Obesity has nearly tripled since 1975, becoming a growing health threat. In 2016, it is estimated that more than 1.9 billion adults worldwide are overweight, with more than 650 million of them officially obese.
Obesity can be defined as abnormal or excessive fat accumulation that poses a risk to health, with a body mass index (BMI) of over 30 being the official indicator of whether a person is obese or not.
And, According to statistics According to the World Health Organization (WHO), more than four million people die each 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 types of cancer.
In general, the advice for overweight and obese people is to eat a healthy diet and exercise regularly, but the reality is not that simple.
Hunger is controlled by powerful hormones and chemicals in the brain, and involves the areas of the brain responsible for desire and reward. In many people with obesity, hormones, and even the brain’s reward system, malfunction, changing eating behavior and causing a strong physiological desire to eat more.
But, fortunately, this is where weight loss drugs come into play; they can tackle obesity-related hormones directly, which in turn can change behavior by regulating appetite and reducing cravings.
And, more recently, obesity is finally being treated as a root cause of disease, causing biotech companies to race to develop new weight loss drugs that are more effective at reducing obesity, as well as having fewer side effects for the people who take them.
New GLP-1 analogues: a breakthrough for obesity
GLP-1 analogues – which mimic the GLP-1 hormone released in the gut in response to eating – were originally developed as a treatment for diabetes, but when one side effect of these drugs was discovered to be weight loss, companies saw the promise and began developing them as anti-obesity drugs as well.
This is thanks to the fact that GLP-1 analogues have several effects in obese individuals, including slowing stomach emptying, reducing appetite by acting on the brain, and increasing insulin release, helping to regulate blood sugar levels.
Now, a new GLP-1 analogue, semaglutide, is seen as a breakthrough in anti-obesity treatment, having been approved by the US Food and Drug Administration (FDA) in 2021 specifically for weight loss.
It 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 found to be much more effective at enabling people to lose weight.
In clinical trials, Wegovy was shown to reduce weight in individuals with a BMI of 27 or more by 15% over a 68-week period and, on average, people lost about one-eighth of that body weight in the first month.
Wegovy is also given as a once-weekly injection at a dose of 2.4 milligrams, which is an improvement over earlier formulations such as Saxenda, which needed to be given every other day, causing a burden for the patient.
Glyscend Therapeutics announced positive topline phase 2a results for its diabetes and obesity drug
Moving on from GLP-1, there are also other types of weight loss drugs under development that work differently to currently approved drugs.
Glyscend Therapeutics is one of the companies looking to develop a new generation of first-class, gut-targeted polymer therapies that are administered orally, and are developing GLY-200 for the treatment of type 2 diabetes and obesity.
“Our lead compound, GLY-200, is designed to alter duodenal signaling by cross-linking to native intestinal mucin in a pH-dependent manner, enhancing its natural barrier properties. This enhanced mucus barrier results in a pharmacological ‘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,” explains Glyscend chief executive officer (CEO) Ashish Nimgaonkar.
In developing this treatment, the company wanted to address the need for a non-invasive, scalable alternative that could replicate the effectiveness of metabolic surgery, which is invasive, expensive, and can introduce potential complications.
“In addition, none of the currently available treatments are thought to alter the disease, except for metabolic surgery. This has an immediate profound effect on blood glucose improvement and weight loss, with reduction of long term macro and microvascular complications,” said Nimgaonkar.
It was recently announced that data across completed phase 1 and 2a trials showing that the novel mechanism of GLY-200 offers significant and clinically relevant reductions in glucose and postprandial body weight, supporting its advancement into a phase 2b trial.
APH-012: The new weight loss candidate from Aphaia Pharma shows promise
Meanwhile, Aphaia Pharma is also developing a promising drug candidate for weight loss, APH-012, focusing on why L-cells – nutrient-sensing cells in the distal part of the gut – in patients with metabolic diseases largely lose contact with food, as this leads to a lack of endocrine, neuroendocrine and nervous stimulation, which in turn promotes the development of obesity.
“One reason is that they have motility problems with their small intestine, so the passage of food is delayed, or slowed down. They eat large amounts of food in a composition that is never optimized, which really means too much protein, too much fat, and not enough carbohydrates, and not enough fiber besides that,” explains Steffen-Sebastian Bolz, chief scientific officer (CSO) of Aphaia Pharma.
Another reason, he says, is the fact that the foods we eat today – especially in Western countries – are highly refined; we consume industrial foods where the different components, such as sugar, have been separated and then reintroduced into the processed product.
“We knew we needed to formulate something that passed through the food bolus regardless of motility to get to the distal part of the intestine where the nutrient-sensing cells (L-cells) were located. We designed something that behaves like a liquid, because the liquid just drops in… and we have to decide what we want to get there,” said Bolz.
“We developed small glucose-containing beads that travel down and hit L-cells with very low inter-patient variability. And approximately exactly 1.5 hours after consumption, you see an increase in the main metabolic hormones GLP-1, glycentin, oxyntomodulin, etc. This is very promising because we are only replicating what nature has defined for millions of years. We didn’t find anything back.
APH-012 is currently in phase 2 of clinical development; the research began towards the end of 2022, and is expected to be completed in May next year.
Reducing side effects
The weight loss drug Aphaia Pharma also seems to cause very few side effects.
“We stimulate the release of GLP-1 and all other hormones at concentrations comparable to eating, and because of that, we don’t expect any side effects,” explains Bolz.
This is important, because currently approved weight loss medications can have some pretty nasty side effects. And, even though Wegovy caused fewer side effects than earlier GLP-1 analogues, such as Saxenda, they still caused side effects that could be so difficult to endure that they actually caused people to stop the medication completely.
“In terms of nausea, despite multiple dose titration steps to reduce gastrointestinal (GI) side effects, moderate to severe nausea is frequently observed with the newer GLP-1 agonists which may lead to discontinuation of treatment. The US prescribing information for Wegovy and Mounjaro reported 4.3% and 6.6% of subjects discontinuing treatment due to gastrointestinal adverse events in controlled clinical trials, respectively. The possibility of discontinuing clinical practice is much higher,” commented Nimgaonkar.
The drug candidate Glyscend itself also appeared to cause 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 over the two-week treatment period, and most reports of nausea were short-lived and resolved within one day.
“While direct head-to-head studies of GLY-200 compared with other weight loss drugs such as Wegovy are not complete and comparisons of GI side effect history 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,” said Nimgaonkar.
A growing market for weight loss drugs
As obesity becomes more common in the general population, the market for weight loss drugs is growing with it.
In fact, with more and more biotech companies looking to develop new weight loss drugs, it is estimated that the global obesity therapy market could be worth $100 billion by around 2030, if not more.
“Obesity is a real disease with short and long term clinical and psychosocial consequences for individuals. We therefore strongly believe that these patients should have access to effective therapies that are easy to administer and affordable,” said Nimgaonkar.