting neurohormonal adjustments in order to not maintain a weight-reduced state, which is what leads to the classic weight cycling back and forth that we see with folks that lose large amounts of weight just with lifestyle. And it's really something that we want to avoid. In the huge NIH symposium that took place a couple of years ago talking about the alterations in human physiology in the weight-reduce estate, one of the big things that we see here is that there is both a neuro adjustment in both reward, energy drive, a number of pitutary hormonal signaling profiles and energy expenditure. And there is this major shift in patient perception about food intake. So you're really going to get it from both sides. And it makes it very difficult just from a lifestyle basis, especially, let's be honest, we live in a very obesogenic modern society. I tell people how to find my clinic by the fact that we're located behind a Wendy's. And I know that they actually find it because of that because when they tore the Wendy's down to rebuild it, our no-show rate went up for 3 months. So this is just the reality of the world we live in. So something that actually helps from a neurohormonal perspective to maintain weight loss in the long term is a very attractive option. So next slide, please. We know that melanocortin 4 signaling, because it's downstream from leptin, is very useful in that weight-reduced estate. Now the other issue is that while GLP-1s are absolutely fantastic, they don't work for everybody. We know even from the Wegovy trials, even with folks who have intensive lifestyle changes, not all of them have a clinically significant response in weight. Not all of them even meet the FDA approval. So we had a patient here, came in, motivated, physically active lifestyle, was just really struggling and got -- followed a dietitian, got lifestyle, I kind of sent him on stuff. We got him on some Ozempic, titrated up to 1 milligram, didn't have any terrible, terrible side effects, but had enough to absolutely know that he was taking the medication, we verified and everything. Unfortunately, it really didn't do anything for him. He took the medication, worked up to a reasonable treatment dose. This was back when lower doses where all that was available. And with the genetics where we were testing and some of these other symptoms, we tested him and found genetics that were suspicious for BBS and instituted a clinical workup and diagnosed him. We started him on setmelanotide. I literally did not recognize him the next time he came in because he came in and he was down 37 pounds. And I said like, are you okay? Is something wrong? And he's like, no, I'm just -- I'm working my physically active job and I started the medication. And oh, yes, I don't crave sugar anymore, so I stopped drinking sodas. And he just have this kind of laundry list of all of these things that just in his head, for some reason, they just suddenly made sense and he didn't need to do. And so on the therapy, he's down over 100 pounds and his BMI just gradually drifted down to a stable body weight. He is now at maintenance, pretty much living a healthy life and just checking in every few months. So this is one of those things that because of the massive scale of obesity, hundreds and hundreds of millions of people, everyone goes like, well, there's an 80% response rate, 90% response rate. Well, that's true. But when you look at how many people even in the United States are either going to have to discontinue GLPs due to tolerability or are going to fail to respond, there is still a 10 million, 20-plus million person market in folks that are going to need alternative therapy solutions. So all right. With that, that's kind of what I've got for now. I'll hand it back over to Carl. He's on the next slide. I think you're on mute, Carl.

