DiMarchi to be honored for breakthrough research in obesity drug discovery: IU News

DiMarchi to be honored for breakthrough research in obesity drug discovery: IU News

BLOOMINGTON, Ind. — Indiana University Distinguished Professor Richard DiMarchi will receive the 2024 Mani L. Bhaumik Breakthrough of the Year Award, presented by the American Association for the Advancement of Science, for his pioneering research that laid the foundation for drugs that are transforming the treatment of obesity worldwide.

Richard DiMarchi poses at IU Bloomington.Richard DiMarchi is a Distinguished Professor of Chemistry and Gill Chair in Biomolecular Sciences in the IU College of Arts and Sciences. Photo by Chris Meyer, Indiana University

The award honors scientists whose research exemplifies Science’s 2023 Breakthrough of the Year, which recognizes the GLP-1 drug class transforming the management of obesity and related chronic diseases. DiMarchi, the Linda and Jack Gill Chair in Biomolecular Science in the IU College of Arts and Sciences, and co-recipient Lotte Bjerre Knudsen, chief scientific advisor at Novo Nordisk, were selected by a committee of editors and senior leadership at Science for their transformative work to advance understanding of GLP-1 agonists. They will receive the award April 26 at a ceremony in Washington, D.C.

DiMarchi, a member of the National Academy of Medicine and the National Inventors Hall of Fame, is a co-inventor of more than 100 U.S. patents, co-author of more than 250 scientific papers and co-founder of eight successful biotechnology start-up companies. He has been a leader in the discovery, development and manufacture of new drugs that improve countless lives impacted by diabetes and other endocrine diseases.

“For decades, Richard DiMarchi’s groundbreaking research and innovative spirit have had profound effects on improving health across the globe,” IU President Pamela Whitten said. “A pioneer in the field of chemical biotechnology, his research is a testament to the life-changing global impact Indiana University researchers have in society and the scientific advancements being made that are changing the future of medicine.”

Laying the foundation

Headlines have been dominated in recent months by a new class of drugs, like Ozempic and Mounjaro, based on gastrointestinal hormones that include GLP-1, and their ability to control Type 2 diabetes without insulin while reducing body weight. But while these positive effects may have been news to many, DiMarchi was helping lay the foundation for their emergence for the past 40 years.

Richard DiMarchi in his lab at IU Bloomington.

DiMarchi’s groundbreaking discoveries have improved the quality of life for millions of people worldwide. Photo courtesy of the IU College of Arts and Sciences

He trained at Rockefeller University with Bruce Merrifield, who was awarded the 1984 Nobel Prize in Chemistry for his transformative contribution to the synthesis of peptides, a natural polymer of amino acids. Since then, DiMarchi has been a fervent proponent of peptide-based drugs through a period when pharmaceutical company interest was directed elsewhere, to conventional oral molecules.

DiMarchi’s research has championed the biosynthesis and chemical optimization of macromolecules, such as peptides and proteins, with enhanced therapeutic properties. He has spent much of his career focused on improving the lives of individuals with diabetes, and in more recent decades, obesity. While peptide-based drugs function like other smaller hormones in the body, they possess certain chemical attributes that render them capable of treating diseases where conventional drugs are not effective — insulin being the prime historical example.

“Richard DiMarchi has been at the forefront of advancing biotechnology in Indiana for more than four decades, and his scientific discoveries have improved millions of lives in our state and beyond,” IU Vice President for Research Russell J. Mumper said. “As a leader in drug discovery and innovation, you can see his research in action and his passion for work. He exemplifies the power of transformative research to change lives and impact our economy.”

Making discoveries

DiMarchi had a successful 20-year career at Lilly Research Labs, where he helped launch the era of biotechnology, endocrine research and product development. There, he discovered the active peptide ingredient in Humalog, an injectable, fast-acting insulin to treat diabetes. It represents the first rDNA-derived molecule chemically optimized for human use. He also contributed to the development of Forteo, glucagon and other therapeutics aimed at treating endocrine diseases.

Richard DiMarchi talks to his colleague Kishore Thalluri in his lab at IU Bloomington.

Collaborations with IU researchers, like faculty research assistant scientist Kishore Thalluri, and external partners have been integral to DiMarchi’s success. Photo by Chris Meyer, Indiana University

At Lilly, DiMarchi initiated GLP-1 research through a collaboration with Karolinska Institute professor Suad Efendic, a leading physician-scientist in diabetes. They were the first to determine that GLP-1 was able to reduce body weight in overweight adult-onset diabetic patients.

While leading diabetes research at Lilly, DiMarchi observed the rapidly growing need for insulin and the increase in adult-onset diabetes that was associated with the emerging epidemic of obesity. Overweight individuals are typically less insulin-sensitive, which can lead to diabetes and often require insulin treatment to control hyperglycemia. However, there was a lack of interest in the pharmaceutical sector to pursue a drug that could treat obesity. It was not considered a disease, it presented a less-than-clear path to drug registration, and the prospect of a drug requiring injection was perceived as commercially unattractive, DiMarchi said.

As a result, DiMarchi and Efendic’s precedent-setting early achievement in lowering body weight was largely ignored while interest in GLP-1 as a diabetes drug progressed with several candidates, including what eventually emerged from Lilly as Trulicity, the first weekly medicine approved in this drug class.

