The identification of new targets for obesity therapeutics represents a key priority for the pharmaceutical industry. This has been driven by the large and growing numbers of obese individuals around the world, the high incidence of serious co-morbidities, and a market predicted to reach $3.7 billion by 2008. Obesity occurs when calorific intake exceeds energy expenditure. LeadDiscovery has recently analyzed two emerging anti-obesity targets, ghrelin which regulates food intake (click here for more), and the retinoids which also plays a role in both food intake as well as energy expenditure (click here for more).

Leptin has received considerable interest with respect to obesity. Leptin is released into the blood from fat cells and circulates to the brain where it crosses the blood-brain barrier to act at receptors within the central nervous system. Leptin inhibits food intake, reduces body weight and stimulates energy expenditure. Leptin expression increases after food intake and decreases during fasting. Reduced expression has been shown to evoke insulin resistance, while a leptin agonist has recently been shown to not only reduce body weight and glucose levels in obese animals but also to increase insulin sensitivity. Despite the promise that leptin agonists may have for the treatment of both diabetes and obesity, such molecules have only met with limited success in clinical trials. This lack of effect has been suggested to result from the development of leptin resistance and therefore the identification of molecules that act via a similar intracellular pathway to that of leptin but which are not subjected to resistance under conditions of obesity have been sought. One such molecule is ciliary neurotrophic factor (CNTF), a mediator released by Schwann cells. In a clinical trial, although CNTF was found to have minimal neuroprotective activity in amyotrophic lateral sclerosis patients it was observed to produce weight loss. Subsequent studies reported that CNFT and leptin shared a common signaling pathway involving STAT3 and Janus kinase. Thus Regeneron Pharmaceuticals have been developing Axokine, a human recombinant form of CNTF, for the treatment of obesity.

Recently published results from a phase II, placebo-controlled, double blind randomized firmly support Axokine as a candidate anti-obesity candidate. This study demonstrates that at 0.3, 1.0 and 2.0 microgram/kilo, Axokine treatment for 3 months significantly reduced body weight and body weight index compared to placebo controls. At the intermediate dose, Axokine produced a 5% weight loss in nearly 10% of patients. Weight loss was continuous over 3 months and importantly, although weight loss stopped after termination of treatment, rebound weight gain was not observed for at least 6 months following treatment termination. Thereafter, rebound weigh gain occurred slowly. Treatment-related adverse effects were reported to include treatment site reaction, nausea and cough. The frequency of nausea and cough were greater in Axokine-treated patients compared to placebo control only at the highest dose, contrasting with anti-obesity activity which was quantitatively greater at 1.0 compared to 2.0 microgram/kilo.

Most recently, through a press release, Regeneron have announced preliminary data from a phase III trial designed to determine the efficacy of the 1.0 microgram/kilo dose of Axokine. The trial was a double-blind, randomized, placebo-controlled trial including 501 placebo-treated and 1,467 Axokine-treated non-diabetic participants from 65 study sites across the United States. For 12 months, in addition to counseling in a dietary and lifestyle modification program, subjects received daily subcutaneous injections of either placebo or Axokine at a dose of 1.0 microgram per kilogram of body weight. A greater proportion of Axokine-treated patients lost at least 5% of their initial body weight compared with patients treated with a weight control program alone (25.1% vs. 17.6%, p<.001). Participants receiving Axokine also experienced a greater average weight loss than the weight control program population (6.2 lbs vs. 2.6 lbs, p<.001). Further, Axokine -treated patients showed improvements in obesity-associated co-morbidities. Of considerable interest, this study identified a sub-group of patients (approximately 30% of all treated patients) that lost 16.6lbs over the course of the trial. The degree of weight loss is related, at least in part, to the development of CNTF antibodies.

Data produced to date concerning Axokine is highly promising and further development is eagerly awaited. One area of development concerns a PEGylated form of Axokine that is designed to have a longer serum half-life. Data describing the efficacy and immunogenicity of this molecule is eagerly awaited.

Entry date Friday, June 06, 2003

Interested in collaborating with this group? Contact leaddiscovery@bioportfolio.co.uk