Now for a few comments on Axokine and its use for the treatment of obesity in Type 2 diabetic patients. Peter, better late than never, I guess.
Axokine is a modified derivative of ciliary neurotrophic factor, the precise peptide sequence apparently not made public. As you know, it is now undergoing Ph I studies in mild to moderately obese yet otherwise healthy volunteers. The route of administration is subcutaneous. The half-life of the peptide and therefore the frequency of drug dosage (ie, injections) is not known to the public. Some of the issues with the first generation CNTF compound were the generation of cough and nausea, and the development of antibodies. This peptide apparently is effective in all obesity models tested to date, including those of the ob/ob and db/db mutant mice in which either the adipocyte-derived leptin peptide or the hypothalamic leptin receptor isoform involved in STAT signaling are compromised.
It is unclear, at least to me, as to whether the major effects of the peptide are to decrease appetitive behavior or increase thermogenesis, or both. There is very little literature on the role of this peptide in feeding models. The work of Ralph Laufer that you cited is of high quality. (I know of him from his Ph.D. thesis days in Zvi Selinger's lab in Israel) It is clear that it works independent of that of leptin, but uses the same signaling pathways at least in part. The mechanism by which CNTF brings about its physiological effects are uncertain, but a couple of "lesser quality" publications from a University of Florida lab suggests that it may involve the neuropeptide Y system.
I guess the major things that concern me about the use of Axokine for the treatment of obesity is that it may produce cachexia and atrophy of skeletal muscles, in addition to the wanted anorectic effects. It also remains to be seen whether the generation of antibodies in man will be a problem, as this would be detrimental for the drug strategy. Drug administration by the subcutaneous route is not desirable as well. Nevertheless, the reports from the Phase I trials will be interesting. I hope they publicize the reads on muscle mass changes as well as fat mass changes. I also hope that the trial is carried out for a long enough period of time. At the end of the day, however, I suspect the obesity market will have an orally active receptor targeted drug that both increases the expenditure of energy and decreases food intake. Having said all of this, REGN seems like a reasonable buy at these levels. I like the ALS program using BDNF and I like their angiogenesis program, though it is still early. I also like the insight provided by Roy Vagelos, who you realize ran MRK for some time. Nonetheless, 371 employees at the first of the year is a high number, but the burn is reduced by the Procter and Gamble collaboration. This also caps the upside potential as well.
Perhaps Miljenko can provide a few comments, as I know he follows REGN closely. |
