Obesity - the big epidemic

There’s little doubt that obesity now ranks among the most serious global challenges facing health professionals. According to a recent study, the latest estimates suggest that globally some 500 million adults are obese (defined as a body mass index, or BMI, of 30 kg/m² or higher). Incredibly, that represents some 10% of men and 14% of women on the planet – roughly double the rates in 1980. These figures alone suggest that obesity is a truly global problem, and if action isn’t effective, experts predict that there will be more than 1 billion obese adults by 2030.

Beyond diet, exercise, and in extreme cases, surgery (in particular gastric band or gastric bypass surgery), the mainstay of therapeutic treatment for obesity since the 1990s has been Roche's prescription product Xenical^® (orlistat) and GlaxoSmithKline's half-dose OTC version Alli^®. Orlistat has been taken by 38 million people. However in 2011, the EMA begun a review of anti-obesity products containing orlistat, which investigated liver toxicity. Some 21 suspected cases of hepatic events were reported with Xenical in less than 18 months, four of them severe and one fatal. In 2012, the EMA concluded that the benefits of orlistat continue to outweigh its risks, and recommended that the marketing authorisations be maintained with minor amendments. Global sales of orlistat are almost flat at around $650 million annually.

Market leaders

A number of new therapeutics for obesity have been approved in the last few years. The first of a new generation of drugs, Belviq^® (lorcaserin HCl), from Eisai/Arena Pharma, was FDA approved in 2012. The drug targets the 5-HT2C receptor, with the aim of giving patients a full feeling without eating. Estimates of potential sales vary widely, but Eisai is set to expand sales by recruiting additional sales representatives, direct consumer advertising and offering savings cards. Some analysts predict sales of $600 million by 2017, representing about 20 % of the obesity drug market. Arena withdrew its European marketing application in 2013 but plans to resubmit in the future.

Belviq’s main competitor is Qsymia^®/Qsiva^® (phentermine plus topiramate), from Vivus, which appears to have better efficacy than Belviq and was FDA approved in 2012. Despite optimistic sales forecasts of $1.2 billion by 2017, disappointing results have led this to be moderated downwards. Both Belviq and Qsymia face challenges highlighted by the EU’s reluctance to approve them: these drugs offer limited benefits: studies suggest that people on Belviq may lose less than 4% of their body weight while those on Qsymia may lose about 9% of their weight. Even then, this lost weight may return. Meanwhile the drugs can produce a number of side effects, including dizziness, nausea, fatigue, depression and even increased CV risks.

New treatments

The hunt for new obesity blockbusters has led to the approval of two new therapies in the last year. Dual-action Contrave^®, which combines bupropion and naltrexone, was FDA approved in 2014. Marketed by Takeda and Orexigen Therapeutics, the drug was also CHMP recommended as Mysimba^®. Though studies suggest weight loss of around 9% is possible, consideration of possible CV risks mean that the FDA and EMA both rule that if patients have not lost at least 5% of their body weight after 16 weeks, treatment should be stopped. Despite this, analysts suggest Contrave will raise $634 million in sales by 2020.

The other 2014 FDA approval was for Saxenda^® (liraglutide 3mg), an injectable from Novo Nordisk. Saxenda lowers blood glucose by stimulating the release of insulin and lowering glucagon secretion when blood sugar levels are high, and also by slowing gastric emptying. It also reduces body weight and body fat mass through mechanisms involving reduced hunger and lowered energy intake. The EMA’s CHMP recommended marketing authorisation in early 2015, and some analysts estimate the new obesity indication could bring $1 billion in sales annually, even though weight loss data from Phase III trials are unspectacular (losses range between 6 and 9%) while there have been concerns over potential side effects including thyroid tumours and pancreatitis. Moreover, many patients do not welcome injections. Novo Nordisk has indicated that it is not targeting the average obese population but the ‘niche obese’ who are obese and have co-morbidities.

Next generation therapies

Currently in Phase III trials in the EU, tesofensine, from Saniona (formerly from NeuroSearch), works on three different appetite regulatory centers of the brain – the neurotransmitters noradrenaline, dopamine and serotonin. Trials indicate weight loss can reach more than 10% of body weight, making tesofensine a potential blockbuster, but blood pressure side effects may be a problem. Saniona is seeking patent protection for a combination of tesofesine plus beta blocker (metoprolol) to control the blood pressure side effect.

RM 493, from Rhythm, targets the MC4 receptor which modulates weight through a combination of effects on food intake and energy homeostasis. Phase II trials indicate an increase in resting energy expenditure by 6%, but further trials are needed to see how this affects weight loss. This drug appears focused on Prader-Willi Syndrome.

ZGN 433 (beloranib), from Zafgen, is also showing good potential in Phase II trials for obesity, and is also being investigated in Prader-Willi Syndrome. This drug reportedly makes the body produce less fat and improves cardio-metabolic function. Phase II data indicates weight loss of up to 10% is possible. Researchers suggest that ZGN 433 has the potential to be the first drug to produce weight loss approaching that of bariatric surgery. Combined with the finding that the drug exhibits fewer side effects than Belviq, Qsymia or Saxenda, it could prove highly successful.

Alternative therapies

A number of alternatives to drug therapies are under development or on the market, including insert devices such as ReShape Medical’s dual-intragastric balloon which takes up space in the stomach. AspireAssist, from Aspire Bariatrics, works by allowing patients to drain a portion of their stomach contents into the toilet after each meal through an endoscopically-implanted tube. CE Mark approved in the EU, AspireAssist has helped patients lose up to 20 kgs in trials. In contrast, the Maestro^® System from EnteroMedics includes an implantable device that intermittently blocks inter-abdominal vagus nerve signalling, which is involved in regulating stomach emptying and signaling to the brain that the stomach feels empty or full. Though weight loss results in trials have been limited, the device is FDA and CE approved. Finally, the TransPyloric Shuttle™, from BAROnova, is a mechanical device that is expected to slow the digestion process and create the sensation of fullness, which should slow or stop patients from overeating. This minimally invasive device is fitted in a 10 minute procedure, and is currently undergoing pivotal trials in the US and EU.

References:

1. National, regional, and global trends in body-mass index since 1980: systematic analysis of health examination surveys and epidemiological studies with 960 country-years and 9.1 million participants. Finucane MM, Stevens GA, Cowan MJ, et al. Lancet 2011;377:557-67.
2. Drug treatment of obesity: Current status and future prospects. Kakkar AK, Dahiya N. Eur J Intern Med 2015;26:89-94.