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Business Of Biotech
The Business And Science Of Obesity With Roger Cone, Ph.D., Founder Of Courage Therapeutics
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On this week's episode, Roger Cone, Ph.D., Founder and Chair of the Scientific Advisory Board at Courage Therapeutics, talks about discovering obesity-related protein receptors in the brain, how he spun his academic discoveries out into a biotech company developing new obesity drugs, the need for obesity treatments with fewer side effects than currently available GLP-1 therapies, and the value of pairing scientific leadership with a strong business partner as CEO.
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Ben Comer:Welcome back to the Business of Biotech. I'm your host, Ben Comer, chief editor at life science leader, and today I'm speaking with Dr. Roger Cone, founder and chair of the scientific advisory board at Courage Therapeutics, a pre-clinical company focused on obesity and eating disorders. Courage Therapeutics' intellectual property is based on Rogers' discoveries and decades of research into the melanocortin system, a pathway crucial to eating behaviors and energy homeostasis. Rogers is a professor at the University of Michigan and has a number of other roles and responsibilities at UM's Life Sciences Institute and Biosciences Initiative. Courage Therapeutics is a University of Michigan spinout and the third company Roger has founded, so we'll find out what he's learned from those experiences, what role Courage Therapeutics might play in the white-hot obesity space and how he approaches company leadership as a founding scientist. Thanks so much for being here, Roger.
Roger Cone, Ph.D.:Thank you, Ben.
Ben Comer:I want to start with a little bit of your background and experience and I guess, first of all I'm curious about how you set out on the path of researching how the body regulates hunger, caloric intake and energy expenditure and other related eating disorders.
Roger Cone, Ph.D.:Well, great question, and, like so many other things in science, there was a bit of serendipity involved. Many, many years ago, I was engaged in cloning G-protein coupled receptors, just when cloning cloning began, actually, and and?
Roger Cone, Ph.D.:that was the what mid eighties, early eighties late eighties, late eighties, late eighties I was cloning receptors, GPCRs, and they had just the technology for identifying and cloning GPCRs had just been developed. And we cloned the MSH receptor, the receptor in your melanocytes that regulates pigment production. We cloned the ACTH receptor, the receptor in your adrenal gland that regulates the stress hormone, the glucocorticoids that your body produces. And then we found that there were three other receptors in that same family. Those first two receptors were highly related. We found three more highly related receptors in the family.
Roger Cone, Ph.D.:We had no idea. Nobody knew what they did, They'd never been seen before and they were orphans in that regard, and so we just gave them numbers MC3, MC4, and MC5. And so we just gave them numbers MC3, MC4, and MC5. We proceeded to delete them from mice and we proceeded to develop agonists and antagonists to find what the orphans did. And MC3 and MC4 were in the brain and we ultimately discovered that MC3 and MC4 were critical to feeding behavior and the regulation of body weight. And I've studied those receptors ever since.
Roger Cone, Ph.D.:Yeah, could you give me a sense of just what that was like when you made that discovery of the orphans and, you know, started working on the, you know, the knockout mouse models? I mean, as someone who won't have a chance to make a discovery like that, I'm just curious about you know how you might describe what it felt like to actually first make the discovery and then go and start, you know, exploring those receptors and what they could potentially do.
Roger Cone, Ph.D.:Yeah, it was a fantastic time in my career. At that time there was not a single human obesity gene known, or not a single obesity gene known, and what happened was that, and the way that we discovered that the MC4 was involved in energy homeostasis was that there were five monogenic obesity models in the mouse at Jackson Labs, the lab that produces all the mouse strains that most people work with, and over the years they had found five super obese mice, that in which the obesity syndrome was monogenic. They knew from genetic studies. It was passed on by a single gene, and the five obesity strains were called OBDB for obesity and diabetes, called OB-DB for obesity and diabetes, ob-db, fatty tubby and agouti.
Roger Cone, Ph.D.:And we had some clues that the agouti animal might have something to do with the melanocortin peptides, because this mutation not only made the animals morbidly obese, it also converted their coat color from black to yellow, and so we knew that there was a gene that was impacting both body weight, which is controlled by the brain, and pigmentation, which is controlled by the melanocytes, and here we had a receptor family with, you know, one member critically important in pigment production and another member in the brain with unknown activity, and so we tested the hypothesis that maybe this defect was affecting both the melanocortin-1 and 4 receptors, the MSH receptor and the orphan, and indeed we were able to prove that the Agouti mutation is a mutation which blocks both the MSH receptor and the MC4 receptor in the brain at the same time.
