A study published in Science on 2 July has identified rare genetic mutations in the GPR75 gene that confer protection against obesity. Scientists from the Regeneron Genetics Centre, a subsidiary of Regeneron Pharmaceuticals, sequenced almost 650,000 individuals from the UK, the US and Mexico, and found protective ‘loss of function’ GPR75 mutations in around one in every 3,000 people sequenced. These individuals had a 54% lower risk of obesity and weighed around 5.3kg less on average than those without the mutation. Armed with this data, Regeneron is now aiming to pursue a range of therapeutic approaches to target GPR75, including antibodies, small molecules and gene silencing.
The development of therapeutics that mimic the GPR75 mutation’s protective properties may be a welcome addition to the field. Such novel approaches could potentially address some of the unmet needs associated with current obesity drugs, most of which exert their effects by regulating appetite and increasing satiety. These drugs are, however, often associated with limited efficacy profiles and can be poorly tolerated. For example, Novo Nordisk’s glucagon-like peptide-1 (GLP-1) receptor agonist Saxenda (liraglutide), the current market leader, mimics the effects of native GLP-1, a physiological regulator of appetite and calorie intake. It is, however, associated with high rates of discontinuation due to adverse events, mostly due to gastrointestinal events such as nausea, diarrhoea and constipation.
The obesity market is characterised by significant untapped potential due to its low pharmacological treatment rate despite its exceptionally high prevalence. Low pharmacological treatment rates for obese patients reflect a range of factors. These include societal perceptions of obesity as a lifestyle choice rather than a disease requiring medical intervention, poor benefit-risk profiles of obesity drugs, and reimbursement barriers, as insurers have historically been reluctant to pay for obesity drugs.
Despite this, the approval last month of a once-weekly GLP-1 receptor agonist, Novo Nordisk’s Wegovy (semaglutide), has generated considerable excitement within this space. Wegovy is the first obesity drug to receive US Food and Drug Administration (FDA) approval in adults since the approval of Saxenda in December 2014. The drug is also currently at the pre-registration stage of development in the European Union. Wegovy has demonstrated efficacy results that are unprecedented within the obesity field, with patients achieving a mean weight loss of 15.3kg in a Phase III trial. Because of this, although some patients may face reimbursement challenges, Wegovy has the potential to markedly improve drug treatment rates.
In addition to this, the obesity pipeline is robust. According to GlobalData’s pipeline product database, there are 340 drugs in active development for obesity worldwide, ranging from discovery to pre-registration stages, which indicates that Regeneron’s GPR75-targeted therapies could face a considerable degree of competition. There are several novel therapeutic approaches currently in development, including eight gene therapies, four cell therapies and two vaccines.