Arena Pharmaceuticals announced today results from the dosing phase of its Phase 1b clinical trial of APD356, an orally administered small molecule designed to regulate satiety (and perhaps metabolism) for the treatment of obesity. APD356 is a selective agonist of 5-HT2C serotonin receptors, which are concentrated in the hypothalamus, an area of the brain believed to play an important role in regulating food intake and metabolism.
The Phase 1b clinical trial of APD356 was a randomized, double-blinded, placebo-controlled, multiple-dose, dose-escalation study designed to evaluate the safety of APD356 at steady state drug levels during repeated daily dosing for 14 days. Highlights of the Phase 1b study include:
- APD356 was well tolerated.
- Side effects were similar to placebo at the 3 and 10 mg doses of APD356, but tended to occur more frequently than placebo at the 20 mg dose. The most common side effects, occurring primarily at the 20 mg dose, were headache, nausea and vomiting. These side effects were generally mild in nature.
- APD356 continued to demonstrate predictable pharmacokinetic behavior; time to maximum plasma concentration (Tmax) was approximately two hours after dose administration, estimated plasma half-life (t1/2) was about 10 hours, and steady state plasma levels were achieved by day five.
"These results are consistent with our expectations of APD356 based on the Phase 1a trial and preclinical data, and support our intention to initiate a Phase 2 trial examining weight loss as the primary endpoint," stated William Shanahan, M.D., Arena's Vice President and Chief Medical Officer. "We are currently on track to begin dosing APD356 in a Phase 2, multiple-dose, 28-day trial of 400 obese volunteers by year's end. We plan to compare daily doses of 1, 5, and 15 mg of APD356 to placebo."
Doses for the Phase 2 trial were chosen to bracket the 10 mg dose previously shown in the Phase 1a trial to demonstrate a pharmacologic signal (a reduction in meal size) with a single dose. The 1 mg dose was chosen as the lowest dose because Arena believes that a 1 mg dose has the potential to produce therapeutic drug levels in the CNS if APD356, as observed in rats, achieves higher concentrations in human brain than in blood.
The Phase 1b clinical trial enrolled 27 subjects (15 males and 12 females) with an average BMI of 31 (+/- 6), and a BMI range of 25 to 58. Participants were administered 3, 10 and 20 mg doses of APD356 or placebo in successive cohorts of 9 subjects (6 APD356, 3 placebo) and were kept within a Phase 1 unit. Participants were instructed to maintain their usual exercise patterns, and were offered sufficient food to maintain their desired intake levels.
APD356 was well tolerated; there were no severe or serious adverse events reported, no withdrawals due to an adverse event, and no reports of euphoria, dysphoria, or disorientation. APD356 continued to demonstrate very predictable pharmacokinetic behavior, similar to that found in the Phase 1a trial of APD356. The maximum plasma concentration (Cmax) and exposures (AUC0-24 and AUC0-inf) increased dose proportionately with increasing doses of APD356. There were no apparent gender differences in pharmacokinetic parameters.
Based on a comparison of Day 14 echocardiograms with those taken at screening, there was no evidence of a drug effect on heart valves or pulmonary artery pressure. As part of the follow-up phase of the trial, results will be obtained from longer-term echoes (performed at 2 months and 3 months post dosing) to confirm continued absence of drug effect.
This Phase 1b study was designed as a safety study and was not meant to detect significant weight change between treatment groups. As expected with a small number of participants in an artificial setting, considerable variations in weight change within each group were noted, and, when compared with placebo, none of the mean changes in weight in the active arms were statistically significant.