Roger Cone, Ph.D.:Well, within a year of our discovery of that which we published in one of the top journals, Nature, within a year of the discovery of that, human geneticists working with early obese kids had discovered that the most common cause of monogenic obesity in kids was due to mutations in the MC4 receptor, Philippe Froguel in France and Stephen O'Rahilly in England published those discoveries. So not only was it incredibly exciting to find one of the first obesity genes, but literally within a year or so, human geneticists discovered that what was true in the mouse was true in people as well.
Ben Comer:And when you say monogenic obesity, you're talking about obesity that can be directly attributed to a single gene mutation. Is that correct, correct? What percentage I guess, if percentage I guess of, of, if you had to kind of ballpark it, of overall obesity, would you say is, uh, is monogeneic.
Roger Cone, Ph.D.:Uh well, I don't have to ballpark it. There's been a lot of research on that from geneticists like Steve O'Reilly and uh he's demonstrated that the prevalence of obesity due to mutations in the MC4 receptor is very common. It's as high as one in a thousand individuals has early onset obesity due to mutations in the MC4 receptor.
Ben Comer:And this is something that you can discover through genotyping a patient, I assume whether they have that mutation or not.
Roger Cone, Ph.D.:It's not uncommon now if children present with early onset severe obesity, it's not uncommon for endocrinologists to request some DNA sequencing to find out if they have a leptin mutation or an MC4 mutation corresponding to those mouse models I talked about, because there's different treatments available depending on the genetic background for this severe syndromic obesity.
Ben Comer:So these discoveries and this research was started off in the late 80s with you know, at your lab. And where were actually? Where were you based at that time? I don't think you were at the University of Michigan yet, right?
Roger Cone, Ph.D.:Correct, I was at the Vollum Institute at Oregon Health Sciences University.
Ben Comer:Okay, all right, and you have been continuing this research ever since then and I'm curious about you, know what you might say has kept you interested and kept you focused on this area, you know, for upwards of 30 years.
Roger Cone, Ph.D.:Well, I got fascinated by the mechanisms underlying energy homeostasis. Energy homeostasis most people don't think about that. You know, when we think about homeostatic systems, we think about things like body temperature. You know, we're all basically at 98.6 unless we get a fever. We think about blood oxygen, things like that, sleep-wake cycles. You know, we think about things like that when we think about physiological homeostasis.
Roger Cone, Ph.D.:Many people don't understand that your long-term fat stores are also controlled homeostatically by the brain and critically, involving the central melanocortin circuits and hormones such as the fat hormone leptin, which tells the brain how much long-term energy you have on board. So three basic forms of energy that we use every day glucose in our bloodstreams, glycogen in our liver and fat in the fat cells. Typically, your blood glucose is good for a few hours. Then you start tapping into liver glycogen, start burning liver glycogen if you skip a few meals and then, within a few days, you start burning fat. So fat is our long-term energy store and, evolutionarily, in all vertebrates and invertebrates for that matter those energy stores are conserved and the brain has developed very sophisticated mechanics for conserving the amount of fat that you have.
Roger Cone, Ph.D.:Now you would ask then well, why do people become obese if those fat levels are stored? They are conserved homeostatically, like the temperature in the room, and I have two answers to that. First of all, if you actually look at how people become obese, it's incredibly tiny incremental gains in fat mass that occur over a long period of time. In fact, if over 20 years, typically you get out of school and 20 years later you're 20 pounds overweight or whatnot, that's only a pound per year that you're putting on on average, or basically 3,500 kcals in a year, 10 kcals in a day. That's the equivalent of storing one potato chip worth of energy more per day than you're burning the. You know 40% of Americans being overweight or obese. Even in the light of that, the brain is still doing a really, really good job of conserving your long-term fat stores. So that process is incredibly complex and 30 years later I'm still trying to solve critical issues to understand how the brain regulates body weight.
Ben Comer:So the freshman 15 that you hear about probably takes a full year it's the full freshman year to get you to that 15-pound increase.
Roger Cone, Ph.D.:Oh yeah, at least.
Ben Comer:All right, I wanted to ask you a question. Obviously, there is a lot of discussion, a lot of interest, a lot of excitement about the GLP-1 therapies and their ability to help people lose weight and a number of other things as well. I wonder what you might say as someone who's worked, you know, kind of broadly, not in the GLP space specifically, but more broadly in this larger metabolic space, I guess I'll call it. What would you say about how the obesity research field has changed or evolved since you know you started working in it, maybe like before the discovery and promotion of GLP-1s, and now kind of where it stands today?
