Posted by Doc Bushwell here, pharmaceutical bogeyperson of the fast food-pharma-medical establishments’ collusion against the fundamentalist fat activists (FFAs). Yes, that’s right. We bench monkey pharma researchers lie awake at night, tossing, turning and vigorously scratching our nether regions, while we plot new ways of wresting money and adipose tissue from these hapless souls.
Truth be told, many large pharmaceutical companies have major obesity research programs which have fed, and intend to feed, the pipeline with compounds as clinical candidate hopefuls in the war against obesity. Some, like Sanofi-Aventis’ rimonabant/Accomplia, the CB-1 receptor antagonist, have moved far into the clinic in the hopes of replacing nastier entities like fen-phen. The purveyors of the newer meds hope to claim a sizeable chunk of this sizeable market.
Although we bench monkeys would like to think that good science drives target selection in discovery research, and in fact this is not an uncommon event, the pecuniary creatures in market analysis have increasingly worked their wiles into the earlier stages in the drug discovery process. Good science, although of paramount importance to us discovery types…
… is not always first and foremost in marketing’s mindset. Consequently, many pharma companies have research efforts directed toward obesity. Other than the niche-directed biotech boutiques, to remain competitive, obesity targets seemingly must be on the research docket of a large pharmaceutical company.
In terms of pure science, I have to admit there’s a certain degree of “Ah ha!” coolness surrounding some of the targets related to obesity. The “Ah ha!” factor is an especially seductive influence in science. Are there little spurts of dopamine released at those moments, tickling the reward centers of the brain druing the moment of discovery, and thereby making the process addictive? Enzymes involved with various parts of fatty acid metabolism and certain G-protein coupled receptors like the CB-1 receptor mentioned above and the ghrelin receptor represent interesting potential targets, and well, I can’t tell you about the others. But as enticing and challenging as those targets might be for the cell biologist, the med chemist and the biochemist, those of us grizzled old veterans of the pharma biz know the potential pitfalls of bringing forward drugs for chronic indications, and certainly obesity falls into the latter category.
For drugs which treat disease states afflicting patients over the span of decades, for example, high blood pressure or arthritis, the long term safety of the meds is of great concern. The patient takes these drugs daily for months, and more likely years, so adverse side effects are not particularly tolerable. This contrasts with a cancer patient who bears the brunt of cytotoxic chemicals coursing through his or her system in the effort to drive back tumor growth although more refined and targetted approaches may allow cancer to be treated as a chronic condition. The estimated costs to bring a drug to market from its discovery vary from $800 million to $1.2 billion, and the proper trials to determine efficacy and long term safety of a potential obesity drug would factor significantly in this cost. All in the name of what? A 10-20% weight loss versus placebo?
To be fair, even if weight loss is rather modest, rimonabant appears to have a beneficial effect on blood glucose levels and circulating in patients with Type 2 daibetes according to the results of the RIO-DIABETESclinical trial. The findings were reported on June 12 at the American Diabetes Association conference in San Diego. The beneficial effects on blood glucose and triglycerides appeared to extend beyond what was expected from weight loss alone. Still, the FDA issued the good news- bad news “approvable” letter earlier this year and indicated that Sanofi-Aventis needed to address undisclosed issues with the drug. In other trials, it appears that there was a 2.7-fold increase in psychiatric disorders in patients dosed with the drug over those taking placebo. Given the emerging knowledge of the endocannabinoid system’s role in anxiety and depression, this shouldn’t be entirely unexpected. The Vioxx-buggered FDA is skittish, so it remains to be seen if “approvable” translates to “approved.”
So maybe obesity is a viable therapeutic area. I’m not so sure, and I freely admit that my bio-papal blessings on the targets which are brought into my shop are sprinkled with bias. One Friday evening while snarfing down pizza and quaffing beer at the local watering hole, a group of us discovery shlubs lamented the significant research efforts directed toward obesity One of the senior medicinal chemists working on an obesity target opined that his intellectual blood, sweat and tears were being spilled on a hypothetical pill which a 300 pound person would swallow, only to lose a walloping ten to twenty pounds as a result, then sue the manufacturer when his or her stools take on the ballistic strength of an AK-47 or when once pliant skin becomes an infected, arid wasteland due to some pharmacologically induced f*ckup of fat metabolism. All of us gathered around that pub table recognized that yes, there exists a population of the morbidly obese who quite likely have some genetic variants which predispose them to the condition, and indeed, maybe a pill could be of benefit. Maybe. However, each pizza devouring, beer sloshing investigator believe that diet and exercise are first line treatments for most garden-variety forms of obesity.
So to the FFAs who believe that the pharma industry wants you to be obese, well, to an extent you are right since your excess white adipose tissue shines like a golden goose egg (more like 1.0 * 10^9 goose eggs) to the devils in pharma marketing. However, let me assure you, many of us who actually try to discover drugs wish you’d just walk, bike, swim or run more, and eat less, so we can direct our attention and our “Ah ha!” cravings toward drugs to treat cancer, infectious diseases, immune disorders, neurological diseases, and other such trivial pursuits.
And now we return to Mr. Beck’s Heavy Hitters program…
June 14, 2006
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