The long-awaited approval of Arena Pharmaceuticals Inc.'s Belviq (lorcaserin) looks to bode well for its contemporaries – Vivus Inc.'s Qnexa (phentermine/topiramate), which has a PDUFA date of July 17, and Orexigen Therapeutics Inc.'s Contrave (naltrexone/bupropion), which is in an FDA-required cardiovascular outcomes study to address a complete response letter – but it could also offer some assurances for other companies with earlier-stage obesity candidates coming down the pike. (See story this issue.)

Already in Phase III testing is diabetes drug Victoza (liraglutide) from Novo Nordisk A/S. In 2010, the Bagsvaerd, Denmark-based big pharma decided to re-initiate studies of the GLP-1 analogue in obesity, where earlier studies had demonstrated the drug's ability to produce sustainable weight loss in patients, including those at risk of developing diabetes.

Closest to late-stage development is San Diego-based Orexigen's second obesity candidate, Empatic (zonisamide SR/bupropion SR), which has completed Phase II testing. Like Contrave, Empatic is a fixed-dose combination of two approved drugs – bupropion, which acts on weight control by stimulating the pro-opiomelanocortin (POMC) neurons (a group of brain cells important for controlling appetite and food intake), and zonisamide, which is believed to further stimulate POMC neurons by increasing monoamines.

Another drug ready for Phase III is tesofensine, a serotonin-noradrenaline-dopamine reuptake inhibitor. Previously held by Danish biotech NeuroSearch A/S, that program was passed on to the firm's research division NsDiscovery for out-licensing last year. It has been waiting for a partner ever since. (See BioWorld Today, Jan. 12, 2011.)

London-based Proximagen Group plc, recently nabbed by Upsher-Smith Laboratories Ltd. in a $555 million CVR-based deal, holds worldwide rights to PRX00933, an oral 5-HT2c agonist, which has demonstrated a dose-dependent and statistically significant decrease in body weight in Phase II testing. Proximagen has been evaluating commercial opportunities for its drug while it waited to see how the FDA would decide on Arena's Belviq. (See BioWorld Today, June 14, 2012.)

And last year, Zafgen Inc., of Cambridge, Mass., pulled in $33 million in a funding round to support Phase II testing of beloranib (ZGN-433), a selective methionine aminopeptidase 2 (MetAP2) inhibitor. Blocking MetAP2 is believed to reduce the production of new fatty acid molecules by the liver and help to convert stored fats into useful energy. (See BioWorld Today, July 7, 2011.)

But most of the obesity candidates in development are Phase I-stage or earlier. Some of those include:

• Albany, N.Y.-based AMRI recently completed a Phase I study of melanin-containing hormone receptor 1 antagonist ALB-127158(a), which found the compound safe, with no drug-related changes in cardiovascular parameters, and demonstrated reductions in hunger, desire to eat and test meal consumption. AMRI is looking for a partner for further development.

• Cranbury, N.J.-based Palatin Technologies Inc. and partner London-based AstraZeneca plc moved into a Phase I trial with AZD2820, a subcutaneously administered peptide melanocortin-4 receptor (MC4R) partial agonist, though that trial in healthy obese male subjects recently was halted to investigate a serious adverse event.

• Arrowhead Research Corp.'s Adipotide (Prohibitin-TP01) is designed induce apoptosis in the vasculature of adipose tissue. Recently published data showed that the drug induced rapid metabolic changes in mouse models, and the Pasadena, Calif.-based firm has moved into Phase I testing.

• Also targeting MC4R is RM-493, from Rhythm Pharmaceuticals Inc., of Boston, which recently closed a $25 million financing to help fund Phase I testing of that drug in obesity, as well as in diabetes. (See BioWorld Today, June 13, 2012.)

• Isis Pharmaceuticals Inc., of Carlsbad, Calif., has started Phase I testing of ISIS-FGFR4Rx, a drug designed to reduce the production of fibroblast growth factor receptor 4 in liver and fatty tissue through an antisense mechanism.

• Danish firm Zealand Pharma A/S is preparing to start Phase I testing under its partnership with Boehringer Ingelheim GmbH for ZP929, a glucagon/GLP-1 dual agonist. In preclinical studies, the drug, in combination with long-acting insulin, caused a greater loss in body weight and fat mass compared to treatment with GLP-1 drug Victoza. (See BioWorld Today, June 17, 2011.)

• Israeli biotech Prolor Biotech Inc. has shown preclinical success with MOD-6030, another GLP-1/glucagon dual receptor agonist. Animals receiving MOD-6030 had a 28 percent reduction in weight.

• Bridge Bioresearch plc, of London, has completed preclinical studies of 2hyroxyoleic acid (2OHOA) for obesity and metabolic disorders. 2OHOA is derived from the major lipid component of the Mediterranean diet, oleic acid.

• Unigene Laboratories Inc., of Boonton, N.J., anticipates moving into Phase I testing in the first half of 2013 with its anorexigenic peptide UGP281, designed to target the amylin receptor. In preclinical testing, that drug showed a dose-dependent decrease in body weight of 10 percent to 15 percent when given subcutaneously to rats and dogs over a seven-day treatment period.

• Tranzyme Pharma Inc., of Durham, N.C., is in preclinical development with TZP-301, a ghrelin antagonist.

• Boston-based Ember Therapeutics Inc. is targeting obesity via brown fat. It recently signed a deal with Joslin Diabetes Center to develop drugs targeting BMP7, a protein that may induce brown fat production.

• Also targeting brown fat, BioRestorative Therapies Inc., of Jupiter, Fla., recently inked a research agreement with the University of Utah to identify brown fat tissue and develop and characterize brown fat cell lines, with the goal of filing an investigational new drug application.

• Canadian firm Xenon Pharmaceuticals Inc. is collaborating with Novartis AG on drugs targeting stearoyl-CoA desaturase-1 (SCD1), a gene that acts as a switch to control fat storage. (See BioWorld Today, Jan. 12, 2012.)

• And Swedish collaborators Betagenon AB and Baltic Bio AB recently identified O304, an AMPK activator, with potential for treating obesity.