Roger Cone, Ph.D.:So it's been a really remarkable period of time in the history of science to see the field go. When I started out from a place where we didn't have a single obesity gene and there were no obesity therapeutics that really worked. You know, phentermine and fen-phen was used molecules that block fat uptake for the gut but had terrible side effects. So there was really nothing that was mechanism-based and highly effective really until the GLP-1 drugs came along or set melanotide and MC4 agonist. Most people won't have heard of that because it's used for rare syndromic obesity, but I want to describe that because it gets to the broader role that basic research has had. So what's happened, which is a classic example of how biomedical research powers progress, is that by discovery of the mechanisms and the molecules that regulate satiety, hunger, food intake, discovery of the gut peptides like GLP-1, discovery of the hypothalamic circuits involving leptin and the melanocortin circuit system, ultimately the pharmaceutical industry was able to develop now two highly effective, different mechanism-based therapeutics for obesity. On the one end, we have set melanotide from Rhythm Pharmaceuticals, which is a MC4 agonist. The trade name is Imcivree. It's an MC4 agonist that's highly effective in treating syndromic obesity where the syndromes have a defect in the primary melanocortin system, so making the agonist for MSH. Those patients lose 20-25% body weight. They're effectively normalized because the drug replaces the endogenous activator of the MC4 receptor that's defective in certain types of syndromic obesity, such as palm seed deficiency or hypothalamic obesity, as it's called, which results from a tumor called craniopharyngioma. Anyway, so on the one end we have mechanism-based therapies that have dramatic positive mechanism-based effects, reducing obesity and rare syndromic obesity early onset syndromic obesity and then, through the evolution of understanding of the biology of the GLP-1s and spectacular work in both academia and the pharmaceutical industry, we have the development of the GLP-1-based drugs, like Wegovy and Mounjaro, which are just analogs of the native GLP-1 peptide. The remarkable story there is that GLP-1 is a peptide made by the gut but it's incredibly weak and has a very modest effect on hunger and food intake, primarily because your native GLP-1, made by the gut when you're full, only has a half-life of about a minute, and so it has an incretin effect working on the pancreas to improve glucose-mediated insulin release to help you take up the glucose that you obtain from eating a meal. But it really doesn't get into the brain very well and do very much in terms of making you feel full. It has a little effect.
Roger Cone, Ph.D.:What academia and ultimately the pharmaceutical industry did was they started playing with GLP to make it better. They asked well, what if we made it more stable and long acting? Could it do a better job at reducing food intake? And if you look at the evolution of the GLP-1 analogs, from liraglutide to semaglutide to terzepatide, we've gone from, you know, 5% to 7% weight loss with liraglutide to 10% to 15% with 10% weight loss, let's say, with Wagovi, and all the way up to 15% to 20% weight loss in some studies with terzepatide. And it's simply by tweaking the molecule and making it more stable and making some other modest changes to the GLP-1 hormone that the pharmaceutical industry has been able to make these very successful and safe drugs. They're basically simply analogs of your own hormones but do a little better job of making you feel full and reducing food intake.
Ben Comer:And that weight loss benefit has a lot to do with extending the half-life, I believe, which I think was a pretty big hurdle for academics and the pharmaceutical companies to get over. I mean, I just I know that with exenatide, which was originally marketed as Byetta, very short half-life, potentially very effective in larger doses, but you start getting into toxicities and you know the patent expired before it was ever really optimized for a weight loss indication. It was only ever approved for diabetes. So that's a really interesting development that you know those drugs were the originals liraglutide, exenatide. It's been quite some time since those original approvals. I wanted to add with setmelanotide, that was only approved in the last few years. Is that right? Do you know what year that was first approved?
Roger Cone, Ph.D.:Yeah, 2020.
Ben Comer:2020. Wow yeah.
Roger Cone, Ph.D.:Okay, it gets to the fact that drug development is very, very complicated and takes a long time. The clinical trials take a long time. The development of the molecules to make them safe and effective takes a long time. The success rate is small. So yeah, we cloned the melanocortin receptors. We published the first cloning in 1992. The first drug based on the MC4 didn't get approved by the FDA until 2020.
Ben Comer:Right, yes, well, I can hear our audience for the business of biotech nodding their head and agreeing along with you on those comments about the challenges and length of time that it takes to do drug delivery or drug development. Excuse me, I want to talk a little bit about Courage Therapeutics. This is the third biotech company that you founded and before actually we get into what Courage is up to, I wonder if you could tell us a little bit about the two previous companies that you founded and maybe what those experiences were like.