Setting the standard

DiMarchi joined the IU chemistry faculty in 2003 as Gill Chair at the interdisciplinary Linda and Jack Gill Center for Neurosciences; there he began collaborating with Helmholtz Munich CEO Matthias Tschöp, who was a professor in the University of Cincinnati College of Medicine at the time. Their goal was to discover a stable, aqueously soluble form of glucagon, and they rapidly progressed to integrating multiple complimentary hormones into a single medicine. DiMarchi’s lab chemically discovered such peptides, which Tschöp and his colleagues demonstrated as mechanistically unique and pharmacologically superior in rodents.

IU faculty who are Gill Chairs pose at IU Bloomington.

DiMarchi and other Gill Chairs in the Gill Center for Biomolecular Science at IU were brought together to advance interdisciplinary research and train the next generation of neuroscientists. Photo courtesy of Richard DiMarchi

“At IU, we took GLP-1 chemistry and pharmacology to another level, making the fundamental observation that when you integrate more than one mechanism such as glucagon and GIP into a drug, you can achieve far greater efficacy,” DiMarchi said.

The collaborative research demonstrated that glucagon had been narrowly mischaracterized as a counter-regulatory hormone, serving only to oppose insulin’s glucose-lowering action. It is much more than previously appreciated. It is a regulatory hormone as much as insulin, with unique biological actions that provide chronic health benefits to the liver, kidney and potentially other organs. Additionally, they demonstrated that sustained administration of GIP and GLP-1 led to an unexpected and unprecedented lowering of body weight, with further improvement in glucose control.

“These discoveries have led to the industry reversing its perspective on obesity as a disease and peptides as drugs,” DiMarchi said. “Now you have a plethora of peptides with integrated hormone action exhibiting increased efficacy in Type 2 diabetes, and with dramatic improvements in other areas, from body weight to fatty liver, cardiovascular disease, and with the potential to even slow cognitive decline.”

Media kit: Access video and photos of DiMarchi

Integrating multiple biological activities into one single peptide is chemically challenging — like aligning all faces on a Rubik’s Cube — and was precedent-setting, as nature designs these hormones for selectivity, DiMarchi said. And now its discovery has set an important precedent in drug development for complex diseases.

“It moves us to a point where we can operate at a higher level of molecular complexity to treat diseases where solutions have escaped us, allowing us to find answers to problems that present in different patients in different ways,” DiMarchi said. “My hope is that we’ll find this chemical approach can be replicated in treating other diseases where we have tremendous need, such as osteoarthritis, liver and kidney fibrosis, or brain diseases such as Parkinson’s and Alzheimer’s.”

Improving quality of life

The Mani L. Bhaumik Breakthrough of the Year Award is a recognition of DiMarchi’s important collaborative discoveries at IU and his prior achievements at Lilly. Over the past two decades, partnerships with Merck, Roche, BMS, Novo and others have advanced these discoveries and inspired global interest in building upon the scientific direction he established with Tschöp to reach patients worldwide.

Richard DiMarchi presents his research at Metabolism Day 2024.

DiMarchi presented his research during Metabolism Day 2024 at the University of Copenhagen’s Novo Nordisk Foundation Center for Basic Metabolic Research. Photo by Ricky John Molloy, courtesy of the University of Copenhagen

“This is not the first time I have been associated with the discovery, development and registration of an important drug, but in this instance, there is the opportunity to reach a much larger community, given the global epidemic of obesity,” DiMarchi said. “The impact could exponentially exceed the millions of patients that have benefited from chemical optimization of insulin.

“It is amazingly gratifying and humbling to see that these drugs have progressed to become miraculous molecules that restore health and a fuller, more prosperous life.”

However, DiMarchi emphasized, it takes an enormous number of scientists to translate a research hypothesis into a breakthrough drug, and breakthrough discoveries require leadership, creativity and persistence. While several prominent scientists have rightly been recognized for their contributions in this field — even while questions persist of whether anti-obesity drugs are even necessary — many others have remained largely invisible.

“The ability to manage excess bodyweight as we have traditionally addressed excess glucose, cholesterol and blood pressure is an incredibly great accomplishment,” DiMarchi said. “For those focused on patient care, it is the ultimate prize. We should collectively recognize and celebrate this shared accomplishment.”

Inspiring future innovators

According to DiMarchi, working with IU students — and mentoring their development into future innovators and entrepreneurs — is his most prized legacy.

Richard DiMarchi poses with students who work in his lab.

IU students who have studied in DiMarchi’s lab have impactful careers as professors, pharmaceutical and biotechnology scientists and administrators. 2009 photo courtesy of Richard DiMarchi

“The goal from the start at IU was to enable students and collaborators with the vision, the excitement and the technical capabilities to make even greater contributions,” DiMarchi said. “These students and research fellows have individually and collectively made the incredible molecular discoveries that have enriched the transformative advance in what was once perceived as a near-impossible disease to be medicinally manageable. I could not be prouder or more grateful for their contributions.”

DiMarchi’s success demonstrates IU researchers’ important legacy in pursuing discoveries that have a positive impact on our world.

“The College of Arts and Sciences is proud to have outstanding researchers and entrepreneurs such as Professor DiMarchi on campus, who are advancing knowledge and making discoveries that are transforming our world for the better,” said Rick Van Kooten, executive dean of the College. “He inspires students and other faculty with his work and how it translates to benefit society at large.”

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