Rhythm Pharmaceuticals, Inc. Common Stock Morgan Stanley 24th Annual Global Healthcare Conference

Yeah. Thanks, Mike. Yeah. Just to set the stage on Rhythm a bit, it's a good moment for the company. For those who are following, we like to set the company framework up, getting people to think about three pillars. Obviously, we're working on melanocortin 4 pathway. Our first approved drug, IMCIVREE, first-generation product, was approved in 2020. It's now approved in a couple of genetic, Bardet-Biedl syndrome in 2022, and most recently, HO in the spring of this year. The three pillars we're focused on are a genetic pillar, and we think there's a number of genetic causes of impaired signaling through the melanocortin 4 pathway.

We did the EMANATE trial and the DAYBREAK trials, which were not positive, but they provided us a lot of information and I think gave us a sense of how we are going to tackle that pillar next, which is taking the genes of greatest interest and focusing on trying to determine the variants that have true loss of function, because with that understanding, then you can run those trials with a much higher probability of success. I think we're pretty confident that the biology, of course, is going to work there. The middle pillar is hypothalamic obesity, 10,000 patients, significant opportunity. I'm sure we'll talk a little bit more about that. Launch is underway. The third pillar is Prader-Willi, and we released some preliminary data out of a study, open label study by Dr. Miller using setmelanotide.

We've told the world, which we will update everybody on which assets specifically we'll take into phase III and then try to give people some sense of timeline, some before the end of the year. Prader-Willi is, as I said, third pillar, and it's a significant opportunity. I think we're quite convinced that the biology is real and works there, and we plan to invest accordingly, and so that'll be a major effort for Rhythm going forward in 2027.

Yeah. HO is interesting. I'll contrast it with Bardet-Biedl syndrome, our first approval in 2022, which is, as I said, about 5,000 patients and really a classic ultra-rare disease. It's a genetic disease. It's a syndrome. These patients have classic ultra-rare disease challenges trying to get to a diagnosis. Very few experts. There was only one center of excellence in the U.S. when we launched. We've now helped the development of about five other centers. But that's a world where you continue to find patients, and you'll continue to find patients for the next decade, two decades. We expect that opportunity to grow and grow steadily, but a modest pace, and it's driven very much by, it just takes time for these patients to come to awareness, and part of the challenge is there's not a concentrated way to tackle that disease.

They are often cared for by primary care physicians. There's no dedicated specialist who's taking care of them. Although they may see any number of specialists and get to a diagnosis, there's not a concentrated point where they're being taken care of uniformly. HO, in contrast, which is this entity most commonly due to occurring when patients who have a tumor in that area of the brain, hypothalamus, and pituitary in that region, they get it resected. These are benign tumors, but in the process of that treatment, resection and/or radiation, the hypothalamus, that part of the hypothalamus gets damaged where this pathway sits, and so they lose the signaling. They have a loss of alpha-melanocyte-stimulating hormone, which is the key signaling hormone in this pathway. They literally come off the surgical table hungry and are gaining a pound or two a week. That's a classic presentation post-surgery.

There's a very clear before and after to these patients. Up until now, patients going into surgery, about 80%-85% of them will have one or more hormonal deficiency, hypothyroid, adrenal insufficiency, et cetera. They are educated on that when they go into surgery. The surgical team will tell them, "You may develop hypothyroidism, but we can treat that. We can replace your thyroid medicine. It's okay." As a rule, they are not told that hypothalamic obesity is a possibility, and that occurs in about 50% of the patients. Part of the reason they're historically not told is, A, the surgical team may not be so cognizant of it.

Secondly, even if they are, it's one of those situations where they tell the patient about a potential complication and the patient and their family go, "Okay, so what do we do if that happens?" We do not really have a treatment. You have created a level of anxiety in the patient and their family without being able to give them some reassurance that you have a way of dealing with that. That is the world that we have entered into, really a devastating complication. The beauty of this treatment is in HO, it is really a pure. The drug itself taught us what was the cause of that disease.

It was a little bit, I think there were a number of hypotheses not so clear going into our trials, but the response to a precision medicine, this melanocortin 4 receptor agonist, literally a hormonal replacement, taught the world that that is the underlying biology for this. That is where we are. The team, out of the gate, what has been surprising, as we get a little bit surprising to me, maybe it should not be based on what I just told you, is the level of awareness, even among endocrinologists, is, I would say, modest. It is not like they are taught about this during fellowship training and the like. It is a relatively new disease, back to being defined as much by the medication. The medication has really given definition to that, and defined it as a distinct entity, number one. Number two, many endocrinologists do not like treating obesity.

Obesity treatment has become very much writing scripts for GLP-1s, and so they will manage other endocrine problems, but they-- "I do not do obesity," and they will send the patient to an obesity clinic or some other part of the organization. This part of their disease may well be outsourced, if you will, to another part of the system and the like. We are entering this world where we have got to create awareness. We have got to help create more experts and, like I said, I think there is a prevalent population here, which is out there and not carrying a diagnosis. Those are the classic rare disease challenges. On the upside, this is a classic specialty opportunity. Unlike Bardet-Biedl syndrome, which is dispersed and being cared for maybe by multiple different specialists and/or primary care physicians, these patients will reliably pass through and/or be primarily cared for by an endocrinologist.

As a company, we approach this in a very different way, which is we can cover all endocrinologists. We had a sales force of about 16 people for Bardet-Biedl syndrome because that was not the strategy. We have hired 42 dedicated salespeople for HO because the goal will be to knock on certainly all of the top-tier endocrinologists, which is about half of that 10,000 number as a start. A lot of advantages, some residual challenges, and of course, we are positive about our first quarter.