Roger Cone, Ph.D.:Sure. So because I'm in the GPCR field, it's been very interesting and there's been various points in the development of the cloning and characterization of GPCRs where I had some interesting entrees into biotech, um Northwest neurologic. So when I was at um, when I was at the volume Institute, that the GPCRs were being cloned for the first time and in many of the GPCR families that was critically important because it made it much easier to develop receptors, subtype specific compounds, um, when you once you had the cloned receptor subtypes. So in the melanocortin family there's five subtypes. The serotonin family has a very large number of subtypes and so in addition to cloning receptors at the Volum Institute, some of the dopamine receptors were first cloned there. The neurotransmitter transporters were first cloned at the Volum Institute. Some of the dopamine receptors were first cloned there. The neurotransmitter transporters were first cloned at the Volum Institute by Susan Amara and so we had a bunch of investigators there identifying the genes for receptor and channel subtypes for the first time.
Roger Cone, Ph.D.:We thought we could use this technology to improve drug development and drug discovery. So we formed Northwest Neurologic and we actually had a number of pharma contracts to help pharma companies develop better drugs. We helped provide some of the data that was used in the FDA approval for venlafaxine, for example. And then quickly, we got a buyout offer early on and so our exit was that our company and technology was picked up by Neurocrine Biosciences of San Diego. So that was my first company experience. I was a young assistant professor. I was in Oregon, where it's quite a bit harder to raise venture capital, et cetera, et cetera. So, you know, rather than grow the company, uh, we, we uh sold it off to Neurocrine Biosciences really early in our development. But it was a lot of fun and we felt we did some good, you know, working with with Wyeth on venlafaxine and, um, uh, I.
Roger Cone, Ph.D.:I went on to serve Neurocrine on their SAB for I don't know, five years perhaps after they purchased the company, they made an effort to develop melanocortin drugs. The molecule they developed, the small molecule they developed, had toxicity and so that killed the program and, as I mentioned, ultimately Rhythm was successful in developing the first FDA-approved MC4 agonist. But it was a great experience, got to know fabulous scientists like Wylie Vale, who was one of the scientific founders of Neurocrine, and it also provided lots of tools and funding for my basic research lab as well. That's one thing I would point out to investigators who are considering getting involved in company formation in biotech, particularly if you're in a field where you can benefit from having really state of the art pharmaceutical tools for your research. My work with companies over the years has given me access to really state-of-the-art tools for basic research as well.
Ben Comer:Yeah, yeah. So you got a taste for company formation. Then with the second company, was that a similar network of people that you were working with, or was that something completely different?
Roger Cone, Ph.D.:completely different. Yeah, the second company was a zebrafish company designed to try to leverage the zebrafish as a genetic model for gene discovery, for drug target discovery based on conservation of multiple physiological processes from zebrafish, from a very simple vertebrate to humans. So you know, many basic researchers use the roundworm C elegans or the fruit fly to study basic physiologic mechanisms, but really you need to get into a vertebrate to get after many of the critically conserved vertebrate physiological mechanisms. And so as the technology was developing and this was of course and so as the technology was developing and this was of course long before the genome was available and before it was possible to simply go online and find genes of interest, it was very useful to have a genetic model system where we could interrogate all the genes at one time. So that company, Xenomics, created a library of mutations in every gene in the zebrafish and the basic model was to provide that as a tool for discovering new drug targets.
Roger Cone, Ph.D.:And the company was developing very nicely and we had raised significant funding and had some exciting research projects identifying drug targets in collaboration with other academics and with industry. And then the fall of 2008 came around. The market collapsed at a critical time for the company where we needed to do the next raise and we ended up having to liquidate the company. Next raise and we ended up having to liquidate the company. Probably the best outcome in the sense that, of course, genome technology quickly took over the world and the value of having a library of mutations in every gene in the zebrafish is not now what it was then.
Ben Comer:Before we move on to Courage. I'm curious. You know, as an academic scientist, uh founding, uh a biotech company for the first time, how did you um, I guess learn about the? You know the, the business aspects of financial aspects. Maybe you you already knew about that, knew what was going to be expected, knew what you had to do to raise funds. I mean, you had a successful exit. So clearly you know you guys knew what you were doing. But was that a challenge for you? And I'm thinking of you know others who might be listening to this episode, who are working in academia, who have a great idea for a biotech company but are perhaps, you know, concerned about the. You know the whole picture of company formation and the. You know concerned about the. You know the whole picture of company formation and the. You know the necessary to put it, to state it lightly, requirement for funding, what you know. How did you manage that? How did? Did you kind of learn as you went? Or did you have someone that you worked with? How'd you go about doing that?
Roger Cone, Ph.D.:Absolutely the latter. Having experts to work with, I would never get involved with company formation on my own. A I don't have any expertise in the business end of things, and B I just love science and want to do science. And so, in the case of my first two companies, I had a business partner, a fellow named Richard Sessions, who was an MBA and was very keen to be entrepreneurial and start companies, and he actually gathered scientists together at the Vollum Institute. He was the managing director of the Institute at that time and said I think there's enough technology here for a great company. Do you all want to participate? I'll do all the business, all the business work. And he did, and he did, and so that was a great relationship, a wonderful guy I had.
