Michele D. Huie
TCOYD Newsletter, Vol. 24, 2008

Dr. Baron never intended to become a diabetologist, though diabetes was a “big part of his thinking” as his younger brother Neal was diagnosed with type 1 back in 1965 at the age of 5. Dr. Baron admits he largely “went to medical school by default,” as his friends were going. He enjoyed the clinical years, and planned on becoming a heart surgeon, then thought about going into psychiatry, and finally he decided on internal medicine. During his residency, he realized that while he liked interacting with patients, his real passion was understanding the science behind the medicine.

Following his postdoctoral studies, Dr. Baron held academic and clinical positions in the Division of Endocrinology and Metabolism at the University of California, San Diego, and the Veterans Administration Medical Center in San Diego. In 1989, Dr. Baron moved to Indiana University School of Medicine, where he served as Professor of Medicine and Chief, Division of Endocrinology and Metabolism, and “spent 11 years there growing a research lab.” While at IU, he focused his research on the etiology and therapy of type 2 diabetes.

Moving to Amylin

In the late 90s, Dr. Baron was recovering from lymphoma. He’d had chemotherapy, and radiation therapy, and his outlook on life was deeply impacted by this. “I was living with no regrets,” he said, “…one life to live.”

“I never had any desire to go into industry; like most in academic medicine, I had an impression of industry as venal,” he said. But in 1999 Dr. Baron received an email from Dr. Orville Kolterman at Amylin (Senior Vice President, Clinical and Regulatory) asking, ‘Can we talk?’. Kolterman and Joseph Cook, the CEO at the time, showed Dr. Baron some data on exenatide [Byetta]. “They tried to hire me to lead this program at a time when Amylin had 38 people and only three months of funding left. I gave it some thought. I believed exenatide was going to revolutionize the treatment of type 2 diabetes, and I decided, ‘I’m not going to have the regret of not having been a part of that.’”

Dr. Baron left his formal academic career and became Amylin’s 50th employee. To this day, he dedicates his time to managing the company’s research—“everything from an idea to proof-of-concept for drugs for diabetes and obesity.”

R&D - The Target Driven Approach

Typically, research and development (R&D) is done on a target driven approach. In this manner, researchers screen millions of compounds to see if any of these molecules interact in some manner with the chosen target (the area/ function in the body that the drug is developed to treat). Very few do, and the ones that positively interact with the target (1 in 5,000) are called hits. Fewer still are compounds that look like medicine. These are called leads. For example, some molecules cannot be massproduced, some can’t be absorbed in the body, some aren't stable; thus the body won't be able to use them. Then researchers whittle down the leads, making sure the drug is specific for the target and doesn’t impact anything else in the body. This is the target driven approach. Of course, very few leads actually turn into FDA-approved drugs.

“Drug development is really the domain of failure more than the domain of success.” To explain, he pointed out that it is vitally important for pharmaceutical companies to fail fast, that is, to know quickly that a drug ultimately won’t work so that the company doesn’t spend exorbitant sums of money on a doomed project. “You try to get to a go-or-no-go decision as rapidly as possible, but it’s very difficult to do,” he said. “From the time you discover a molecule to the time you market it—that takes about 12 to 14 years on average, and about 1.5 billion dollars. Decisions you make very early on are so critical.”

Amylin’s Approach

Amylin Pharmaceuticals was founded in 1987 on the discovery of a hormone, amylin, produced by the same beta cells of the pancreas that make insulin. Amylin’s scientists discover and investigate new peptide hormones. Peptide hormones are hormones with endocrine functions such as insulin (from the pancreas), thyroid hormone (from the thyroid gland), epinephrine (from the adrenal gland) and endorphins (from the hypothalamus). By discovering new hormones, the company challenges the traditional target driven approach to R&D. “We actually discover new hormones, then take the hormones and put them directly into the animal model of the disease of interest. We start with the medicine and find its utility, as opposed to finding a target and screening a bunch of molecules against a target.”

One of the most apparent differences between Amylin and other pharmaceutical companies is that Amylin only deals with injectable medications. “If you have an injectable, it has to have a significant effect because people aren’t going to inject it otherwise. So we have been forced by virtue of our focus on peptide hormones to say, ‘Listen, if we are going to do something, it has to make a difference, not just a market difference. It has to make a difference to patients.’”

The Pipeline

There are two things Dr. Baron tells us he is most excited about. The first is once-a-week Byetta [Exenatide LAR]. Byetta is the first in a class of medicines for type 2 diabetes called incretin mimetics. This drug mimics the effect of naturally occurring hormones released in the intestines, and helps the body secrete insulin and other hormones in a physiologic manner. Currently, Byetta is taken by injection twice a day with the two main meals. Dr. Baron says the once-a-week version of this drug “demonstrates the best data for a diabetes drug ever.” Seventy-six percent of people using the drug in studies achieved an A1C value of 7 percent or below and lost excess weight at the same time—a combination of benefits not seen with any other drug.

The area of obesity ties with Byetta for most exciting drug development for Dr. Baron. A hormone called leptin was discovered about a decade ago at Rockefeller University. Leptin comes out of fat cells; the more fat cells you have the more leptin you have. It signals the brain about the energy storage in the body, and regulates energy expenditure. People who lack leptin are massively obese and ravenous most of the time. When leptin is replaced, the body fat melts away.

But leptin does not work as a cure for obesity, which has been a huge disappointment to scientists around the world looking for an effective obesity treatment. “It doesn’t work in obese people; it doesn’t work in obese rats. However, what we discovered here about four years ago is that when you combine leptin and amylin (the peptide hormone that is the company’s namesake), you can get significant weight loss.” Clinical trials in overweight humans using “amyleptin”—combined leptin and amylin—will come to fruition soon, and look promising. “Combining hormones to get better therapies is something we are very keen on. This is the thrill of my work,” says Dr. Baron. “Here, I can have the thrill of making a difference in very large populations of patients.”

It is a marvel to think of how far we’ve come in understanding and treating diabetes in the last two decades. Who knew 20 years ago that the beta cells of the pancreas not only produce insulin, but also produce amylin—a hormone that works in conjunction with insulin to flatten out post meal blood sugar spikes? The more we learn about the naturally occurring hormones in the body, the better we can tackle the ups and downs of living with diabetes. “We believe that natural hormones, which have evolved over billions of years, are inherently safer than small molecules that people make—that are human inventions,” he said. “We are going after things that are in nature.”

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