Courage to Collaborate
What happens when academia and industry team up to tackle anorexia nervosa
“I had a lot of time on my hands, so I started digging into the science.”
It was 2018, and Dan Housman had taken a leave of absence from his job as a managing director in Deloitte’s health care and life science consulting practice to support his daughter as she underwent in-patient treatment for anorexia nervosa. During all the downtime at the hospital and outpatient facilities, he decided to learn as much as he could about the disease.
Housman was frustrated by the lack of any FDA- approved drugs for a deadly illness affecting so many children like his daughter. With a background in molecular biology, he was determined to figure out whether some genetic glitch could be driving the illness at a cellular level.
“I was convinced, and I continue to be convinced, that you’re not going to develop anorexia nervosa without some biological difference driving this extreme condition. And that difference should be something we can address with new medicines, not just psychological treatments,” he says.
He pored over scientific papers and researched his family’s own genetic history. Eventually, he narrowed in on a potential candidate that could be involved in the disease: a cellular protein called the melanocortin 4 receptor (or MC4R).
“I made a list of everyone who researched MC4R and had found ways to chemically turn it off or on in the lab,” Housman recalls. “And, of course, Roger was right up there at the top of the list.”
Roger Cone has been studying melanocortin receptors since the early 1990s, when he and his colleagues published the first cloning of the melanocortin receptor genes.
“We found the first two receptors, which were known to regulate pigmentation and adrenal steroid production. When more receptor genes were discovered by my lab and others, nobody even knew what they were,” recalls Cone, now the Mary Sue Coleman Director of the University of Michigan Life Sciences Institute. “Then, when I found out MC3R and MC4R were expressed in neurons, I became fascinated with figuring out why these proteins that we thought were involved in pigmentation and hormonal regulation would be so active in the brain.”
Research over the past three decades, including many studies led by Cone, has revealed that the melanocortin family plays central roles in metabolism and energy balance. Cone’s team helped define how MC4R regulates the body’s energy balance by controlling how much energy is stored as fat. When body weight dips too low, MC4R is suppressed to stimulate appetite and restore weight. Mutations in the gene that encodes MC4R lead to early-onset obesity, a genetic condition that affects up to one in 300 people.
This role in energy balance is what grabbed Housman’s attention. Multiple members of his family, including two who have anorexia nervosa, carry a genetic abnormality that he thought might be over-activating MC4R. Stimulating this protein can result in lower food intake — one drug already exists to treat a type of syndromic obesity by increasing MC4R’s activity. Housman wondered if another drug could be developed to do the opposite: dampen MC4R and stimulate appetite in patients with anorexia nervosa.
“I emailed Roger about the possibility of developing a drug to act against MC4R, and I think the timing was just fortuitous,” Housman says. “He wrote back and said he wasn’t sure that antagonizing MC4R would work, but he had some very new findings that looked even more promising.”
Those findings were related to another melanocortin receptor, MC3R. The Cone lab had cloned MC3R, and even deleted it out of the mouse genome to characterize it, but then largely ignored it for two decades.
“We had defined this protein more than 20 years ago, but we could never really understand what it actually did,” Cone says. “It seemed to have all these conflicting effects on body mass and appetite in our animal models. Mutations in the MC3R could cause the animals to gain too much weight in some instances and lose too much weight in others.”
Around the time that Housman was reaching out to MC4R researchers, Cone’s lab unraveled the mystery: MC3R was responsible for defining how far out of balance the energy state could get before MC4R kicked in to affect appetite.
As a negative regulator of MC4R neurons, MC3R suppresses MC4R to increase appetite and food consumption. Basically, it does naturally what Housman hoped a drug could do.
But that’s not all it was doing.
“We also found that it’s active in other brain regions, where it’s involved in anxiety and fear. Boosting MC3R can boost appetite while also reducing those competing motivational states,” Cone explains. “Those results seemed ideal for addressing anorexia nervosa, where there is not only this lack of eating but also anxiety and fear around eating and gaining weight.”
“I flew out to Ann Arbor with a couple of advisors, and we met with Roger, and I said, ‘Let’s do it,’” Housman recalls. “Let’s form a company around this and see if we can get a drug to market.”
Working with U-M’s Innovation Partnerships, which supports university researchers to increase the impact of their work, the team formed Courage Therapeutics.
There’s a strong crosstalk between the basic science helping to advance drug discovery, and the drugs that are discovered helping to advance our basic science program. It’s resulted in a lot of really compelling science that I would have been unable to do just in my own lab.
Nearly two million Americans develop anorexia nervosa at some point in their lifetime. It has the highest mortality rate of any psychiatric illness. While the National Institutes of Health invests about $273 million a year in research on schizophrenia, for example — a psychiatric illness with a similar prevalence to anorexia and half the mortality rate — it spends about 5% as much on anorexia.
Moreover, recent research has found that it is, in fact, not just a psychological condition but also a genetic one. And there is no approved pharmaceutical treatment.
“It’s an area that really needs more attention,” Cone says.
The Courage Therapeutics team hopes to meet this need by merging the expertise and resources available within academia and industry.
As an industry-academia collaboration, the team can explore paths to discovery that would not be open to either group separately. For example, the startup qualifies for Small Business Technology Transfer funding from the NIH. This program supports early- stage small businesses working in partnership with nonprofit research institutions to bring scientific innovations to the market.
Through an agreement between U-M and Courage, the company sponsors research in the Cone lab and then has the right to license the outputs of that research. And with support from Courage, the Cone lab can create tools that advance both basic discovery science and the development of novel compounds that interact with the melanocortin system. Courage has already received three NIH grants that provide support to the Cone laboratory.
“There’s a strong crosstalk between the basic science helping to advance drug discovery, and the drugs that are discovered helping to advance our basic science program,” Cone says. “It’s resulted in a lot of really compelling science that I would have been unable to do just in my own lab.”
“It’s a great example not just for a startup, but for an active, successful collaboration between industry and academia,” adds Stefan Koehler, the director of therapeutics licensing for Innovation Partnerships, who manages U-M’s relationship with Courage.
These types of partnerships can help connect the research to the application and can ultimately lead to better science.
The company also can partner with leading scientists outside the university to bring in expertise that complements the work being done in the Cone lab. That’s how Tomi Sawyer became involved in the project.
Sawyer specializes in developing peptide drugs — short chains of amino acids designed to trigger reactions that synthetic small molecules can’t address and that larger proteins perhaps can’t reach. His 40-plus-year career as a peptide drug hunter has spanned pharmaceutical companies such as Parke-Davis, Pfizer and Merck, as well as the biotech industry. He is credited with multiple drugs that have advanced in the clinic and to the market, including one melanocortin peptide.
Through Courage, Sawyer and the Cone lab have been able to combine their know-how to design and test approximately 500 compounds so far to identify the best candidates for treating not only anorexia, but also obesity.
“The partnership between Courage and U-M has really become an engine for drug discovery,” Sawyer says.
The group’s goal is to develop lead compounds that they or a strategic partner can take into clinical trials, and eventually provide a marketable treatment for patients. Their work with MC4R-focused treatments for obesity has already produced compounds resulting in significant interest from potential industry partners. Work on MC3R has led to the first highly specific drug-like peptide agonist which is currently in the preclinical testing stage for disorders such as anorexia nervosa.
“There is a lot of synergy that can come from this kind of collaboration,” adds Housman. “We conduct research to better understand how things work. At some point, that research also could have real-world applications. These types of partnerships can help connect the research to the application and can ultimately lead to better science. We intend to use the science to make a new medicine against a deadly disease that continues to impact my family and so many other people we care about.”