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Slim pickings

Tolerability issues have led to a dearth of obesity treatments, but new therapies may bear fruit

A single red apple in a treeAt the beginning of the year, the European Medicines Agency (EMA) recommended the suspension of marketing authorisation for sibutramine (Reductil, Abbott Laboratories). The UK National Institute for Health and Clinical Excellence (NICE) consequently withdrew its recommendation for sibutramine, leaving obese patients in the UK with only one pharmaceutical option: orlistat.

Orlistat, which is indicated for the treatment of adults with a body mass index (BMI) of ≥30kg/m2 (>28kg/m2 in patients with cardiovascular risk factors), is marketed as the prescription medicine Xenical (Roche) and over the counter as alli (GlaxoSmithKline). Orlistat is effective at reducing dietary fat absorption by about 30 per cent, however, its effects on body weight are generally modest. A systematic review of 63 randomised placebo-controlled trials, conducted by researchers in Canada, showed that orlistat was associated with a 2.7kg reduction in body weight and a 2.45cm reduction in waist circumference after six to 12 months. However, this review also showed that orlistat has significant benefits with regard to cholesterol levels and diastolic blood pressure.

Further studies by GlaxoSmithKline (GSK) have indicated that orlistat is associated with improvement in low density lipoprotein (LDL) cholesterol levels, which are independent of weight loss. While the drug is not being developed for this indication, orlistat may benefit patients with both obesity and hypercholesterolaemia.

Studies using orlistat in patients with other co-morbidities of obesity are also in the pipeline. Speaking as part of the inThought Expert Discussion Series in July, Dr Arne Astrup, president of The International Association for the Study of Obesity, stated that: "The cardiovascular endpoints for stroke and myocardial infarction are the most important co-morbidities in obesity. It means when we are going to treat obese patients with drugs, we need to be certain that these drugs are reducing the risk of developing these endpoints, otherwise the reduction in body weight might be cosmetic."

Reductil
The suspended drug, sibutramine, is a monoamine reuptake inhibitor, which was originally intended as an antidepressant, though efficacy for this indication was uncertain. During phase I and early phase II trials, however, it was found that non-obese subjects lost weight without any active efforts to do so, and as a consequence sibutramine was developed and launched worldwide for the treatment of obesity.

The Canadian review showed that sibutramine was associated with a much greater (5kg) average reduction in body weight than orlistat, however, sibutramine was associated with adverse increases in systolic and diastolic blood pressure (of 0.88mmHg and 1.44mmHg, respectively). Because of these blood pressure increases, the Sibutramine Cardiovascular Outcome Trial (SCOUT), a study to investigate the cardiovascular (CV) safety of sibutramine in high-risk patients, was instigated. Preliminary data indicated that sibutramine was associated with an increased risk of serious CV complications in the studied patient population.

A subsequent safety review by the EMA's Committee for Medicinal Products for Human Use (CHMP) concluded that the risks associated with sibutramine-containing weight-loss medicines outweighed their benefits. After a similar review, the US Food and Drug Administration (FDA) requested that Abbott add a new contraindication to the drug label (marketed as Meridia in the US), stating that it was not to be used in patients with a history of cardiovascular disease (CVD), because evidence indicated that the increased risk of CV events occurs only in patients with a history of CVD. The CHMP, however, was of the opinion that these safety concerns are relevant to all patients, since all obese and overweight patients are likely to have an increased risk of CV complications.

Acomplia
Rimonabant (Acomplia) — also previously available for the treatment of obesity but now taken off the market — was a selective cannabinoid receptor CB1 antagonist being developed by sanofi-aventis for the treatment of a range of conditions including obesity, type 2 diabetes and atherosclerosis. As cannabis smokers often experience extreme hunger bouts, it was suggested that if the binding of cannabinoids to neuronal CB1 receptors increases appetite, blocking the binding of endocannabinoids to these receptors might reduce it.

Unfortunately, post-marketing reports indicated that the drug was associated with serious psychiatric adverse events, particularly depression, which, in the CHMP's opinion, could not be adequately addressed by risk minimisation measures. The EMA, therefore, recommended the suspension of marketing authorisation for rimonabant in October 2008. Sanofi-aventis subsequently withdrew its New Drug Application (NDA) for rimonabant in the treatment of obesity in the US.

These tolerability issues have perhaps mired the development of new drug therapies for obesity. In the inThought Expert Discussion Series, Dr Astrup commented that, while the FDA is "quite positive towards getting such drugs on the market", there is concern about another setback in this therapeutic area.

Qnexa
Despite the hurdles, new therapies are under investigation. Vivus, for example, is developing a fixed combination of phentermine/topiramate (branded as Qnexa) to address both appetite and satiety in obese patients. In July, the FDA's Endocrinologic and Metabolic Drugs Advisory Committee voted 10 to 6 against Qnexa's approval, citing a lack of long-term safety data, although the safety of the individual components has been well studied: phentermine is an amphetamine-like appetite suppressant, known to cause adverse CV effects, such as increased heart rate and blood pressure, while topiramate is an anticonvulsant with weight-loss properties and is a known teratogen. Also, like other antiepileptics, topiramate is believed to increase the risk of suicidal thoughts and behaviours.

