Obesity is a global public health issue, with a prevalence in adults now exceeding 35 per cent and 20 per cent, in the US and EU, respectively. Anti-obesity drugs are a source of considerable controversy, with a number of leading medicines having been taken off the market amid safety concerns.
At present, drug therapy alone does not seem a realistic way to manage weight and must be used in combination with dietary measures and physical exercise. The only currently approved long-term drug therapy for obesity is a lipase inhibitor called orlistat, which was launched in 1998 and prevents the absorption of lipids in the gastrointestinal tract. The persistent increase in obesity rates and associated morbidity, as well as the combined shortage of effective drugs has generated substantial research activity into new drug treatments.
Obesity generally requires long-term treatment and this brings a greater risk for drug therapies to cause side effects, particularly if they target the central nervous system. In recent years, several centrally-acting anti-obesity drugs have been withdrawn from the market after post-marketing surveillance showed they were associated with serious adverse cardiovascular or psychiatric effects.
In 2010, sibutramine, a selective noradrenaline/serotonin reuptake inhibitor, was withdrawn from the market due to its association with increased cardiovascular events and strokes. The first selective cannabinoid CB1 receptor antagonist, rimonabant, was withdrawn in 2009 after post-marketing reports indicated that the drug was associated with serious psychiatric adverse events, particularly depression. In addition, two non-selective serotonin receptor agonists, fenfluramine and dexfenfluramine, were found to be responsible for heart valve damage and were withdrawn from markets around the world in the late 1990s.
As a consequence, regulatory committees have become increasingly reluctant to approve weight loss drugs without clearly supportive long-term tolerability and safety data.
At the head of the queue of new anti-obesity drug candidates vying for approval is VIVUS Pharmaceuticals' oral fixed-dose combination tablet containing immediate-release phentermine and controlled-release topiramate (Qnexa). Phentermine is an appetite suppressant and stimulant of the amphetamine class, while topiramate is an anticonvulsant with weight loss properties. Phentermine/topiramate has demonstrated an 8.6 per cent placebo-adjusted weight loss at 24 weeks.
It has also shown a positive impact on secondary measures, including blood pressure and cholesterol. However, concerns about increased heart rate and teratogenic risk could significantly limit its use and resulted in its first New Drug Application (NDA) submission not being approved by the US Food and Drug Administration (FDA).
In October 2011, VIVUS resubmitted the NDA with two-year safety data from the 1,000-patient SEQUEL extension study and FDA advisers subsequently voted 20:2 in favour of the FDA adopting phentermine/topiramate as an obesity therapy. The FDA's final decision is expected on July 17, 2012, with recommendations for post-marketing surveillance of cardiovascular risk and an indication against use in pregnant women.
A Marketing Authorisation Application (MAA) was filed with the European Medicines Agency (EMA) in December 2010; however, the EMA's Committee for Medicinal Products for Human Use (CHMP) has requested additional information on risk minimisation activities to reflect issues relating to cardiovascular, neuropsychiatric and potential teratogenic effects of the product. Additionally, VIVUS was asked to address the benefit/risk ratio of different product doses, use in different patient populations and expected long-term treatment benefit of phentermine/topiramate. VIVUS anticipates responding to the CHMP in the second quarter of 2012.
Arena Pharmaceuticals is developing an appetite suppressant called lorcaserin, a novel selective agonist of serotonin 2C receptors that are located in the hypothalamus, the brain area associated with regulation of satiety. The compound is approximately 100-fold selective for the serotonin 2C receptor over the serotonin 2B receptor. As a single agent, lorcaserin offers modest weight loss, no better than currently marketed agents (3.6 per cent placebo-adjusted weight loss). While this may be inferior to other late-stage agents in development discussed here, the ultimate value of lorcaserin may be dependent on combination use with phentermine.
Once commercialised, it is likely that lorcaserin would be paired with phentermine, creating a new 'fen-phen' combination. The US FDA rejected Arena's first NDA submission due to concerns over its safety, particularly its carcinogenicity. Arena resubmitted its NDA with further safety data and this was accepted for review in January 2012. A meeting of the FDA's Endocrinologic and Metabolic Drugs Advisory Committee took place in May 2012 to discuss the NDA for lorcaserin and a final decision on its approval in the US is scheduled for June 27, 2012. Arena's regulatory application in Europe was accepted for review in March 2012.
