Antiobesity drugs are amazing people by how fast they melt off pounds. But it's no surprise to Richard DiMarchi.
DiMarchi, a chemical biotechnology and drug discovery pioneer, helped create life-altering drugs for patients impacted by diabetes and other endocrine diseases. But he also laid the foundation for drugs like Ozempic and Mounjaro that control type 2 diabetes without insulin, while lowering body weight. This trait of these compounds kicked off the boom in antiobesity drugs.
DiMarchi is a distinguished professor of chemistry and Gill Chair in Biomolecular Sciences at Indiana University. He's also a former group vice president at Eli Lilly and later a vice president at Novo Nordisk.
In a career spanning decades, DiMarchi developed breakthrough drugs that revolutionized diabetes treatment. All the while, he muted skeptics, who said it couldn't be done.
Find Your Starting Point Like Richard DiMarchi
DiMarchi says the accomplishments built "the foundation for this new class of drugs based on gut hormones that have ability to control type 2 diabetes without insulin, while reducing body weight." Take glucagon-like peptide-1 receptor agonists (GLP-1s).
"Such drugs mimic the actions of the natural hormone GLP-1 released after eating, and constitute a part of the more powerful peptides where such pharmacology is complemented by additional hormonal mechanisms of action," he said.
DiMarchi's academic research has broadened the understanding of glucagon physiology and the discovery of a single drug, not a mixture, has multiple modes of action for the treatment of diabetes and obesity.
But DiMarchi's role in developing the popular antiobesity drugs is just one in a list of achievements as a groundbreaking researcher and innovator.
He contributed to the discovery and development of recombinant DNA (rDNA)-derived Humalog, rGlucagon and Forteo. Humalog, an injectable, fast-acting insulin to treat diabetes, became the first rDNA-derived molecule chemically optimized for human use.
What has been his formula for success in leading drug development?
"I don't believe there is a single formula, but a central element is focus on doing something that is different from what everyone else is doing," said DiMarchi, 72. "I pride myself on being a person aiming to do something different, something seemingly impossible or at least improbable."
Tap Your Creativity
DiMarchi says "a breakthrough requires inventive creativity. It is not an iterative improvement. What others are doing is not to be repeated, it is reason to do something else."
DiMarchi's path to success began early in his career. A native of Brooklyn, he left New York's Rockefeller University, where he did his postdoctoral fellowship, for Eli Lilly in Indianapolis. He started as a bench scientist in 1981 working on the biosynthesis of human insulin, which became Humulin.
"The reason I came to Lilly was less to make this one molecule than it was to learn the technology in how to synthesize these molecules in microorganisms," said DiMarchi.
In 1982, Eli Lilly launched Humulin, the first mass-produced biosynthetic insulin. "It was a launching point for the biotech industry," DiMarchi said. "The venture capital community saw they could profitably invest and reinvest significantly in drugs made with this technology."
DiMarchi saw potential in further developing and commercializing this biotechnology. "Once we had validated this technology, we had a commercial method to make virtually any peptide or protein on a commercial scale, at a suitable cost," he said. "My vision was that these natural sourced peptides and proteins could be chemically optimized for medicinal purposes."
DiMarchi: Optimize Your Breakthroughs
His approach evolves century-old medicinal methods that used synthetic chemistry to "optimize" natural products such as antibiotics to discover breakthrough medicines.
"What I envisioned in biotechnology was an analogous optimization of peptides and proteins which nature has optimized for physiological purposes, now being enhanced for pharmacological use," he said.
DiMarchi smashed the prevailing view that changing natural human sequence was a "risky proposition more likely to increase toxicity than pharmaceutical performance," he said.
Find A New Way
As research director of biotechnology at Eli Lilly, DiMarchi and his colleagues changed the structure of insulin to make it work better around mealtime for insulin-dependent diabetics.
That drug, Humalog, an injectable fast-acting insulin to treat diabetes, became the first rDNA-derived drug FDA approved as a substance that had been "purposefully optimized to superior performance that exceeded the natural form of the hormone."
In 1996, the FDA-approved this "synthetic macromolecule" as a lifesaving, daily therapy for millions of patients. It proved to be a blockbuster drug for Eli Lilly.