According to Dr Astrup, the most significant hurdles to the approval of phentermine/topiramate are these neuropsychiatric adverse effects. He stresses that, while such effects may be considered justified in the treatment of epilepsy, they are significantly less acceptable in obesity. He believes, however, that with more data, phentermine/topiramate has a good shot at approval.

Results from the company's 12-month SEQUEL extension study (an extension of the CONQUER study), which enrolled 650 obese or overweight patients, are expected before the end of the third quarter of 2010. inThought analysts have forecast that phentermine/topiramate has a 69 per cent probability of gaining approval.

Lorcaserin and Contrave
Other weight-loss drugs awaiting approval include lorcaserin and naltrexone/bupropion (Contrave).

Lorcaserin, which is being developed by Arena Pharmaceuticals, selectively stimulates the serotonin 2C receptor, located in the hypothalamus ­­­— the brain area associated with the regulation of satiety and metabolism. The compound is approximately 100-fold selective for the serotonin 2C receptor compared with the serotonin 2B receptor. This improves lorcaserin's tolerability compared with other non-selective serotonergic agents, given that the serotonin 2B receptor is believed to be primarily implicated in the risk of cardiac valvulopathy associated with these agents.

The FDA accepted the NDA for lorcaserin in February 2010 and the Endocrinologic and Metabolic Drugs Advisory Committee is scheduled to meet to discuss the NDA in September. Dr Astrup thinks lorcaserin is very likely to be approved, given its relatively benign safety profile, high selectivity for its target and the solid understanding of its mechanism of action.

The FDA has also tentatively scheduled an advisory committee meeting in December to discuss the NDA for Contrave. Like phentermine/topiramate, this is a fixed combination of two well-known drugs: naltrexone (an opioid receptor antagonist marketed for the treatment of narcotic and alcohol dependency) and bupropion (a dopamine and norepinephrine reuptake inhibitor prescribed as an antidepressant and for smoking cessation). It is designed to help with weight management and treat symptoms of depression in overweight and obese patients. According to Dr Astrup, however, one of the significant drawbacks of this combination is that, unlike orlistat and rimonabant, it provides no significant benefits with regard to CV risk factors.

inThought believes that lorcaserin and naltrexone/bupropion each have a 70 per cent chance of gaining approval.

 

Generic name Trade Name (Company) Indication  Country
Anastrozole  (Roxane Laboratories) Breast cancer  US
Azelastine  (Caraco Pharmaceutical Laboratories)  Allergic conjunctivitis US
Bupropion  (Caraco Pharmaceutical Laboratories) Depression, smoking cessation  US
Cabazitaxel  Jevtana (sanofi-aventis)  Prostate cancer US
Cyclobenzaprine  (Glenmark Generics; InvaGen) Muscle spasm US
Dantrolene  Revonto (US WorldMeds)  Malignant hyperthermia US
Enoxaparin sodium (Sandoz) Thrombosis  US
Influenza vaccine NasoVac (Serum Institute of India) Influenza  India
Japanese encephalitis vaccine Ixiaro (Intercell) Japanese encephalitis  Switzerland
Metformin/pioglitazone Metact (Takeda) Type 2 diabetes mellitus Japan
Methylphenidate  (Breckenridge Pharmaceutical; Tris Pharma) Attention-deficit hyperactivity disorder, narcolepsy US
Metoprolol  (Wockhardt) Hypertension, angina US
N-acetyl-s-farnsylcysteine Arazine (Rohto Pharmaceutical) Inflammation  Japan
Naratriptan  (Roxane Laboratories) Migraine  US
Norethindrone acetate (Glenmark Generics) Secondary amenorrhoea, endometriosis, abnormal uterine bleeding US
Paracetamol  Triaminic (Novartis) Fever, pain (in children)  US
Perflutren  Definity (Lantheus Medical Imaging) Ultrasound contrast imaging agent India
Pioglitazone  Actos OD (Takeda) Type 2 diabetes mellitus  Japan
Polidocanol   Asclera (Merz Aesthetics) Varicose veins  US
Ramelteon  Rozerem (Takeda) Insomnia  Japan
Tamsulosin  (Caraco Pharmaceutical Laboratories)  Benign prostatic hyperplasia US

The Author
Pipeline was written by Steve McMillan of Adis International (Wolters Kluwer Pharma Solutions), using data derived from Adis R&D Insight, Clinical Trials Insight and inThought.
For information on Adis services, contact Kuljeet Sohanpal on 0207 981 0714 or email: Kuljeet.Sohanpal@wolterskluwer.com

To comment on this article, email pm@pmlive.com

4th October 2010

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