Roger Cone, Ph.D.:I did not intend to start a company. Rhythm obviously had done well bringing setme lanotide to market. A entrepreneur from Boston contacted me and said you know, I think I think we can do better. I think we can generate next-gen melanocortin compounds and I think there's multiple other clinical applications using both the MC3 and the MC4 receptor. So if I do all the business work and raise the money, would you be interested in being the scientific founder? And so I've always been at institutions that have allowed me to do this and been very supportive of company formation, and then I've been very fortunate to have great business partners who've done the incorporation, legal, fundraising, all those things that need to be done.
Ben Comer:And I think you're talking about Dan Hausman, who is Courageous CEO, correct?
Roger Cone, Ph.D.:Correct, he was the fellow at Boston.
Ben Comer:Yeah Well, can you and again I'm thinking of our listeners here can you give me a sense of that relationship, you know, just kind of on a day-to-day basis, like how you guys work together to you know progress assets move the company forward.
Roger Cone, Ph.D.:So you know again, I just consider myself incredibly lucky having bumped into Dan. Dan had sold a prior company of his in the software space and said I'll devote 100% of my time and not take any pay to create this company. He was personally motivated and he talks about this publicly. His daughter suffered terribly from anorexia nervosa and the company was focused around originally focused around seeing if we could use the Melanocortin system to develop the first treatments ever for anorexia nervosa, and that's a critical piece of the company. Now we ended up making faster progress on new compounds for various types of obesity, but we also have a program focused on developing therapeutics for anorexia nervosa as well. So he was personally motivated. He had the time and energy to devote a hundred percent effort to growing the company.
Roger Cone, Ph.D.:We brought on other board members, including leaders in the field, like Steve O'Rahilly, a leading human obesity endocrinologist and geneticist, and Fred Mermelstein, a drug development expert. So we brought on really talented people as advisors and board members and we scheduled weekly one-hour board meetings. We began developing the ideas for our approach. I then wrote STTR grants to fund the company. Dan raised some angel funds. I wrote a bunch of STTRs and we funded the company for four years on a very small initial angel round plus three different STTRs that we've funded.
Ben Comer:That's fantastic. I appreciate that background. I wanted to ask about the process of spinning out the company from the University of Michigan and you know. I wonder what you could say about that, just in terms of securing the IP and what that process was like.
Roger Cone, Ph.D.:So initially I had some patents before Dan came along, one in particular that was relevant to the company and continued to generate IP. Working with the company, the STTRs provided subcontracts to my lab at the University of Michigan and so right away Dan began a negotiation for an option agreement with the University of Michigan from the pre-existing and the forward-looking IP in a well-defined space based on this initial option agreement. So he succeeded in negotiating an option agreement with the university that gave the company rights to narrowly defined IP coming out of my lab and subsequently, with the STTR funding, the IP ends up being jointly owned between the company and the university, as defined by the option agreement, owned between the company and the university as defined by the option agreement. With this round of funding that we've just completed, the company is now finalizing a full license agreement with the university for all of the IP that we've generated in the last four years.
Ben Comer:Yeah, that was a correct me if I'm wrong. $7.8 million seed investment from Arsenal Bridge Ventures that came in in May, is that correct?
Roger Cone, Ph.D.:So about half of that has come in and they're raising the final amount now, but the target is $7.8. And they're still so. We had a first early close so that we could start funding some additional research right away, and now they're finishing up the rest of the round.
Ben Comer:So does Dan get you out of the lab to come talk to those investors, go to some of those meetings and answer questions, or are you completely you know walled off from that kind of activity?
Roger Cone, Ph.D.:No, I'm still the science guy and you know a lot of the work is done without me, but when investors want more detail on some of the science, I'll hop on a Zoom, Got it. Yeah, got it Answer questions? Yeah.
Ben Comer:Yeah, okay, I wanted to add just because I don't even need to say this, but a number of successful companies have begun as spin-outs from universities, as spin outs from universities, and I'm curious what you would say about the kinds of support, outside of financial support, that the University of Michigan provides. Are they working with you on courage therapeutics?
Roger Cone, Ph.D.:So absolutely so where to begin? So most universities allow faculty one day a week or 20% of their time roughly that sort of average to consult, to consult for drug companies or or other institutions, to be on the board of other research institutions or departments or what have you and? And so Michigan, like other universities, allows me 20% of my time to do other things that are relevant to my research but not directly under the umbrella of the University of Michigan, and so my company work falls under that time that allows me to do those types of things. I also serve on the HHMI scientific review board and you know I serve on some other, yeah.
