From Scientific Discovery To Next Generation Treatments For Obesity

By Ben Comer, Chief Editor, Life Science Leader

Roger Cone, Ph.D., a professor at the University of Michigan and the founder and chair of the scientific advisory board at Courage Therapeutics, has been thinking about the biological mechanics of obesity and eating disorders for decades — long before the emergence and blockbuster sales of GLP-1 inhibitors.

On a recent episode of the Business of Biotech, Cone talked about his journey into the intricate world of hunger, caloric intake, and energy expenditure, beginning in the late 1980s. At the Vollum Institute in Portland, Oregon, Cone worked in the nascent field of cloning G protein-coupled receptors (GPCRs). His team successfully cloned known receptors like the MSH receptor, crucial for pigment production, and the ACTH receptor — a receptor in the adrenal glands, which regulates stress hormones. However, the real breakthrough came with the discovery of three entirely new "orphan" receptors, which were named MC3, MC4, and MC5. With no known function, these orphans presented a tantalizing mystery. Through methodical deletion from mice and the development of agonists and antagonists, Dr. Cone's team made a pivotal discovery: MC3 and MC4, located in the brain, are critical to feeding behavior and the regulation of body weight. This fundamental insight became the focus of Cone’s academic career, and the backbone of Courage Therapeutics.

Cone's team investigated five "super obese" monogenic mouse models from The Jackson Laboratory, specifically focusing on the agouti mouse, which was morbidly obese but also had a distinctive yellow coat color. This dual phenotype suggested a gene influencing both body weight (controlled by the brain) and pigmentation (controlled by melanocytes). Their hypothesis, that the agouti defect impacted both the MSH and MC4 receptors, proved correct: the agouti mutation blocked both receptors simultaneously. This finding, published in Nature, quickly translated to human health. Within a year, geneticists Philippe Froguel in France and Stephen O'Rahilly in England published research showing that mutations in the MC4 receptor were the most common cause of monogenic obesity in early-onset obese children, affecting as many as one in a thousand individuals. This established a direct link between Dr. Cone's basic research and a significant human health condition, and underscored the importance of understanding the melanocortin system.

Dr. Cone's enduring fascination with the melanocortin system stems from its role in energy homeostasis, a concept he believes is understudied. While body temperature and blood oxygen are widely recognized homeostatic systems, few realize that long-term fat stores are also controlled homeostatically by the brain, with the central melanocortin circuits and hormones like leptin playing a key role. Cone explained that while our bodies utilize glucose and glycogen for short-term energy, fat serves as our crucial long-term energy store. Despite the widespread prevalence of obesity, the brain's regulatory system is remarkably efficient; even a modest gain of one pound per year over two decades, he calculates, amounts to storing just 10 kilocalories (or one potato chip) more per day than one burns. That complex process drives Cone’s research into how the brain regulates body weight.

New Drug Approvals For Obesity

The obesity research field has undergone a dramatic transformation since the beginning of Cone's academic career. When he got started, effective, mechanism-based therapeutics for obesity were virtually nonexistent, with early drugs like Phentermine and Fen-Phen producing severe side effects. However, the fundamental discoveries in the melanocortin system, alongside insights into gut peptides like GLP-1, eventually paved the way for effective treatments. One notable success stemming from Cone’s early discoveries is Imcivree (setmelanotide), an MC4 agonist developed by Rhythm Pharmaceuticals. Approved by the FDA in 2020, Imcivree is highly effective in treating rare syndromic forms of obesity caused by defects in the melanocortin system, normalizing body weight in patients by replacing the missing endogenous activator of the MC4 receptor.

More broadly, GLP-1 drugs like Novo Nordisk’s Wegovy (semaglutide) and Eli Lilly’s Zepbound (tirzepatide) have revolutionized the treatment of obesity. Dr. Cone explains that while native GLP-1, produced by the gut, has a very short half-life of about a minute, and modest effects on hunger, scientific development has created more stable and long-acting analogs. This improved stability dramatically increased GLP-1 efficacy, progressing from 5% to 7% weight loss with earlier compounds like liraglutide, to 15 to 20% reductions in body weight with tirzepatide. Extending the half-life was a major hurdle to the class of drugs, says Cone, citing challenges with older GLP-1 mimetics like exenatide .

