HT Drugs and Weight Loss Clinical Data

Few drugs, 5-HT or otherwise, are robustly tested in clinical trails for weight control. D-fenfluramine (Redux) was voluntarily withdrawn in 1997 due to primary pulmonary hypertension, a move that dealt a blow to the development of serotoninergic antiobesity compounds (Abeniam et al. 1996). Subsequently, the noradrenergic and 5-HT reuptake inhibitor sibutramine (Reductil, Meridia) was approved for the treatment of obesity. This has been in the market nearly 10 years. Since these, no new 5-HT antiobesity drugs have been licensed (Halford 2006a, b). From the metaanalysis of Haddock et al. (Haddock et al. 2002), fenfluramine produces average placebo subtracted of 2.41 kg and d-fenfluramine one of 3.82 kg. With regard to selective reuptake inhibitors, the noradrenergic and serotoninergic reuptake inhibitor sibutramine has been shown to produce placebo subtracted weight loss of 4.45 or 4.3 kg, in two metaanalyses of clinical data (Arterburn et al. 2004; Padwal et al. 2003).

Considerable effort has been made to develop a new generation of side-effect-free 5-HT drugs (Vickers and Dourish 2004). Some of the compounds have passed into phase 1 and (in the case of BVT-933 from Biovitrum and GlaxoSmithKline) phase 2 trials, it is regrettable that their effects of human appetite, food intake, and body weight remain largely unknown. One issue may have been drug affinity to 5-HT receptors other than 5-HT2C, causing unwanted side effects during the clinical trial studies. However, lorcaserin-APD356 (Arena Pharmaceuticals) is currently undergoing clinical trials (Smith et al. 2005a). The structure of lorcaserin is undisclosed, but it is likely to have come from a series of novel 3-benzazepine derivatives (Smith et al. 2005a). The other 5-HT2C agonist under development is ATHX-105 from Athersys. Although approval for clinical testing was given in 2006, and phase 1 testing started a year later and finished January 2008, little is known about the effects of this drug on food intake or appetite expression. However, a 12-week double-blind, placebo controlled weight loss trial in the obese was scheduled to start in September 2008, potentially completing in April 2009.

Lorcaserin (ADP356) has successfully completed as series of clinical trials. In a phase 1b safety dose-escalation study no effect on heart values or pulmonary artery pressure was observed (Smith et al. 2005b). In phase 2a trials, a 15-mg dose produced a statistically significant mean weight loss of 1.3 kg (compared with 0.4 kg in the placebo group) over a 28-day treatment period. Phase 2b trials show that treatment with lorcaserin was associated with a highly significant average weight loss of 1.8, 2.6, and 3.6 kg at daily doses of 10, 15, and 20 mg, respectively, over the 12-week treatment period. In comparison, those in the placebo group lost just 0.3 kg in that time.

In 2006 lorcaserin entered the first of three phase 3 clinical trials [behavioral modification and lorcaserin for overweight and obesity management (BLOOM), behavioral modification and lorcaserin second study for obesity management (BLOSSOM) and behavioral modification and lorcaserin for overweight and obesity management in diabetes mellitus (BLOOM-DM)]. However, it has been commented that the effects of lorcaserin on weight loss in the preceding 12-week phase 2b trial appeared to be no greater than its "antecedent" d-fenfluramine and possible less than is currently achieved with sibutramine (Heal et al. 2008). Despite commonality of design, it is difficult to compare phase 2 trials directly, particular as unusually no dietary advice was given to participants during lorcaserin trails. Whether Heal et al. (Heal et al. 2008) are proved correct in their assertion will be shortly be demonstrated with the imminent completion of these lorcaserin phase 3 trials.

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