Ben Comer:You have a lot, a number of roles. I was going to ask you about that at the University of Michigan.
Roger Cone, Ph.D.:Yeah, so you know, as I was saying, I mean, I I probably don't spend more than you know, a couple hours a week directly working for the company. You know, giving scientific presentations to investors or putting together documents or what have you for the company. Um, and then I get to do a lot of really great research in my lab that I get to publish. So you know a couple of things. One is universities allow you the time to do this. Secondly is Michigan and other universities will manage your conflicts of interest for you. So you just need to be transparent and tell them what you're doing, and they'll provide a conflict of interest management plan to avoid any conflict of interest between your university duties and your role in a company you might be involved in. And so that involves disclosing my activities with the company, which I do on a regular basis, involves disclosing my activities with the company, which I do on a regular basis. And you know, when I submit grants, they ask questions about it, this and that. And then there's various other regulations that ensure that the university's rights are held. So the IP ownership is well-defined in advance, et cetera.
Roger Cone, Ph.D.:And so the university has been incredibly supportive. They've provided me with a conflict of interest management plan. They regularly address any conflict of interest issues that might come up. They have taken an interest in the company, so part of the license agreement they get a percent of the company. This is fairly standard at most universities and additionally they've connected me with some investment from here at the university.
Roger Cone, Ph.D.:So we have a Michigan Biomedical Ventures Fund, which is a venture philanthropy fund funded by Michigan alums that helps with startups, and so part of our angel fund was resulted from investment from the Michigan Biomedical Ventures Fund, or MBVF. Many universities have similar funds, either venture philanthropy or true venture funds, so a small piece of investment from that helped the company out. Of course, tech Transfer has been very active in helping us file patents as well, so Michigan has been very supportive. They want to see their investigators not only teach and do research and do all the things that professors normally do. They also want to see the work of the university have societal impact and in the case of biomedical research that involves either licensing your technology to other companies or forming your own companies to move them forward.
Ben Comer:I would imagine it's also a draw for you know potential incoming students. You know who may be interested in working in this field.
Roger Cone, Ph.D.:So my institute, the Life Sciences Institute, provides most of the core drug discovery technology for the entire University of Michigan. We have all the chemical libraries here. We do high-throughput screening here x-ray crystallography, cryo-em, structural biology, natural products, chemistry All of these are provided as core resources to the entire university. People take their NIH grants. They come here and they say, okay, I want to do a screen at this target and they can pay for that at cost, using standard recharge rates to get work done. And then if they discover something particularly interesting, they can talk to the university about licensing it out to a company or creating a company, but taking potentially useful technology and seeing it do societal good.
Roger Cone, Ph.D.:So the university is highly supportive of drug discovery. We have a very robust drug discovery environment here at University of Michigan and right two floors below me is the High Throughput Screening Center with the same tools that are found in industry. We have state-of-the-art equipment for high-throughput screening and chemical libraries and such, and our screening center is run by a fellow that we recruited from Bristol Myers who ran their high-throughput screening for eight years. So we bring in industry level expertise to do the work. So, yeah, many universities provide these types of resources for their investigators.
Ben Comer:Well, that is a solid pitch for the University of Michigan that you just gave. Let's talk about some of the development work that you're doing at Courage Therapeutics. I mentioned at the top that you're in the preclinical stages, but could you describe where you are at the know, where you are at the company? You know what you're focused on at this moment and then maybe you know the potential for a product that is synergenistic with a GLP-1 product.
Roger Cone, Ph.D.:Right, right, great question. So so here's where we're at. We've spent four years doing SAR to try to develop best-in-class MC3 and MC4 agonists for anorexia nervosa and various forms of obesity respectively. Cite that the issues with the current drug on the market, setmelanotide, are that the compound lacks adequate potency to treat many of the obesity syndromes and to treat dietary obesity. For example, it lacks adequate potency to treat MC4 haploinsufficiency, the most common genetic cause of human syndromic obesity. Furthermore, that compound, that that drug, lacks receptor subtype specificity, meaning it acts at multiple melanocortin receptors and so it causes hyperpigmentation through activation of the msh, or mc1 receptor, as we call it. So best in class for us meant to develop mc4 compounds with better potency and better specificity to be able to treat some of the syndromes that set melanotide can't treat without the side effects. So we've developed those compounds and basically what's in between us and the clinic is safety and talk. So we're doing safety talks and efficacy studies now to nominate compounds to go into the clinic and so we could be six to 18 months away from being ready for clinical studies in obesity. We're still at the research phase with our MC3 agonists. We've got some really good drug-like molecules and we're doing the preclinical research on them now, and so then what happened was we discovered this unique phenomenon that we're calling melanocortin hypersensitization, and we've published on this in a recent 2024 paper in the Journal of Clinical Investigation. What we found is that and this is my brilliant postdoc, Naima Dahir, who's soon going to be taking a faculty position at UT Southwestern what we discovered through her work was that even when we give sub-threshold doses of MC4 agonists, we can hypersensitize animals to the weight loss effects of any of the GLP-1 drugs. We can effectively dose shift them about five-fold to the left, and that's all published in this Journal of Clinical Investigation paper.