Orexigen Therapeutics, in collaboration with Takeda, is developing a fixed-dose combination of sustained-release naltrexone and sustained-release bupropion (Contrave) in a single tri-layer tablet. Naltrexone is an opioid receptor antagonist marketed in the US for the treatment of narcotic and alcohol dependency, while bupropion is a dopamine and norepinephrine reuptake inhibitor prescribed as an antidepressant and smoking cessation aid. In combination, the agents are thought to stimulate proopiomelanocortin neuronal firing and modulate food cravings through an effect on the reward pathways.
Naltrexone/buproprion demonstrated a 4.8 per cent placebo-adjusted weight loss in phase III studies. An NDA was submitted in June 2010 and, although it lacked long-term data, Orexigen tried to mitigate this by outlining a risk management strategy that would involve a post-approval trial to examine the cardiovascular risks associated with the drug. Advisors to the FDA voted 13:7 for the approval of the drug; however, in January 2011, the FDA advised Orexigen that it would need to conduct a cardiovascular outcomes trial before registrational approval. Orexigen has a Special Protocol Assessment on this trial, which will enrol approximately 10,000 patients. Initiation is expected in the second quarter of 2012. InThought analysts estimate the approval date for naltrexone/buproprion to be in the year 2016.
Orexigen has also completed phase IIb development of a fixed-dose combination tablet of sustained-release zonisamide and sustained-release bupropion for the treatment of obesity (Empatic). Zonisamide is an anticonvulsant that is approved as an adjunctive treatment for partial seizures. Bupropion/zonisamide demonstrated promising 24-week data, with a placebo-adjusted weight loss in the intent-to-treat group of up to 7.5 per cent, and in completers of up to 9.1 per cent.
Orexigen is currently assessing the regulatory process for VIVUS Pharmaceuticals' phentermine/topiramate product, which also contains an anticonvulsant, in order to inform further development of bupropion/zonisamide. The company intends to discuss plans for phase III development with the FDA once this information becomes available. The FDA has already indicated that Orexigen may not be required to conduct a phase III cardiovascular outcomes trial for bupropion/zonisamide, pending specific data on both the combination and naltrexone/bupropion.
Novo Nordisk is developing its diabetic drug, liraglutide, a subcutaneously injected glucagon-like peptide 1 (GLP-1) analogue, for the treatment of obesity. The peripherally-acting agent mimics the activity of GLP-1 that is released from the gastrointestinal tract upon ingestion of food. GLP-1 promotes feelings of satiety by slowing gastric emptying, among its other metabolic benefits. In a 26-week phase II study, liraglutide reduced mean body weight in obese patients by between 4.8 and 7.2kg, versus 4.1kg with orlistat and 2.8kg with placebo. Liraglutide's safety profile appears manageable, but the requirement for daily subcutaneous injection may hamper adoption.
Novo Nordisk is currently conducting three phase III trials of liraglutide for obesity that are expected to be completed in 2013.
NeuroSearch is developing tesofensine, an orally administered noradrenaline, dopamine and serotonin re-uptake inhibitor, for the treatment of obesity. Tesofensine has demonstrated a 10.6 per cent placebo-adjusted weight loss, representing the best absolute efficacy seen in phase II obesity trials for the compounds that InThought analysts model. However, concerns about elevated blood pressure and increased heart rate remain. Cardiovascular safety will be a key issue in phase III studies and the risk of neuropsychiatric adverse events cannot be ignored. Based on written feedback from the FDA and EMA, NeuroSearch has concluded that the phase III programme will include two one-year obesity trials, with weight loss as the primary outcome.
The phase III programme will also include a study of at least two years' duration to investigate the cardiovascular safety of tesofensine. These pivotal phase III trials will be implemented after a commercial partner has been selected. InThought analysts estimate the approval date for tesofensine in obesity to be in 2015.
Centrally-acting drugs remain promising for the treatment of obesity due to the fact that the largest effects are, at present, expected to come from these targets. However, peripherally-acting drugs, such as liraglutide, may be advantageous in terms of side effects. As the multiple and complex mechanisms involved in the regulation of appetite become better understood, more effective and better tolerated drugs will be developed. Major product withdrawals of anti-obesity drugs and the fact that effective therapies will be prescribed to a large and diverse group of people, regulatory authorities will continue to require long-term safety data of novel drugs and combinations before considering approval.
Pipeline was written by Ben Benson-Cooper of Adis International (Springer Healthcare), using data derived from Adis R&D Insight, Clinical Trials Insight and inThought. For further information on Adis services, please contact Daniela Ranzani on +39 02 423 4562 or Email: Daniela.Ranzani@wolterskluwer.com