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Spotlight

The Pharmaceutical Fight Against Obesity

Wed, 09/09/2015 - 13:33

Obesity treatments tend to have a common limitation, focusing on outcomes rather than processes. Medical advice tends towards a slightly more aggressive version of the basic rules of healthy living: reducing fat and bad carbohydrates, increasing exercise and mobility; and keeping related illnesses at bay with a high fiber intake. While wealthier patients can look to bariatric treatments as an alternative, for the majority of people living with obesity the treatment landscape has been a bleak one.

The use of drugs against obesity is a complex issue. First, obesity is not simply a physiological problem. The illness is governed by a complicated matrix of social and psychological factors, linked with factors like the individual’s own well-being all of which are likely to inhibit the effectiveness of a drug-based intervention. Where pharmacological interventions have been attempted, their history does not give much cause for optimism. Amphetamine derivatives were used throughout the 1950s and 1960s, but discontinued in the decade that followed owing to concerns about cardiovascular risk and their potential for abuse. Serotonin-releasing agents emerged as a solution in the 1980s. Once again, though, links to serious health issues such as pulmonary hypertension and cardiac problems– forced their discontinuation.

The following generation of anti-obesity drugs born in the mid 1990s inhibited hunger by working with cannabinoid receptors in the brain. In this way, appetite could be controlled and weight gain suppressed. By 2008, links surfaced between a major brand leader and severe psychological symptoms, which was subsequently withdrawn from the market. The major competitor followed soon after, associated with digestive problems.

The field of anti-obesity medication is littered with a plethora of “magic bullets” that have proven ineffective. Some have been withdrawn because of adverse effects not fully exposed by clinical trials, while others fail to make it out of the laboratory. However, major pharmaceutical companies are beginning to venture into new territories. At the beginning of January, EnteroMedics’ Maestro Rechargeable System was approved by the FDA. The product sends electrical signals to block the nerves around the stomach, decrease hunger spasms, and create the feeling of satisfaction. The next major candidate for chemical interventions is Contrave. A combination of naltrexone – approved for the treatment of alcohol and drug addictions – and the mood stabilizer bupropion, the drug is aimed at patients who are unable to lose weight through diet and exercise alone and who do not have the avenue of weight-loss surgery open to them. 

Other avenues remain open, with variants on the common anti-obesity template currently undergoing in preclinical trials. The targeting of pathways in metabolic tissues such as adipocytes, liver muscle, and skeletal tissues, is one option. Since the body is programmed to conserve its weight, metabolisms tend to slow down in response to reduced calories. Amlexanox tweaks metabolic response, by inhibiting two genes associated with energy storage and caloric burn. With the “brake” released, the body is free to burn energy without the metabolism noticing. Other possible next generation anti-obesity drugs employ GLP-1 receptor agonists, which lower body weight. In general, these drugs are adaptations of existing products used to treat diabetes.

While vagal blockade treatments such as the Maestro VBLOC System continue to be explored, the trend has shifted towards launching new combinations and altering existing medications. A look at the FDA’s to-do list of pending drug approvals indicates the degree to which these companies are examining obesity treatments as potential territories for expansion. Liragitude, for instance, is simply the type 2 diabetes drug Victoza administered at a higher dosage. Contrave combines existing endocrinal and cardiovascular compounds to produce a new formula to combat obesity, while Beloranib is an entirely new molecule with a US$45 million investment powering it to the forefront of the market.

Medical devices are also evolving. Pioneering gastric and intragastric balloons have been launched by Apollo Endosurgery and Allurion Technologies, while GI Dynamics’ duodenal-jejunal bypass sleeves are awaiting FDA approval by the end of 2015. Yet other drugs, such as Glucagon, act on pancreatic hormones to contain further complications of obesity such as type-2 diabetes. The body’s intake of fat lowers, while the metabolism moves faster. The ideal is a “polytherapeutic” drug, made up of combination agents that act on more than one biological mechanism. The goal of an anti-obesity drug capable of producing effects as dramatic and lasting as surgeries remains distant, but it is possible to envision integrated therapies including drugs, surgery, and eventual lifestyle changes.