MC4R Agonist Drug Candidates Demonstrate Potential to Transform GLP1 Obesity Therapy

Newton, MA, July 17, 2024 — Courage, a pre-clinical stage biotech company, announced groundbreaking results, funded in part by an NIDDK funded STTR research grant on obesity. The article “Subthreshold activation of the melanocortin system causes generalized sensitization to anorectic agents in mice” was published in the Journal of Clinical Investigation by senior author and Courage co-founder Dr. Roger Cone. It reports on synergy between GLP1RA and MC4R agonist drugs, demonstrating that low doses of MC4R agonists can significantly improve the dose-responsiveness of GLP1RA drugs to reduce food intake and drive weight loss through a novel mechanism that can improve GLP1RA weight loss efficacy without increasing side effects.

“This synergy between the MC4R circuit and GLP1RA agents could revolutionize the obesity treatment landscape similar to how GLP1/GIP combinations such as tirzepatide have recently shown dramatic improvements in weight loss,” said Dan Housman CEO.

Courage completed a successful four-year drug discovery campaign resulting in a market leading portfolio of optimized MC4R peptide agonist drug candidates designed to address the combination opportunity. Clinical candidates have demonstrated significantly higher potency and selectivity in animal models than setmelanotide, the only MC4R agonist currently approved for obesity treatment. The selectivity eliminates MC1R activity which drives a pigmentation side effect that has limited pharma development of MC4R agonists in dietary obesity. Combining Courage products with GLP1RA drugs such as Ozempic and Mounjaro in new ways is expected to improve the safety of GLP1RA drugs by lowering nausea, increasing physical activity, and reducing gastrointestinal discomfort.

“Based on their deep expertise in the field of melanocortin biology, Courage scientists have developed a range of peptide drugs that activate the MC4R. The potency and specificity of these drugs represent a significant advance on the only currently licensed activator of this receptor, setmelanotide. Their current paper in the Journal of Clinical Investigation Dahir et al adds to the evidence that combining low doses of a melanocortin 4 agonist with anti-obesity drugs acting through the GLP1Receptor can lead to greater weight loss in mice than when these drugs are used alone. Combining a specific and potent MC4R agonist with a drug acting on GLP1R opens up the exciting possibility of novel “dual action” anti-obesity agents with improved efficacy, safety and tolerability said Stephen O’Rahilly, Professor of Clinical Biochemistry and Medicine at the University of Cambridge and chair of Courage’s Scientific Advisory Board.

The company is initiating pre-clinical studies to bring product candidates into the clinic. Additionally, Courage is seeking partnerships with GLP1RA drug companies.
Go to the article: “Subthreshold activation of the melanocortin system causes generalized sensitization to anorectic agents in mice,” Journal of Clinical Investigation.

How New Research Could Change the Way We Fight the Opioid Epidemic

Jupiter, FL, July 17, 2024 — New research from a Max Planck Florida Institute for Neuroscience researcher could transform how we understand the way opioids affect the brain. Despite significant discussion surrounding the ongoing opioid crisis, current understanding of how opioids function in the brain is quite limited. This is primarily due to challenges in observing and measuring opioid effects in the brain in real-time. However, a recent technological breakthrough, led by Dr. Lin Tian and her research team and collaborators, recently published in Nature Neuroscience, has overcome these limitations and is set to transform how scientists study opioid signaling in the brain.

What do we know about opioid signaling?

Pharmaceutical opioids, such as morphine and oxycodone, and illicit opioid drugs like heroin, affect the brain and body by binding to opioid receptors on the surface of cells in the nervous system. These receptors normally respond to naturally produced chemicals that are released in your brain, called endogenous opioids, including endorphins, enkephalins, and dynorphins.

Released in response to pleasurable activities such as laughter, sex, and exercise and aversive activities like injury and trauma, these chemicals bind opioid receptors and reduce the ability of neurons to receive and transmit signals. These cellular effects ultimately lead to the cognitive and behavioral effects associated with opioids, including positive feelings, pain relief, and addiction.

Challenges in understanding opioid signaling
Numerous questions remain about how these behavioral effects are caused by opioids and whether it is possible to harness specific opioid properties such as pain relief without undesirable effects, such as addiction. The opioid scientific literature is extensive and has confirmed that targeting the opioid system is of clinical interest – not only for pain management but also, more recently, for the treatment of mental health disorders such as anxiety and depression. Development of therapeutics that can target these health challenges while preventing the tragedy of the current opioid epidemic requires further understanding of the diverse effects of opioids in the brain.

The diversity of opioid effects on the brain is driven by more than 20 different opioid chemicals produced in the brain and more than 500 different synthetic opioids. Most of these different opioids interact with all three types of opioid receptors with different strengths. Their varied effects depend on the concentration of opioid, the specific receptors present and the brain circuits involved.

“Efforts are underway to harness various therapeutic properties of opioids by targeting specific receptor actions and brain circuits to develop more effective and safer therapeutics. However, these efforts have been hampered by our inability to measure diverse opioid signaling in real time in the brain effectively,” said Dr. Tian.
New technology opens door to understanding opioids in brain
Through a massive effort developing and testing over 1,000 variants, Dr. Tian’s team has optimized highly-sensitive biosensors based on the three opioid receptors. These biosensors, originally developed while Tian was at the University of California, Davis, emit fluorescence upon opioid binding to the sensor and turn off when the opioid is no longer there. The biosensors, therefore, serve as a proxy for opioid binding to specific opioid receptors.

Introducing these sensors into the brain of an animal provides a way to visualize opioid signaling across the brain in real-time.

“The power of this new technology is that we now have the tools to understand the natural opioid system in the brain, including how to distinguish between different opioid effects. We can track endogenous opioid release in real-time, triggered by both reward and aversion and see the differences in opioid signaling in different brain circuits.”

Dr. Tian’s team has already been sharing these new tools widely to accelerate the impact this new technology will have on the understanding of opioids.

Citation:
Title: Unlocking opioid neuropeptide dynamics with genetically-encoded biosensors Authors: Chunyang Dong, Raajaram Gowrishankar, Yihan Jin, Xinyi Jenny He, Achla Gupta, Huikun Wang, Nilüfer Sayar Atasoy, Rodolfo Flores-Garcia, Karan Mahe, Nikki Tjahjono, Ruqiang Liang, Aaron Marley, Grace Or Mizuno, Darren Kirin Lo, Qingtao Sun, Jennifer L. Whistler1, Bo Li, Ivone Gomes, Mark Von Zastrow, Hugo A Tejeda, Deniz Atasoy, Lakshmi A Devi, Michael R. Bruchas, Matthew R. Banghart, Lin Tian
Journal: Nature Neuroscience