Corbus Pharmaceuticals Holdings, Inc. Study result

Good morning to those of you who are listening in this morning. We appreciate you being here. I'd like to welcome Dr. Harold Bays. Professor Bays is board certified in endocrinology and internal medicine. He's a member of numerous scientific and medical associations and fellowships. He's also the Medical Director of the Louisville Metabolic and Atherosclerosis Research Center, known as the Monroe Biomedical Research, and a clinical associate professor at the University of Louisville School of Medicine. He has served as an investigator in over 700 phase I all the way to phase IV clinical trials. He is the Chief Science Officer of the Obesity Medicine Association and the Editor-in-Chief of Obesity Pillars®, the Journal of the Obesity Medicine Association. He has written and/or served as contributing author for approximately 400 peer-reviewed scientific manuscripts and book chapters, hundreds of abstracts in major scientific meetings.

He is also the recipient of multiple scientific awards. Dr. Bays, thank you for being here. Thank you for being part of our study. We really appreciate that. With that, let's look at some data together. I think the overall arching question around this project from its inception was, can we design a safe and tolerable CB1 inverse agonist with competitive weight loss to incretin therapies? Obviously, there's a lot built in there. Fundamentally, the question was a question of essentially engineering. This is not a novel target. Those of you who have heard us talk about this over the last 3 years or so, or are familiar with the literature, will recognize that this GPCR, the cannabinoid type 1 receptor, has been extensively characterized for the last nearly 30 years.

We know an enormous amount about where it's found, what it does, and its role in metabolism. The question has always been, rather, can we engineer out the issues that were associated with that first generation of CB1 inverse agonists? 20 years ago, and Dr. Bays and I will touch upon this a bit later, 20 years ago, this was a very high-profile mechanism of action for obesity and associated morbidities. Multiple big pharma were focused on this mechanism, but the focus was to target the CB1 inverse agonism, the action of it, in the brain. These were highly brain-penetrant CB1 inverse agonists. With the rise and subsequent fall of that class, a new effort came about, and the idea was to try and exclude the action from the brain and rather focus it on those peripheral organs, where CB1 is involved in metabolism.

What is unique about our compound, CRB-913, is that it is an exceptionally peripherally restricted CB1 inverse agonist. Just to put that a little bit in proportion, we are at about 2% of the brain levels, or the brain penetration of, for example, rimonabant, a member of that older generation of CB1. Or compared to monlunabant, a recently discontinued CB1 inverse agonist from Novo Nordisk, we are 15 times less brain penetrant than that drug. What has been lacking to date in this field was a tool, was a compound that could truly be thought of as being peripherally restricted. A summary of what you are about to see here today. CANYON-1 is our phase I-B study that explored the efficacy and safety, or I should say safety and efficacy of CRB-913. It enrolled 254 patients across 15 sites in the U.S.

The trial represented a well-balanced representation of the population of obese patients or patients with obesity in the United States, with an average BMI of 37, and of whom 71% were female. The efficacy that was achieved for our top dose, which was 60 milligrams of daily CRB-913, was an average of 5% at 2 weeks with no sign of plateauing. All participants who had completed treatment at that top dose lost weight. Of course, equally important, the emerging safety and tolerability profile appears to be favorable, with a favorable GI tolerability profile versus published data, especially on oral GLP-1s. Most importantly, psychiatric AEs that are broadly in line with the GLP class and markedly different than the older generation, or for that matter, Mounjaro of CB1 inverse agonist. This is a very simple schema of study design.

It is a perfectly ordinary initial proof of concept dose range finding study in obesity with 3 doses as well as a placebo, and using a titration window of 2 weeks, which is fairly standard for these earlier stage studies. These are baseline demographics, and as you can imagine, and as you have seen in so many other U.S.-based studies, the average patient that the study ended up with was female, typically middle-aged, and weighing just over 100 kilos with a BMI of about 37. We will start with the efficacy, because at the core of this question is, does it actually still work? Can you exclude the CB1 inverse agonist from the brain without compromising its efficacy?

