AMRI announces results of Phase I clinical study of obesity compound

The results of AMRI’s Phase I clinical study on its novel MCH1 receptor antagonist, ALB-127158(a), indicate that the compound is well tolerated at the doses tested and shows preliminary evidence of efficacy. Dr Nicholas Moore, director of development and pharmacology at AMRI, presented the results at the 18th European Congress on Obesity.

The placebo-controlled study evaluated the safety, tolerability and efficacy of ALB-127158(a) in male volunteers. The study consisted of three components: a single ascending dose arm (SAD) in lean subjects (BMI ≤ 25), a fed/fasted crossover in overweight subjects (BMI ≥ 27) and a 14-day ascending dose arm (MAD) in overweight subjects. Standard safety assessments, ECG monitoring and PK measurements were conducted.

ALB-127158(a) was well tolerated in both the SAD and the MAD; reported events were mild and showed little dose relationship. One of the most common events reported in both the SAD and the MAD was loss of appetite. No drug-related changes in cardiovascular parameters or sleep were observed during any phase of the study. Reductions in ‘hunger’, ‘desire to eat’ and test meal consumption were observed.

The study met both its primary and secondary objectives, demonstrating safety and tolerability. The data support the continued development of ALB-127158(a) as a potential treatment for obesity.

‘We are pleased with these Phase I results for our compound,’ said Dr Bruce Sargent, senior vice president of drug discovery. ‘MCH1 receptor antagonism has been long recognised as a potentially important approach to treatment of obesity; however, multiple attempts to progress therapeutic agents have been thwarted by non-target related safety issues.

‘We believe that our results are the first to demonstrate good tolerability and pharmacokinetics and therefore support the further evaluation of this molecule.’

Melanin concentrating hormone (MCH) is a potent appetite stimulating peptide known to exert an effect on food intake and body weight regulation. The endogenous peptide MCH has been shown to regulate energy homeostasis through the MCH1 receptor located in the central nervous system (CNS). It is known to stimulate feeding in rats and promote increases in glucose, insulin and leptin levels, mimicking the human metabolic syndrome.

Antagonism of the MCH1 receptor has been shown to reduce food intake in rodents and hence reduce body weight, selectively reducing fat stores. Representing a potential new approach for the treatment of obesity, this target has been a focus of interest in many pharmaceutical companies but most programmes have stalled in the face of preclinical safety challenges.

Preclinical studies of ALB-127158(a) suggested promise for the treatment of human obesity. For example, the compound showed high levels of MCH1 receptor occupancy leading to a sustained, dose-related reduction in food intake in dietary-induced obese mice. The ensuing weight loss in such mice of up to 18% after 28 days of administration was substantially higher than that from the previously established obesity drug, sibutramine.

Weight loss was shown to closely correlate with a reduction in food intake leading to a preferential reduction in fat stores and was accompanied by significant improvements in glucose tolerance. Preclinical safety evaluation, including cardiovascular safety, supported approval by the UK Medicines and Healthcare Products Regulatory Agency for initiation of the Phase I clinical study.