Obesity has nearly tripled since 1975, becoming an ever-growing health threat. In 2016, it was estimated that more than 1.9 billion adults in the world were overweight, with more than 650 million of those being officially obese. \n\n\n\nObesity can be defined as abnormal or excessive fat accumulation that presents a risk to health, with a body mass index (BMI) of over 30 being the official indicator of whether an individual is obese or not. \n\n\n\nAnd, according to statistics from the World Health Organization (WHO), more than four million people die every year as a result of being overweight or obese. This is because obesity is essentially a precursor to disease, potentially leading to type 2 diabetes, heart disease, and even some cancers. \n\n\n\nGenerally, the advice for overweight and obese people is to eat a healthy diet and do regular exercise, but the truth is that it is not quite as simple as that. \n\n\n\nHunger is controlled by powerful hormones and chemicals in the brain, and involves areas of the brain responsible for cravings and rewards. In many individuals with obesity, the hormones, and even the brain’s reward system, are dysfunctional, altering eating behavior and causing a strong physiological desire to eat more. \n\n\n\nBut, fortunately, this is where weight loss drugs come in; they can deal with the hormones related to obesity directly, which, in turn, can change behavior by regulating appetite and reducing cravings. \n\n\n\nAnd, in recent times, obesity is finally being treated as the root cause of disease, leading to many biotech companies racing to develop new weight loss drugs that are more and more effective in reducing obesity, as well as having less side effects for the people taking them.\n\n\n\nNew GLP-1 analogues: a breakthrough for obesity\n\n\n\nGLP-1 analogues - which mimic the GLP-1 hormone that is released in the gut in response to eating - had originally been developed as a treatment for diabetes, but when one of the side effects of these medications was found to be weight loss, companies saw the promise and began to develop them as anti-obesity drugs as well. \n\n\n\nThis is thanks to the fact that GLP-1 analogues have several effects on individuals with obesity, including slowing down stomach emptying, reducing appetite by acting on the brain, and boosting the release of insulin, helping to regulate blood sugar levels. \n\n\n\nNow, the newest GLP-1 analogue, semaglutide, is being viewed as a breakthrough as far as anti-obesity medication goes, after being approved by the U.S. Food and Drug Administration (FDA) in 2021 specifically for weight loss. \n\n\n\nIt was the first new weight loss drug - sold under the brand name Wegovy, as well as under Ozempic and Rybelsus for diabetes - to be approved since Saxenda in 2014, and happens to be much more effective in allowing people to lose weight. \n\n\n\nIn clinical trials, Wegovy was shown to reduce body weight in individuals with BMIs of 27 or greater by 15% over a period of 68 weeks and, on average, people lost around an eighth of that weight in the first month. \n\n\n\nWegovy is also given as a once-weekly injection at a dose of 2.4 milligrams, which is an improvement on earlier formulations like Saxenda, which needed to be given on a daily basis, causing a burden for patients. \n\n\n\nGlyscend Therapeutics announces positive topline phase 2a results for diabetes and obesity drug\n\n\n\nMoving away from GLP-1s, there are also other types of weight loss drugs in development that work differently to currently approved drugs.\n\n\n\nGlyscend Therapeutics is one company looking to develop a new generation of orally administered first-in-class gut-targeted polymer therapies, and is developing GLY-200 for the treatment of type 2 diabetes and obesity. \n\n\n\n“Our lead compound, GLY-200, is designed to alter duodenal signaling by crosslinking to native intestinal mucin in a pH-dependent manner, enhancing its natural barrier properties. This enhanced mucus barrier results in a pharmacologic ‘duodenal exclusion’ that may non-invasively and safely reproduce many of the beneficial effects of metabolic surgery, while avoiding the complications associated with invasive surgeries and procedures,” explained Glyscend’s chief executive officer (CEO) Ashish Nimgaonkar. \n\n\n\nIn developing this treatment, the company wanted to address the need for non-invasive, scalable alternatives that could replicate the effectiveness of metabolic surgery, which is invasive, expensive, and can come with possible complications. \n\n\n\n“Moreover, none of the currently available treatments are considered disease-modifying, except for metabolic surgery. It has immediate profound effects on improving blood glucose and weight loss, with longer term reductions in macro- and microvascular complications,” said Nimgaonkar.