The first signs of that were with Mounjaro, but we are delighted that a much more extreme or much more pronounced exclusion from the brain yielded the same type of efficacy or in line with what was seen with Mounjaro. First thing I will point out to you is a very well-behaved placebo cohort. Then we have what appears to be a very satisfactory dose response with nice separation between the 3 doses explored. All 3 doses were statistically significant compared to placebo, as you can see. We have a nice separation as the titration comes into effect between the doses. A reminder that very similarly to what you see with the GLP-1 titration scheme, initially, all the patients are on the lower dose, and then as time passes by, more and more patients get to experience a higher dose of the drug.

Importantly, in a 12-week period, there is no sign of plateauing. That, of course, is very satisfactory for us to see. The mean weight loss using an efficacy estimate that was seen in our top dose was 5%. Another very common way of looking at this would be a threshold analysis. In other words, how many patients lost X amount of weight at 12 weeks? A reminder, this is a short study. It is just 12 weeks. We are delighted that it appears like so many other weight loss studies that you have seen recently from GLP-1s, with the vast majority of patients losing a certain amount of weight, then as we move those thresholds upwards, we start to see the real differences between the doses. There were high single-digit patient members who lost more than 7.5% of their weight in 12 weeks, which is, of course, very encouraging.

The highest weight loss seen in the study was in the 60 milligram cohort, that was an individual that lost just north of 13% of their weight. So obviously an outlier, but it is always nice to see that. This is a slide that, of course, has a caveat. These are cross-trial comparisons, so we need to be careful and cautious as we approach it. Nevertheless, it gives us a certain amount of taste for the context of what does a 5% weight loss in 12 weeks look like compared to oral GLP-1s, which after all, are the most relevant comparison in terms of efficacy or comparing a daily tablet to a daily tablet. I think what we can say is what is emerging so far in this period of time is something that looks to be in line with an oral GLP-1.

Of course, I will reemphasize, this is not a GLP-1. It is not an incretin targeting drug. CB1 is not part of the incretin super family. It is a completely orthogonal, completely different target that does very different things. So we found this to be very satisfactory and encouraging as we begin the journey with CRB-913 in terms of what could it eventually yield in terms of weight loss. Of course, this story is not about efficacy. It is really the safety that is so important. CB1 inverse agonism has been known to cause weight loss for decades. The question is: have we managed to engineer out some of the safety issues that plagued that first generation, and for that matter, plagued monlunabant? This is a slide where we focus on the worst possible adverse events that could happen. So severe TEAEs and serious TEAEs and their equivalent for TRAE.

We had very few severe TEAEs. None of them was psychiatric or gastrointestinal, which was wonderful to see. We had very, very few serious TEAEs, treatment-emerging adverse events. When we look at the treatment-related adverse events, in other words, adverse events are adjudicated as being as a result of the treatment, the picture improves even further. We have the sum total of just one single severe TRAE in the 40 milligram dose, that was a headache. We had no serious TRAEs whatsoever in any of the cohorts. Lastly, looking at treatment discontinuations due to AEs. So due to any AEs, we had some ranging from 3.1% all the way to 13%. You will notice that we have those in placebo as well. This is obviously a double-blind, placebo-controlled study. Patients do not know, nor does the physician know, if they are on active or placebo.

And then if we dig further into the type of AEs that cause discontinuations, we see that we have some that are psychiatric in nature, although remember, none of them was serious or severe. These were all mild or moderate. We even have one such event, for example, in placebo. So this was a participant who judged themselves or were judged to have a psychiatric adverse event that led to discontinuation while being on placebo. We similarly have even fewer GI causes of discontinuations. The total rate of discontinuation for any reason, be it an AE or not, was on average about 20%, which is about standard for obesity studies these days. Of course, a similar number was seen for placebo as well. Let's dig a little bit deeper into this.

If we focus on every single psychiatric AE that we had in this study, and a reminder, they were all either mild or moderate. None were severe or serious. The following picture emerges. Suicidality, there was no traces of suicidality. Much to our delight, we had just one case of depressive symptoms. It was moderate, and like all the psychiatric AEs here, that case was transient and resolved. It was a moderate case of depressive symptoms at the 60 milligram dose. We had low values for anxiety, as did placebo. Our anxiety does not seem to be either dose-dependent or particularly different than placebo. Similarly for insomnia, low values as are seen in placebo. Lastly, irritability. Irritability does seem to be a hallmark here. Our irritability was all mild. It was seen only with a drug not on placebo.