Mark Esposito was a member of the Middlebury track and field team, graduating in 2011. He is the co-founder, CSO and board member of KayoThera, a biotechnology company committed to addressing critical medical needs and potentially revolutionizing the treatment landscape in both oncology and cardiometabolic diseases.
What is the principle behind KayoThera?
Biology boils down to a simple dynamic – too much of something is bad, and so is too little. For KayoThera (a portmanteau of K-O, or knockout, and therapeutics), that "too much" we are correcting is the retinoids, or the signaling metabolites downstream of Vitamin A. We've known for a long time that too little Vitamin A causes childhood mortality as well as blindness. What is less well known is that too much Vitamin A and the downstream retinoids are also harmful. At the elevated amounts that are typical of dietary supplements or many acne treatments, too much retinoid activity raises fats and glucose in the bloodstream, increasing mortality from heart failure while also increasing cancer rates by 20-50%. At KayoThera, our medicines selectively block the metabolism of Vitamin A into the downstream retinoids without affecting the primary role of Vitamin A in vision. We've developed therapies for cancer, obesity and diabetes that block retinoid activity in selective tissues.
Have there been any challenges throughout the process? How did your time at Middlebury help you push through those obstacles?
Building a drug is not just technically difficult, the journey requires an almost masochistic drive to continue working when the money is running out, the experiments are going poorly, or an administration shift dramatically changes the pharmaceutical landscape. I credit much of our success to my time at Middlebury. Only after arriving at Princeton for graduate school did I realize that the benefit of a Middlebury education was not what we learned, but rather how we learned. Much of the learning at Middlebury is a first principles approach: How do we take insights from one field and apply them to another? Why do certain assumptions exist? What rules or assumptions can we break? Which ones should we break?
Middlebury provides an incubating environment to push the boundaries and falsify the assumptions that have been built into a system. I think that is the most valuable aspect of a Middlebury education.
You have brought in nearly $15 million to create more new medicines. Can you share what these are going to focus on and where you are in the process of getting these medications available for people?
KayoThera is building three medicines. KAYO-1609 is a first-in-class immunotherapy that blocks the immunosuppressive effects of retinoids. This pathway is often hijacked by pancreatic, stomach, and breast cancers as well as melanoma, some sarcomas and a unique type of leukemia called T-ALL. We will be enrolling patients in our first clinical trial next year to test if KAYO-1609 can stimulate the immune system to recognize and destroy the tumors. Since our founding, we've built a tremendous team of drug developers to make sure that KAYO-1609 is fully optimized to be safe, effective and readily combinable with other cancer medicines.
Our second medicine, KAYO-1732, is attracting considerable attention right now as obesity and diabetes are redefined by Ozempic. KAYO-1732 has shown an incredible ability to prevent or reverse type 2 diabetes in animal models by controlling the trifecta of glucose, cholesterol and triglycerides. This leads to beneficial effects across many organs and prevents the harmful effects of diabetes on the liver, kidneys and heart. This therapy will be entering regulated studies over the next 16 months so that we can begin human trials in 2026.
The last drug is an anti-obesity drug in development for people coming off Ozempic or who would prefer a different type of obesity treatment. This one is still several years away from human testing.
What is one piece of advice that you would give to current Middlebury student-athletes?
Our assumptions, rules and boundaries are not set by some higher intelligence or set of galactic rules – they are, in my opinion, usually the result of laziness, fear, or a combination of the two. Break the ones that seem foolish and see where it takes you.
What is your Midd Moment?
The admissions essay for the entering class of 2007 asked us to describe what personal responsibility meant. I didn't realize at the time how fundamental this question is to a fulfilling purpose; I was only concerned with trying to get into college. More recently, I find myself meditating on that prompt. It's simple to say that personal responsibility means doing the right thing, even when that is the hardest thing. It's harder to put into practice.
For me, personal responsibility means doing everything you can for the people around you and not asking for anything in return. It means working for your investors now and for the patients you hope to help in the future. Personal responsibility requires you to own your failures and treat your competitors with integrity. On my journey, that responsibility meant that when I made the first discovery that would turn into the drugs KayoThera is developing, I had to continue building, because no one else would.
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