Inside the body with AOD-9604

The company's human studies used single intravenous doses, and oral dosing given either as single doses separated by washout periods or once daily for up to 24 weeks. FDA found no clinical pharmacokinetic or pharmacodynamic study of AOD-9604 by any route. In pigs, oral dosing gave measurable plasma levels, but the calculated oral bioavailability (170%) exceeded the theoretical maximum because the data were highly variable, so it remains unclear. The disulfide-cyclised structure is proposed, but not shown, to help it resist gut enzymes.[src][src]

After an intravenous bolus in pigs, the half-life was about 3 minutes; spiked into rat plasma in vitro, the half-life was about 4 minutes, with successive N-terminal truncation and no intact peptide detectable after 56 minutes. In a separate in vitro study, a truncated fragment (CRSVEGSCG) was significantly more stable in serum than the parent peptide and has been proposed as a longer-lived marker for doping tests. These are animal or in vitro results; human half-life has not been reported.[src][src][src]

In BaF-BO3 cells expressing the human GH receptor, AOD-9604 did not compete with 125I-hGH for binding and did not induce proliferation, unlike hGH. The authors concluded that its metabolic effects are independent of the classic GH receptor pathway. FDA notes the molecular target and mechanism of action remain unknown. This is cell-based evidence only.[src][src]

In obese (ob/ob) mice treated for 14 days, AOD-9604 reduced weight gain, increased in-vivo fat oxidation and plasma glycerol (an index of lipolysis) and reduced adipose mass, without reducing food intake. In obese Zucker rats given AOD-9604 orally for 19 days, weight gain was reduced by more than half, with increased adipose lipolytic activity. Animal-only data; FDA cautions that the studies had no dose-response and no correction for multiple comparisons.[src][src][src][src]

Chronic AOD-9604 raised beta-3 adrenergic receptor mRNA in obese mice to levels comparable with lean mice, and in beta-3 knock-out mice it failed to change body weight or lipolysis. However, an acute experiment still showed increased energy expenditure and fat oxidation in knock-out mice, so the authors concluded the actions are not mediated directly through this receptor. Mouse data only; the direct target is unidentified.[src][src]

Unlike hGH, AOD-9604 did not cause hyperglycaemia or reduce insulin secretion in obese mice, and chronic treatment did not impair insulin sensitivity in obese Zucker rats by euglycaemic clamp. In humans, the company's six trials reported no significant IGF-1 change versus placebo and no anti-AOD-9604 antibodies in the subsets tested, but these summaries are sponsor-authored and lack detail; long-term human data are absent.[src][src][src][src]

The OPTIONS phase 2b study (oral, once daily, plus diet and exercise for 24 weeks; 536 enrolled, 502 randomised) did not meet its primary endpoint of statistically significant weight loss versus placebo at 12 weeks, nor at 24 weeks; the company announced on 21 February 2007 that development for obesity was terminated. The company reported that weight loss versus placebo, after allowing for diet and exercise, was under 1 kg in all dose groups. An earlier 12-week phase 2 study reported about 2.6 kg loss with its best dose versus 0.8 kg with placebo, with a non-linear dose response; the company later stated this fell short of significance on the primary analysis (p=0.1) and was significant only in women. Full phase 2b data do not appear to have been peer-reviewed.[src][src][src][src]