Roger Cone, Ph.D.:So what we think is happening is the following the MC4 compounds largely act in the hypothalamus. The GLP-1 compounds are known to act primarily first in the area postrema of the brainstem, but the melanocortin and the hypothalamic circuits are essential for inhibition of food intake, ultimately by the GLP-1 compounds. And we know this from the work of Kevin Williams and others, where they've demonstrated that if you disrupt the melanocortin circuits, you can block the inhibition of food intake by the GLP-1 drugs. So what we think is happening is we're sensitizing the hypothalamic circuits to the ultimate end site of action of the GLP-1 drugs. Even though they come in and start acting in the brainstem, they need these hypothalamic circuits. If we sensitize the hypothalamic circuits, we can improve the activity of the GLP-1 drugs in inhibition of food intake without increasing their side effect profile, which results from the brainstem action. By the way, that's well known too, the main side effect being nausea resulting from the action of GLP-1 in the centers that generate nausea in the brainstem.
Ben Comer:So you would yeah, sorry, go ahead.
Roger Cone, Ph.D.:Yeah. So anyway, we think there's also application of some of our best in class compounds for um for action as adjuvants for any of the GLP-1 drugs.
Ben Comer:So would that potentially lead to a lower dose needed to achieve the same amount of weight loss with a GLP-1, or is that not how it would work?
Roger Cone, Ph.D.:We've been able to. We have evidence that we can achieve either that we can get the same weight loss with a lower dose of the GLP-1 drug, or we can get more weight loss than the GLP-1 drug allows. Now, this is all in mice. Obviously, we need to translate this and we're gearing up to go and test this in non-human primates next, and then, ultimately, clinical trials.
Ben Comer:So forgive my ignorance on this, but with anorexia nervosa, would the treatment essentially provoke hunger? Is that what the ultimate goal is for a treatment for that disorder, or describe that to me?
Roger Cone, Ph.D.:So there's a couple of interesting bits of data there, and so first of all, let me mention that, as you alluded to, the melanocortin circuits are bidirectional. When you activate them, you inhibit food intake. When you alluded to, the melanocortin circuits are bi-directional. When you activate them, you inhibit food intake. When you inhibit them, you can potently stimulate food intake even in fully sated animals, and there's a preliminary clinical study from Pfizer it's been published, and rat studies from Pfizer that have been published that show that MC4 agonists can stimulate food intake potently and they have a small molecule compound that they're working with a small molecule MC4 antagonist. So anyway, the melanocortin circuits are bidirectional, you can inhibit or stimulate food intake. So certainly in any of the eating disorders one can imagine simply turning on food intake in disordered eating where there's inadequate drive to eat, now it turns out in classic restricting type anorexia nervosa. Most of the thinking suggests that there is still a strong drive to eat but that individuals are suppressing that homeostatic drive, and so it's not clear that making people hungrier in classic restricting type anorexia is necessarily advantageous. However, there is evidence that the leptin-melanocortin circuits and this is from published work of a fellow in Germany there is evidence that chronic maintenance of substandard weight has a number of other impacts, including neuropsychiatric impacts, that lead to the severity of anorexia nervosa. What he's found is that severe hospitalized patients with anorexia nervosa can exhibit significantly reduced depression and anxiety following treatment with leptin. Leptin activates melanocortin circuits. It's very likely those same effects can be achieved with melanocortins. So anyway, in addition to in some eating disorders, in addition to in some eating disorders, simply increasing appetite will be highly efficacious. And it's also likely and there's evidence suggesting some of the neuropsychiatric aspects of anorexia nervosa that prevent people from regaining and prevent people from developing more ordered eating may be treatable with molecules along the leptin-melanic cord pathway as well.
Roger Cone, Ph.D.:So it's complicated, but let me give you an example where it's less complicated than anorexia nervosa, a very complicated neuropsychiatric disorder that's not well understood. Let's look at the anorexia of aging. So it's a very common experience that as people age they lose their appetite, and this becomes really problematic in the elderly, in nursing homes and in people with chronic diseases. They lose their appetite and they start losing lean mass and you know they have a hip fracture or what have you, due to, you know, significant loss of muscle mass and bone mass, and then you know there's a very high morbidity and immortality rate. What if you could improve appetite and restore lean mass and bone mass in the elderly? So I think that's an example where we don't have the neuropsychiatric complications of anorexia, but yet a very significant need for maintaining healthy body weight. That could be ameliorated with a melanocortin compound to stimulate appetite.