\n\n\n\nIt was recently announced that data across completed phase 1 and 2a trials demonstrated that the novel mechanism of GLY-200 offers significantly and clinically relevant reductions in postprandial glucose and body weight, supporting its advancement into a phase 2b trial.\n\n\n\nAPH-012: Aphaia Pharma’s new weight loss drug candidate shows promise \n\n\n\nMeanwhile, Aphaia Pharma is also developing a promising drug candidate for weight loss, APH-012, with a focus on why L-cells - nutrient-sensing cells in the distal part of the intestine - in patients with metabolic disease are largely deprived from contact with food, as this leads to a lack of endocrine, neuroendocrine, and neuronal stimulation, in turn promoting the progression of obesity. \n\n\n\n“One reason is they have motility problems with their small intestines, so the passage of food is delayed, or is slowed down. They eat large quantities of food in a composition that has never been optimized, which actually means far too many proteins, far too many fats, and not enough carbohydrates, and not enough fibers on top of that,” explained Steffen-Sebastian Bolz, chief scientific officer (CSO) of Aphaia Pharma.\n\n\n\nAnother reason, he said, is the fact that the food we consume today - particularly in Western countries - is highly refined; we consume industrialized food whereby the different components, such as sugar, have been separated and then put back into a processed product. \n\n\n\n“We knew we would need to formulate something that bypasses the food bolus independent of motility to get to the distal part of the intestine where nutrient-sensing cells are (L-cells). We designed something that behaves like a fluid, because fluid just falls down…and we had to decide what we wanted to bring down there,” said Bolz.\n\n\n\n“We developed small beads containing glucose that travel down and hit L-cells with a very low interpatient variability. And more or less at exactly 1.5 hours after ingestion, you see the increase in the key metabolic hormones GLP-1, glicentin, oxyntomodulin, etc. It’s very promising because we’re just emulating what nature has defined over millions of years. We did not re-invent anything.” \n\n\n\nAPH-012 is currently in phase 2 of clinical development; the study was initiated towards the end of 2022, and is expected to close in May next year.\n\n\n\nDecreasing side effects \n\n\n\nAphaia Pharma’s weight loss drug also appears to lead to very few side effects. \n\n\n\n“We stimulate the release of GLP-1 and all the other hormones at concentrations that are comparable to a meal, and as such, we don’t expect side effects,” explained Bolz. \n\n\n\nThis is notable because, although the likes of Wegovy cause fewer side effects than previous GLP-1 analogues, such as Saxenda, they do still cause side effects that can be so difficult to put up with that it actually leads to people stopping the medication entirely. \n\n\n\n“In terms of nausea, despite multiple steps of dose-titration to mitigate gastrointestinal (GI) side effects, moderate to severe nausea is often observed with the newer GLP-1 agonists that can lead to treatment discontinuation. The U.S. prescribing information for Wegovy and Mounjaro report 4.3% and 6.6% of subjects discontinued treatment due to gastrointestinal adverse reactions respectively in controlled clinical trials. Discontinuation in clinical practice is likely much higher,” commented Nimgaonkar. \n\n\n\nGlyscend’s own drug candidate also appears to lead to less severe side effects than currently available weight loss drugs, with the number of patients reporting GI side effects in the phase 2 study decreasing over time during the two-week treatment period, and most reports of nausea were short-lived and resolved within a day. \n\n\n\n“While a direct head-to-head study of GLY-200 compared to other weight loss drugs like Wegovy has not been completed and historical comparisons of GI side effects across studies have limitations, early studies suggest that GLY-200 GI side effects may be less severe than most other obesity drugs recently approved or in development,” Nimgaonkar said.\n\n\n\nGrowing market for weight loss drugs\n\n\n\nAs obesity becomes more prevalent in the general population, the weight loss drug market grows with it.\n\n\n\nIn fact, with more and more biotech companies looking to develop new weight loss drugs, it is estimated that the global obesity therapeutic market could be worth $100 billion by around 2030, if not more. \n\n\n\n“Obesity is a real disease with both near- and long-term clinical and psychosocial consequences to the individual. We therefore believe strongly that these patients should have access to effective therapies that are easy to administer and affordable,” said Nimgaonkar.