Courage Therapeutics is now building on these developments, aiming to create "best-in-class" MC3 and MC4 agonists. Dr. Cone highlights the limitations of current treatments like Setmelanotide, which lacks adequate potency for common obesity syndromes and suffers from off-target effects like hyperpigmentation due to lack of receptor subtype specificity. Courage's goal is to create compounds with superior potency and specificity to treat conditions Setmelanotide cannot, without the associated side effects. These compounds are currently in safety and efficacy studies, with an anticipated readiness for clinical trials within 6 to 18 months.

A particularly exciting and recent development from Courage Therapeutics was the discovery of melanocortin hypersensitization, published in The Journal of Clinical Investigation last summer. Cone explains that even subthreshold doses of their MC4 agonists can hypersensitize animals to the weight loss effects of any GLP-1 drug, effectively shifting their dose-response curve five-fold to the left. This synergy arises because while GLP-1 compounds act primarily in the brainstem, the melanocortin and hypothalamic circuits are essential for their ultimate effect on inhibiting food intake. By sensitizing these hypothalamic circuits, Courage aims to enhance GLP-1 activity in reducing food intake without increasing their primary side effect of nausea, which results from brainstem action. This breakthrough could lead to either the same weight loss with a lower dose of GLP-1 or even greater weight loss than GLP-1s currently allow.

Beyond obesity, Courage Therapeutics also is focused on eating disorders like anorexia nervosa. Cone emphasizes the bidirectional nature of melanocortin circuits: activation inhibits food intake, while inhibition potently stimulates it. While classic restricting anorexia nervosa presents complexities due to suppressed hunger despite a strong underlying drive, Cone points to evidence that chronic substandard weight contributes to neuropsychiatric impacts like depression and anxiety. Leptin treatment, which activates melanocortin circuits, has shown promise in reducing these symptoms. He also highlights the anorexia of aging, a common condition in the elderly leading to appetite loss, muscle, and bone degradation. Here, melanocortin compounds could directly stimulate appetite, providing a less complicated but significant therapeutic opportunity.

Despite the success of GLP-1s, Dr. Cone identifies several remaining unmet needs in obesity treatment. A significant percentage of patients cannot tolerate GLP-1s due to nausea, and the degree of weight loss varies widely, with many individuals achieving only 5% to 10% body weight reduction. Courage aims to improve overall weight loss and make treatments more accessible by reducing side effects. Another critical area is the loss of lean muscle mass during weight reduction, a concern often associated with GLP-1s. Courage plans to investigate whether their combination therapies can ameliorate this effect, having observed greater lean mass loss with GLP-1s than with melanocortin compounds in rodent models.

Unwavering Focus, And Strong Business Partners

Dr. Cone’s academic and entrepreneurial journey speaks directly to the power of academic discovery translating into real-world impact. As a founding scientist, Cone highlights the critical role of a strong business partner, like Courage's CEO Dan Hausman, who manages the business, legal, and fundraising aspects, allowing Cone to remain focused on scientific research. [Note: In June, Courage appointed Giovanni Ferrara to the CEO role, succeeding Dan Housman, who will remain an active contributor as a company board member.] Cone also credits the support he has received from the University of Michigan, which actively fosters company formation. The University provides its faculty with dedicated time for external activities, manages potential conflicts of interest, ensures clear IP ownership, and even offers financial support through venture philanthropy funds like the Michigan Biomedical Ventures Fund. The University of Michigan also provides state-of-the-art drug discovery facilities, including chemical libraries and high-throughput screening centers staffed with industry-level expertise, which directly benefits Courage's preclinical work, per Cone.

Looking ahead, Courage Therapeutics priorities are clear: finalize preclinical studies, nominate compounds for safety and toxicity evaluations, and prepare for clinical trials within the next 6 to 18 months. Cone’s pioneering work in the melanocortin system, from its serendipitous discovery to its current potential for synergistic therapies with GLP-1s, exemplifies the transformative power of deep scientific inquiry in addressing some of the most pressing health challenges of our time.