Ben Comer:That's really interesting. I want to go back to obesity because I was curious, you know, given the enormous success of the GLP-1 so far and kind of cascading number of indications that are being added in terms of cardiovascular outcomes, kidney function, even substance use disorders that they could potentially help with, what are the remaining key unmet needs in obesity that are not adequately being met by the GLP-1 therapies and potentially next generation GLP-1 therapies?
Roger Cone, Ph.D.:So great question, and you've hit on a couple of these issues already. I mean one is simply that these drugs are so effective and safe, apparently, that you want to make them available to people that need them. Some people can't tolerate them. A significant percentage of people can't tolerate them due to the nausea. Then there's the issue that, while we talk about the fantastic success of these drugs, if you actually look at the weight loss that individuals experience on these drugs, it's a big, broad bell curve and there's a significant percentage of people who only lose 5% or 10% body weight after a year on the current state-of-the-art GLP-1 compounds.
Roger Cone, Ph.D.:So improving weight loss from these compounds is still very important. Allowing people to successfully go on the drugs is still an unmet need. People that suffer from the side effects too significantly. And then, of course, there's the application of these drugs to all of the different consequences of obesity. Thus far, it appears that a lot of the health benefits of these drugs come from losing weight, and we know that from decades of studies of obesity and the increased prevalence of heart disease, diabetes, hypertension, orthopedic diseases, even cancer risk that comes from obesity. So all of these things will be improved by achieving healthy body weight through the use of these drugs. So so, theoretically, simply making these drugs better, increasing the amount of weight loss that can be achieved for them, will also have applications to reducing risk from cardiovascular disease, diabetes, et cetera, et cetera.
Ben Comer:Yeah, yeah. So what about the, the kind of lean muscle mass that you hear about?
Roger Cone, Ph.D.:I know I forgot to touch on that, so it's still. It's still being investigated. Um, when you lose body weight, you lose fat mass, but you also lose lean mass. Similarly, when you gain weight, you not only gain adipose mass but you gain lean mass as well, simply from gaining weight. Some people refer to that as the gravitas stat that you know, simply weighing more will produce more lean mass, and the exact mechanisms by which that happen aren't known. But when you lose weight through any process diet and exercise, drug B you will lose the lean mass as well.
Roger Cone, Ph.D.:Losing lean mass is at some point not good, as we discussed. Better muscle mass obviously reduces orthopedic problems and injuries and helps prevent diabetes and multiple reasons why you want to have adequate lean mass. There are some studies suggesting that the GLP-1 drugs may produce more lean mass loss than diet and exercise does. The jury's not totally in on that. There's controversy in the literature. Let's say about that.
Roger Cone, Ph.D.:Nonetheless, whether the lean mass is due to the GLP-1, whether there's enhanced loss of lean mass due to the GLP-1 drugs or not, preventing the loss of lean mass from weight loss is important and there are multiple companies pursuing that. We'll certainly look at that with our combination therapies with our dual use of melanocortins and GLP-1 to see if we can ameliorate the weight loss seen with the GLP-1s. We are able to reproduce that in the rodent. It may or may not be relevant to the human, but we can see greater loss of lean mass with the GLP-1 drugs in rodents than we do from the melanocortin compounds in rodents, than we do from the melanocortin compound. So you know, we may be able to study that in our rodent models and it may or may not be relevant in the human, but it's something that needs to be looked at.
Ben Comer:Interesting. Well, I'm coming up at the end of my time with you here, Roger, but maybe we could end with just your kind of top priorities for the rest of 2025 and any kind of final thoughts that you'd like to mention before we wrap up here.
Roger Cone, Ph.D.:So at Courage, you know, our priority is to finish the preclinical studies and nominate compounds for safety and toxicity studies and with the goal of, you know, being ready for the clinic possibly, you know, in six to 18 months. So that's, those are the goals for the company over the next, over 2025 and first part of 2026.
Ben Comer:Well, thanks so much for being on the show. I really appreciate it. We've been speaking with Dr Roger Cohn, founder and chair of the scientific advisory board at Courage Therapeutics. I'm Ben Comer and you've just listened to the. We've been speaking with Dr Roger Cohn, founder and chair of the Scientific Advisory Board at Courage Therapeutics. I'm Ben Comer, and you've just listened to the Business of Biotech. Find us and subscribe anywhere you listen to podcasts and be sure to check out new weekly videocasts of these conversations every Monday under the Business of Biotech tab at Life Science Leader. We'll see you next week and thanks for listening.