The National Inventors Hall of Fame inducted DiMarchi in 2014 for the "molecular design" of Humalog. Significantly, "it established a precedent for optimizing proteins to create superior drugs than found in nature," said the NIHF.
Keep Pushing Innovation Like DiMarchi
DiMarchi didn't stop with Humalog.
"In extending our first commercial success, our chemistry evolved to more adventurous objectives," he said. "What would happen if we were to integrate multiple complementary hormones into a single medicine; could greater efficacy and safety be achieved?"
And DiMarchi was right on the money with the formula for yet another breakthrough.
Eli Lilly's blockbuster drug Mounjaro is a "first in class medicine" that works through two hormonal mechanisms, DiMarchi says. Those hormones are GLP-1 and GIP (glucose-dependent insulinotropic polypeptide). Mounjaro is the first medication in its class to simultaneously activate both the GLP-1 and GIP receptors. The drug is a huge winner for Eli Lilly.
Rack Up Awards
DiMarchi didn't just toil in obscurity. DiMarchi won the 2023 Mani L. Bhaumik Breakthrough of The Year Award from the American Association for the Advancement of Science, which recognizes the GLP-1 drug class as "transforming the management of obesity and related chronic diseases."
"DiMarchi transformed thinking about the hormones this class of therapies should mimic as a critical part of their efficacy," said the AAAS in the April 2024 statement announcing the award, which also honored co-recipient Lotte Bjerre Knudsen, chief scientific advisor at Novo Nordisk
The ability to overcome the setbacks in pursuing his research drives DiMarchi's success as a discovery scientist and pioneering biotechnologist. DiMarchi knows how to prove naysayers wrong.
"I am an iconoclastic person, someone who is willing to challenge long held views to explore whether they are or are not correct," he said.
Find Your Leadership Style Like DiMarchi
DiMarchi's leadership style drove his success as a groundbreaking researcher and innovator.
"My style is one of servant leadership, rolling up your sleeves," he said. "I'm very much involved in the nitty-gritty details of work. I view it important that I recruit those individuals who are similarly prepared, capable and motivated."
Keeping with his leadership style, DiMarchi says he decreased the scope of his role. That way "I could maintain my proficiency and the intimacy of association with the technical details and the scientists who are collaborating with me on the technical aspects of the work. I am more interested in achieving one discovery than I am in supervising large groups of people," he said.
Gather Like-Minded People
DiMarchi also surrounds himself with people who "have the same pioneering spirit as mine. It takes people who have enormous conviction and self confidence that eventually we will succeed, as you spend more time proverbially in the valley of death than on the summit of success."
DiMarchi knows how to guide his team to achieve success.
"One key aspect of DiMarchi's leadership is his ability to identify the important goals and be focused on achieving them," said Diego Perez-Tilve, research associate professor, Department of Pharmacology, Physiology and Neurobiology at University of Cincinnati-College of Medicine.
Perez-Tilve collaborated with DiMarchi for 15 years. "He (DiMarchi) has a laser focus on the long-term achievement of a goal. He has the ability to see the forest beyond the trees. That's what gives people working with him confidence."
Contribute To The Conversation
DiMarchi is also an entrepreneur and scholar. He co-earned more than 100 U.S. patents and coauthored more than 250 peer-reviewed scientific publications. DiMarchi cofounded eight successful biotech companies. One of those companies, MBX BioSciences, went public last year.
Students ask DiMarchi what they should do with their careers. His answer? "Be surrounded by people filled with optimism and have huge outrageous expectations for what is possible. If you can maintain this mission and follow a compass to true north with self-confidence, it's doable," he said.
Richard DiMarchi's Keys
- Pioneered life-altering drugs for patients impacted by diabetes and other endocrine diseases, laying the foundation for antiobesity drugs that control type 2 diabetes without insulin.
- Overcame: Challenges of research and funding in developing new drugs using controversial technology and gaining government approval and market acceptance.
- Lesson: "A breakthrough requires inventive creativity. It is not an iterative improvement. What others are doing is not to be repeated, it is reason to do something else."