Yes, I'm off mute now. Yes, thank you for that. And I said I'm coming in. I'm going to -- I'll go through a couple of things on the Paladin side and really end with the trial design that's upcoming that we've been talking about. For those that aren't aware, we've had a very long-standing interest in melanocortin. Actually, all of our programs are melanocortin-based and have actually very long-standing interest in melanocortin in the treatment of obesity. I think we are very well situated based on the assets that we have to really move a next-generation melanocortin agonist forward. We have a very in-depth knowledge of the structural function relationships between the various effects that melanocortins can have. We actually have assets in bremelanotide, which is FDA-approved for both for female sexual dysfunction. You'll see on the next slide, as Dr. Richards alluded to, it is quite good at reducing weight or food intake and weight. We actually have what we will call the next generation or improved next-generation melanocortin 4 agonists or extremely specific for melanocortin 4 receptor. They will be peptides that have extended availability. So we're talking about 1 week -- at least minimally 1-week duration treatment. And then beyond that, we actually also have orally active small molecules that are active against the receptor as well. So if we think of our assets in this space as in 3 parts, bremelanotide is here and now. We can use that in various studies to interrogate how best to use melanocortin agonist in the treatment of obesity in the current environment and weight loss maintenance. There may be roles for bremelanotide specifically in things like hypothalamic obesity or other indications where we may be able to use it directly. But longer term, we're thinking about bringing new compounds that have better profiles for long-term treatment of -- long-term use of melanocortin in the treatment of obesity. So this is published data. This is what Dr. Richards had alluded to. This is using bremelanotide. On the left, you see a 2-week study in obese patients. And as you can see, you have a very -- by the graph, you have a very rapid reduction in food intake and corresponding weight loss. And these patients lost somewhere around 2.2 kilograms on the drug over the course of the 2 weeks, matching -- it matched the caloric reduction as well. On the right, it's a very interesting study. This was looking at the dose proportionality. And this is a very interesting thing that you see with melanocortins. You're seeing on just what -- there's either 1 or 2 doses of patients given, that's it. And you can see with one dose, you see a reduction in caloric intake and some corresponding weight loss. And then you give them 2 doses a day, and you see almost a doubling of that. So this shows that the effect is rapid and it's additive with dose. So I think it's pretty clear from work we've been doing and a lot of the preclinical work that we have and literature in the use, of course, of setmelanotide that not only do these drugs will melanocortin agonist work in syndromic or monogenetic or syndromic obesity, they work in generalized obesity as well. So we don't believe it to be just limited there. So again, this is just a quick little look at the preclinical work that validates what Dr. Richards is seeing in the clinic. In this study, we're giving PL8905, it's a selective MCR4 agonist, peptide agonist, has about 300, 400 more selectivity for MCR4 versus MCR1. This design was to limit some of the skin darkening, as you can see, a very potent agonist against the receptor. And here, we're giving it with a GLP-1 agonist. So GLP-1 agonist is given by mini-pump. So it's infused continuously, and we're adding in various doses of 8905. And you can see, if you look at just the gray line, the black line at the bottom and then first line in gray one, the gray is giving just the melanocortin agonist by itself. And then if you give it in the background of the GLP-1, you can see a dramatic increase in the weight loss. And that also corresponds, if we're looking at the food side, food intake side, it corresponds with that as well. On the right, it's just a simple little experiment in an MCR4 knockout animal to show that 8905, indeed, its weight loss is being driven through MCR4. If you don't have the receptor -- the mice on the left, they have the receptor, you can see that they lose weight. And then on the right, these are MCR4 knockouts and they don't lose weight. So this is -- so the effect we're seeing here is indeed driven by MCR4. And again, we're seeing preclinically this type of data and then Dr. Richards is translating that with his work in the clinic. This is very exciting to us. And I think on the next slide, in discussions with Dr. Richards, we realized that we can use bremelanotide to see if we can expand out and really take a very more rigorous look in a randomized controlled trial at the combination of tirzepatide with an MCR4 agonist, meaning bremelanotide. This is a study that we have that's cleared through the FDA. We're ready to begin enrolling the patients, which should be somewhere around midyear. So in this study, we're going to be giving tirzepatide 2.5 milligrams. And then for a period of time and then they'll transition into 1 of 4 treatment arms. They'll go on tirzepatide plus bremelanotide at 1.25 milligrams; tirzepatide plus placebo; bremelanotide plus placebo; or placebo and placebo. So this has got all the appropriate controls for us to really rigorously look at how combination therapy works. So in the primary endpoint, we'll be looking at the tirzepatide plus bremelanotide in comparison to tirzepatide alone. We should anticipate seeing an enhanced increase in the weight loss over the treatment period on bremelanotide alone compared to placebo. On placebo arm, we might expect to see a rebound. Those patients should potentially begin to gain weight, so you're removing their therapy. And we're looking -- as we compare the bremelanotide alone to placebo alone, we'll be able to take a look at somewhat what the weight loss maintenance part might look like. So this is a well-designed study. It's going to allow us to take a look at a number of different clinically important questions on how melanocortins can be used in the current environment. And so we're very excited to have the study and have Dr. Richards' input and leadership on getting this study done. So again, I just want to reiterate how we think about -- we don't think about it just on the weight loss side. We really also, as Dr. Richards alluded to or discussed, the melanocortin system does play and I think will play a very key role in reversing or addressing some of the neurohormonal changes and other changes that occur when a patient comes from a state of obesity to a calorically reduced state where they lost their weight. And they're now -- there's this drive or push by the body to essentially go back to -- we don't have enough energy, we got to go back, we got to get that weight back on. But the melanocortin system is fairly well suited based on the science, and the information from that NIH meeting is actually available. I thought if you're interested in this weight-loss maintenance, I highly suggest you go get that information. It's quite an interesting read. But melanocortins will play a very key role here as well to counteract a lot of the issues that these patients are facing and not only do they do it at much lower doses. So we think about both the weight-loss side and the weight-loss maintenance side. Long term, we believe that there's going to be a very key role from melanocortins in the current environment. And that when we think about it, we're one of the few companies that have the appropriate assets and knowledge and experience in bringing these agents forward. So we feel that we are very well positioned to be a major player in bringing melanocortins into the general obesity environment and the weight-loss maintenance environment. I think that's the last slide that I have. I hope that from the presentation slide that you have got some of the key messages and have learned something from Dr. Richards' extensive experience. And we're going to now open this up to the Q&A.

[Operator Instructions] So our first question comes from Joe Pantginis at H.C. Wainwright.

Thanks for hosting this call. A lot of great details. Can you hear me okay?

We can.

Great, great. So I'd like to start with Dr. Richards, please. So obviously, a very promising data and some of the work that you've done as well. So tongue-in-cheek, beyond patients losing their insurance coverage for semaglutide, I want to be able to use your experience to be a little bit of a fortuneteller, if you will, about how you see the combination approach evolving because you have a lot of multiple factors impacting the rebound effect, side effects, where do you feel melanocortins can come in through combo or maintenance. So I wanted to get your views on how you see it evolving.

