Did I Speak Too Soon About The Demise of NPY Blockers?

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 |  Includes: AMGN, MRK
by: Fredric Cohen, M.D.

The AOP of the July Nature Medicine contains the article “Neuropeptide Y acts directly in the periphery on fat tissue and mediates stress-induced obesity and metabolic syndrome” by Kuo et al from Georgetown U.

I’ve only read the abstract and stories so far (like this one from the Scientist and the press release from GU), but it’s enough to have me feeling elated at the discovery. Congratulations to the Georgetown group.

Recall my post back in October 2006, when I used the failure of orally administered MK-0557, Merck’s (NYSE:MRK) NPY antagonist, to discuss the state of pharma R&D knowledge transfer. At the time, I implied that the development of NPY antagonists was all but dead. Seems I may have spoken too soon. Actually, I stick by my call regarding orally administered NPY antagonists, but if Kuo et al’s discovery of the role of NPY in glucocorticoid-mediated fat accumulation holds up to further scrutiny, I’ll be happy to revise that pronouncement as follows: NPY antagonists will have no role as systemically administered drugs aimed at influencing feeding behavior and thus obesity, but they might have a role as locally administered drugs aimed at controlling accumulation of local fat depots.

The stories linked above describe some of the potential therapeutic uses of local NPY antagonist (and agonist) therapy. Cosmetic uses are likely to be the first attempted, as it’s easy to approach the subcutaneous space and assess drug response. Later uses could include non-surgical ablation of visceral fat (N.B. the omental fat dual-source blood supply may approached transcutaneously or intrarterially by experienced vascular interventionalists), which could very well treat metabolic syndrome.

Intriguingly, activation of the peripheral NPY system may explain in full or part why glucocorticoids cause accumulation of fat in selected anatomical locations, including viscerally. Although this explanation isn’t needed to enjoy the benefits of blocking the regeneration of cortisol from cortisone (via inhibition of 11-betahydroxysteroid dehydrogenase 1), as is being attempted with AMG221, Amgen’s (NASDAQ:AMGN) 11 HSD1 inhibitor, it might help explain a failure of this or a similar drug to have the desired effects on visceral fat. For instance, CT-guided skinny needle biopsies of visceral fat may be used to determine adipose tissue NPY and NPYR expression in the presence and absence of 11HSD1 inhibitor. As far as I know, Amgen hasn’t released efficacy findings with this drug, and I’m not suggesting that it will fail to have desired clinical benefits. Of course, the NPY mechanism might also be used to judge the effectiveness of such drugs before they ever get into humans too–a no-go for drugs that don’t block NPY upregulation in stressed mice fed ad libitum?

Bottom line: this newly discovered peripheral NPY mechanism has great promise in metabolism drug discovery, as both a biomarker and as a drug target.