"Obesity is spreading in the U.S. population, where it's an increasing problem. It carries a greater chance of morbidities and mortalities, everything from heightened propensity for cancer, heart disease and atherosclerosis to lipid problems."
So observed cardiac pharmacologist Gary Grover, a senior principal scientist at Bristol-Myers Squibb Pharmaceutical Research Institute in Pennington, N.J.
"We're still in the early days," he commented, "trying to figure out how we can attack this major public health problem."
Obesity is the leading nutritional disorder in the U.S. It's defined as body weight 20 percent or more in excess of ideal weight for height. By this token, 34 percent of adult Americans are obese. Harsher epidemiologists set obesity at 55 percent to 60 percent. And children are fast catching up. In Germany, obesity increased 13 to 20 percent; the rest of Europe not much. In the UK and Canada, obesity was up from 6 to 15 percent in men. In South America, Australia and Africa, it increased 8 to 15 percent in women.
BMS' Gary Grover is senior author of a paper in the Proceedings of the National Academy of Sciences (PNAS), published July 29, 2003. Its title: "Selective thyroid hormone receptor-b activation: A strategy for reduction of weight, cholesterol and lipoprotein (a) with reduced cardiovascular liability."
"The significance of our finding in this PNAS paper," Grover told BioWorld Today, "is that there are very few anti-obesity drugs, if any, that work or retain their activity for longer than a couple of weeks or a month. Most approaches for treating overweight people are on the appetite-suppressant side. We have this sedentary lifestyle. And what we're doing is approaching this situation from the opposite side of the equation: Can we increase the rate at which the food-energy is burned, and is it possible to do it safely? This article is the first step in showing our potentially viable strategy."
First, Do No Harm To Healthy Patients!
"The other thing about obesity," he continued, "is that when you're trying to think about treatments for this condition, an obese individual by and large - even though at risk for diabetes, heart disease and so on - you're treating an otherwise healthy person. So it's critical that the anti-obesity drugs not only work but they have to be very safe. Because it's not as if you're treating a truly life-threatening illness. So the requirement is that the drug really has to be pretty safe. Remember," Grover recalled, "when fen-phen ran into problems?
"When you have people gaining weight," he went on, "it's either because they're eating too much or not burning the food or the energy off quickly enough. So the increased metabolic rate is really how the thyroid hormones reduce weight. You want to increase the metabolic rate, but not too much. You have to increase it 5 [percent] or 10 percent, and spread it over a wide dose range."
Grover and his co-authors enlisted contingents of mice, rats and monkeys for in vivo preclinical trials of an experimental anti-obesity drug named KB-141. KB stands for Karo Bio AB, a biotech company in Huddinge, Sweden.
"This KB-141 compound selectively activates the thyroid beta receptors," Grover recounted. "By doing that, we could get relatively selective increases in metabolic rate and reductions in cholesterol without the unwanted side effect increase in heart rate. KB-141 is a very early compound, and there's a number of different ones that we're working with at an early preclinical stage, and 141 happens to be one of them," he went on. "And the focus of our PNAS paper was to try one of these anti-obesity drugs and see what the effects would be on the thyroid hormone beta receptor. So this study is not about a drug, per se; it's about what happens if we modulate that beta receptor. The in vivo studies," he added, "were all done at BMS in Pennington with rats, mice and monkeys.
"The first thing we did," Grover recounted, "was to treat the animals with thyroid hormone, which affects both alpha and beta subtype receptors. Then we knocked out alpha. All we were looking at was the beta effects. What we found was a desirable profile where we could get these modest increases in metabolic rate and cholesterol lowering without the increases of heart rate. After knocking out the alpha subtype, all we had was beta's effects to look at. We also used T3, a thyroid hormone, along with KB-141. In theory, thyroid hormone in these animals should look like a selective beta stimulator or agonist.
"It appears that alpha mediates most of the heart effects of thyroid hormones. What beta seems to mediate is the cholesterol lowering of the metabolic rate effects. And we really kept this pretty clear separation of activities. We also used KB-141 as a tool, another way, because it activates the beta receptor. The two experiments were looking at the same endpoint, but we approached them from two different angles. We got similar results when we used a beta selective drug and KO'd the alpha receptor. In fact, the results were almost identical."
Monkeys Lost Weight, But Not From Illness
"In the monkey studies that's exactly what we saw. They lost weight. We took three or four studies and put them all together to paint this picture that the beta receptor gave us; this different profile without activation of the alpha receptor. These results were the same in mice, rats and monkeys. We went across three different species and saw similar outcomes. The monkey, of course, being somewhat closer to man, it's always gratifying to see we can repeat the experiment in that primate species. They were losing weight because they were burning the energy, not because they were sick.
"In a week's period, within the dose-dependent drugs we were using, we were seeing anywhere from 3 percent to 5 percent weight loss. With humans we want maybe a 1.5 to 2 percent drop in weight per week. If we were to go a little bit lower in dose, we could achieve that."