Sure. Great question. So -- and I want to be clear, we don't just do combinations with MC4 and GLP, like GLP phentermine/topiramate in that format, like if you have a med, they can cause weight loss and my patients might benefit from it. I'm willing to play around with it. The big thing that I see in terms of combination therapy in the long term is, one, avoiding the dose-dependent AEs that we get. So if you can get a similar or better efficacy with a lower dose of a 2-drug regimen, then you have much better tolerability. And then from a long-term standpoint, just unfortunately, we know that there are a lot of people that have chronic side effects from some of these medications. Like one of the big problems with phentermine/topiramate is that there's the long-term side effects from topiramate that people are willing to put up with during active weight loss and they just don't like when explained that they're going to have to live with those for the next 20 years. And so I really think that because, at least in my clinical experiences, class medications tend to be tolerated quite well, I know some of the trials offset were -- had a lot of AEs, but that's a dosing issue. And I see a lot of folks that they're very much interested in the best side effect profile that will allow them to comfortably maintain. And the key here is the word comfortably because it's not that high-dose GLPs don't work for weight maintenance, they do; but if you miss a dose, you might start regaining weight within 3 to 5 days in a lot of cases. And everyone is trying to figure out how to predict that and all the other stuff, but we're still years and years away from that from a scientific standpoint. So I think that when basically combining medications to get to weight loss, you basically add on or go with combo therapy to get there and then you start peeling back components until you get to the one that is best tolerated and most conveniently dosed. And so I'd say those are the 2 things that I see from patients in terms of weight maintenance. So if they're tolerating a medication very well, great, then they're fine staying on it, even if it's, say, it's a once-a-day oral instead of once a weekly or even if it's a once-a-day injectable. But the other thing is that if we do have more convenient formulations à la weekly, biweekly, something in that area and it still has the same tolerability, then less frequent is obviously preferable.

That's very helpful. And I guess from the company's trial perspective, one of your secondary endpoints is lean muscle mass. So I'm just curious, obviously, there's a lot of observations depending on the drugs, the impact on lean muscle mass for the GLP-1s. But can you provide sort of any of your predictions or earlier data that might talk to melanocortin's impact on lean muscle?

Oh, 100%. So this has actually been shown in a number of long-term, 12- and 24-month studies in setmelanotide in human subjects that there's actually a lean mass protective or, in some cases, like the leptin receptor-deficient patients, a lean mass increasing effect despite total body weight loss. In preclinical models, this is very much supported because of the increases in energy expenditure, adjustments in sympathetic tone and other things that you have, it actually can potentially help with nutrient partitioning and the increased physical activity and the overall stimulant that you get actually has the potential to hopefully blunt some of the loss of lean mass. Now tirzepatide is relatively well tolerated compared to some of the other GLPs with more of like 25 to 30 instead of the 35 to 40 that you see with some of the other analogs like retatrutide or semaglutide. But I'm very hopeful to see improvements in body composition with this combination therapy because that is one of the -- I would be honest, I have seen staggering improvements in body composition clinically even with a very modest and slow rate of weight loss. And so I do believe that there is a melanocortin-specific MOA that helps with repartitioning or the improvement of body composition.

Steve, I'll turn it over to you to read some written questions while we wait for the other analysts.

Thank you. All right. The first question, what do you believe are the most important attributes of a melanocortin agent in treating and/or maintaining weight loss in obese patients that may be superior to the current standards of care?

Okay. One, I would say tolerability is going to be improved versus some of the currently available medications, at least in my clinical experience. And then, two, they have a different side effect profile. Just we don't see as many of the GI issues. And we do potentially, anecdotally, you just hear folks that tolerate the medication quite well and feel better when they're on it. That's hard to quantify. But I do think that because of the -- there's been a lot of concern around GLP-1s from a new perspective, which is my personal opinion is a little bit overblown, but there are a lot of concerns about other interactions or other things that I don't see quite as much of an issue with the MC4 agonism.

All right. Next question. How significant an issue is weight regain post the use of so-called miracle drugs and the rebound effect? And does this end up as a race that you never finish?

So this is the deal, in a perfect world, I wouldn't be terribly concerned about it. But in the reality of treating patients and the current coverage and access issues, it's a major issue. I would say probably 60% of my patients -- yes, 60% of my patients that have been on a GLP-1 have been forced to completely discontinue for at least 1 to 4 months at some point. And we know from the prospective studies, like we're talking like thousands of people in prospective studies that the vast majority are going to regain probably 2/3 to 3/4 of the weight within less than a year. Now in terms of the like is this like a hamster wheel, I would say no. But kind of, again, reframing it in the context of hypertension control, if you're on a 100 milligrams -- or sorry, 50 milligrams of HCTZ and you get your blood pressure under control, but you're having side effects, would you potentially switch to a different medication to maintain blood pressure control with a better side effect profile or if there's a shortage? Yes, absolutely. That's the nice thing. Back in the '80s and '90s, we had like 3 or 4 good drugs, and now we have 50 and counting that are all reasonably tolerated. And additional options are absolutely needed in obesity because we have such a huge population with a variety of pathophysiology in play.