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The Story of Januvia

Nancy A. Thornberry

Ann E. Weber, Ph.D.


Two Merck research scientists, Nancy A. Thornberry and Ann E. Weber, Ph.D. received the 2011 Discoverers Award, the highest honor from the Pharmaceutical Research and Manufacturers of America (PhRMA), for their leadership in the discovery of JANUVIA® (sitagliptin), a once-daily pill that helps patients with type 2 diabetes control glucose in conjunction with diet and exercise. Weber and Thornberry are the first two women in Merck’s 120-year history to lead the team that discovered a new medicine. And for the first time in the Discoverers Award’s 24-year history, women alone were honored for their special achievements of exceptional benefit to humankind.


When JANUVIA was approved, it was the first new oral medication for diabetes in more than a decade, and the first medicine approved by the FDA to inhibit the enzyme DPP-4. By inhibiting DPP-4, JANUVIA helps prevent the degrading of a natural hormone that signals the pancreas to release insulin. Today, JANUVIA is being prescribed to millions of patients with type 2 diabetes and demonstrates Merck's commitment to develop therapies to improve human health around the world.



Preparing for the Task


It all began when Thornberry asked Weber if she’d be interested in collaborating on an exciting program with an interesting target for type 2 diabetes.


"Discovering an important new medicine is the goal of every person who works in pharmaceutical research. Until it actually happens, though, there is no way to know how absolutely thrilling it is, and how incredibly and deeply satisfying it feels."—Nancy A. Thornberry

In the spring of 1999, Thornberry was provided with an opportunity to lead a group of about 30 talented biochemists and molecular biologists, and she spent most of the summer looking for new, promising programs for them to work on. She became aware of some very exciting, new research about the role of a hormone called GLP-1 (glucagon-like peptide-1) in signaling the pancreas to release insulin. She was particularly interested in related studies that showed that an enzyme called DPP-4 (dipeptidyl peptidase-4) was involved in the regulation of GLP-1. This work had led to the hypothesis that DPP-4 inhibition could be a good target for the treatment of type 2 diabetes. In August that same year, she launched a program to discover a novel inhibitor of DPP-4.


When Thornberry approached Weber about collaborating on the project, she was well aware that diabetes had become a global epidemic. Currently, it affects more than 285 million people worldwide —with 438 million cases predicted by 2030. Half of diagnosed patients fail to achieve adequate blood glucose control—and diabetes can lead to blindness, amputations, heart disease and nerve and kidney damage, among many other health consequences.


Weber knew that patients, even while they worried about having too much glucose in the blood, were at risk of having their glucose levels lowered too much using existing treatments. The condition, hypoglycemia, can cause reactions such as heart palpitations or, worse, seizures and loss of consciousness.


Soon, she and Thornberry would be leading a team of scientists who would find, and in record time, the first new oral therapy for type 2 diabetes in more than a decade.


"Discovering an important new medicine is the goal of every person who works in pharmaceutical research," says Thornberry. "Until it actually happens, though, there is no way to know how absolutely thrilling it is, and how incredibly and deeply satisfying it feels."


"Successful Failure"


Just about the time Weber joined the team in early 2000, Merck decided to jump-start the program by acquiring a compound from a small biotech firm that showed promise for inhibiting DPP-4. Studies of the compound began, but within several months, preclinical safety trials showed the compound wasn’t well tolerated, and it had to be abandoned. 


"It was a huge disappointment, a real setback," says Thornberry. "We didn’t know why the compound triggered toxicities. Fortunately, rather than giving up, we got the company’s support to investigate further and try to understand the mechanism of the toxicities."


Rather than dropping the program, or even proceeding with the least investment possible until more was known, Merck executives agreed to pursue research on parallel tracks: the research team, led by Thornberry and Weber, worked to investigate the reason for the poor tolerability of the original in-licensed compound, and simultaneously began a medicinal chemistry effort aimed at identifying a potential drug.



The team set to work on designing and synthesizing new molecules to systematically address the issues with the lead compounds. More than 2,000 new molecules were prepared and investigated, with nearly all of them dropping out of contention one by one. Eventually the team narrowed their search to six possible drug candidates. Then there were two, then one. 


Before those compounds were even identified, the team of scientists now working on the project brought in clinical trial experts to begin considering a host of issues. And the team was, among other things, working to understand why the original molecule wasn’t tolerated well in preclinical studies. Thornberry got the answer in September 2001. She immediately called Weber, who was stuck in England in the aftermath of the 9/11 attacks in New York.


"I clearly remember that day," says Weber. "It was an awful time for our country. I was worried about family and friends in New York City." The news from Thornberry: Evidence suggested that off-target activity, and not the inhibition of the DPP-4 mechanism, had caused the side effects. It meant their hypothesis was correct and work could continue. Says Weber, "The call created a bright spot during an otherwise terrible time."


In Thornberry’s words, the disappointment over the problems with the first compound had become "a successful failure."


Trials, But No Tribulations


There was no delay. The team quickly received approval from Merck executives to move ahead with preclinical and clinical trials. Weber and Thornberry already had been meeting with Gary Herman and Peter Stein, medical doctors who would be involved in the clinical trials if in fact the molecule was approved for further development. Clinical supervisors Keith D. Klein and John Amatruda, both medical doctors, encouraged them to be creative, aggressive and efficient, and backed them up with resources.


Months were saved by planning ahead and anticipating what could be done the minute each study was completed. Separate teams took primary responsibility for individual pieces of the puzzle, while an overarching team focused on the big picture. And all of this work was accomplished with full attention to Merck’s extraordinarily high standards of scientific rigor.


From compound selection to filing with the U.S. Food and Drug Administration (FDA) for review took four-and-a-half years—a process that usually takes a decade.


"In many ways the stars were aligned because we had a beautiful molecule and support from senior management to really go for it," says Herman. But as importantly, he says, the collective team was magical. "We had tremendous trust. Everyone was all in, and we challenged each other aggressively," he says.




JANUVIA was the name given to the compound and it was approved in October 2006. Today, it is being prescribed to millions of patients with type 2 diabetes. Weber says she can’t get her head around that but takes extreme pleasure in hearing that a friend or colleague or their family member is being helped. Her father, a recently retired physician, is especially proud.


"Even with JANUVIA, there is a tremendous unmet need. Diabetes is a progressive disease, and we need to continue to work towards new therapies."

—Nancy A. Thornberry

"He prescribed it for some of his patients before retiring, and even though he was not prescribing JANUVIA because of my connection to it, he always told them, ‘My daughter discovered this’," says Weber.


Thornberry has a more intimate connection—her mother takes JANUVIA. Thornberry’s mother wasn’t about to try JANUVIA just because her daughter discovered it, though. "She wanted to know how it worked and asked me lots of questions before her doctor prescribed it for her," says Thornberry.


The discovery and development of a drug is the ultimate team effort. Thornberry and Weber, among many others at Merck, continue the battle against diabetes, looking for the next generation of medicine.


"Even with JANUVIA, there is a tremendous unmet need," says Thornberry. "Diabetes is a progressive disease, and we need to continue to work towards new therapies."

Read more or watch the video to learn more about the exciting story behind Nancy Thornberry and Ann Weber’s discovery of JANUVIA.

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