Healthy weight gain has preoccupied humanity for centuries, with obesity being the dominant health concern of modern times. While there have been many attempts over the course of history to manage weight gain, from ancient use of herbs and plants to modern-day surgical interventions, a sustainable and long-term solution has remained elusive. But recent advances in our scientific understanding of obesity’s root causes have produced breakthroughs in our ability to treat and manage the disease.
These new obesity treatments couldn’t come sooner, as the problem is growing at an alarming rate. According to the World Health Organization, global obesity rates have almost tripled over the past decade. It is currently estimated that 1 billion people are clinically obese, of which around 650 million are adults, 340 million are adolescents and 39 million are children. The World Obesity Federation predicts that if current trends prevail, 4 billion people will be overweight or obese by 2035. And populations in lower income countries like Asia and Africa are putting on the pounds the fastest.
Data on global trends in the prevalence of obesity (BMI ≥30 kg/m2) in men and women in 1980, 2008 and 2016 from select regions of the world show an increase in obesity across the world. Data from the Noncommunicable Diseases Risk Factor Collaboration (NCD-RisC).
These trends have wide-ranging consequences on public health and the economy, because obesity is a major risk factor for a host of health problems, including diabetes, cardiovascular disease, hypertension, stroke, osteoarthritis and various cancers. Consequently, according to modeling by academics, the economic impact of obesity could reach US$4.32 trillion annually by 2035. This equates to roughly 3% of global GDP or about the same impact as the Covid-19 pandemic in 2020, and includes spending on health care, economic productivity lost to illness and premature deaths due to obesity. The burden is enormous and growing in an uneven manner around the world. By 2060, high-income countries expect a four-fold increase, outstripped by the whopping 12-35-fold increase that low and middle-income countries expect to witness.
As large parts of the world continue to see an increase in sedentary lifestyles and high-calorie diets that push up belt sizes, there has been a proliferation in attempts to treat the disease, and the size of the obesity treatments market has been steadily increasing. Many pharma companies have been vying to develop a working drug to help reduce weight in obese patients. While there are already several non-drug treatment options including lifestyle changes and bariatric surgery, they have not been durable and sufficiently effective in many cases. A cheap and accessible pill that can dramatically reduce a patient’s weight remains highly desirable and the Holy Grail of many pharmaceutical development efforts.
Tackling Obesity with Pharmaceutical Intervention
The early 2000s saw many obesity drugs approved, including medications like Orlistat by GSK, Contrave by Currax Pharma and Qysmia by Vivus. However, many of these caused severe injuries, including heart damage and hypertension, and caused other negative side effects like digestive issues and stomach discomfort, psychiatric or cognitive disturbances. As a result, sales of these drugs never really took off as clinicians were more reluctant to prescribe and patients were less compliant. The obesity drug market struggled to grow for many years as people began to believe that it might be impossible to develop safe and effective obesity medications.
Revelation: a diabetes drug is found to be effective for obesity management
The paradigm shifted with the serendipitous observation that GLP-1-based drugs like Semaglutide, originally developed and approved to treat diabetes, also caused weight loss. GLP-1 incretin mimetics or incretin drugs mimic the release of hormones that stimulate the feeling of fullness and reduces appetite. This discovery stimulated a flurry of interest and attempts by Big Pharma companies to develop incretin drugs for the treatment of obesity.
Novo Nordisk is the pharmaceutical company that markets Semaglutide under the brand names Wegovy, Ozempic, and Rybelsus. While Ozempic was approved in 2017 for diabetes, mounting interest in its off-label use for weight loss has resulted in US$8.7 billion of sales of the drug in 2022. Demand for injectable Wegovy, which was approved for treating obesity in June 2021, has been so high that Novo has struggled to supply it. The company has had to put promotional efforts on hold to avoid stimulating further demand. Novo Nordisk’s stock has also more than doubled in value since June 2021.
Despite its efficacy, GLP-1 drugs still struggle with safety and affordability. Common side effects include nausea, vomiting and diarrhea, with more severe effects including muscle loss, gall bladder stones, pancreatic cancer and suicidal ideation. These risks are significant because many patients have to continue to take the drug for the rest of their lives as stopping results in lost weight regained and even increased. These side effects can be so unbearable that patients stop taking them despite the weight loss. The USD$1,300 monthly cost for patients also makes this forbiddingly expensive as a lifelong prescription.
Nevertheless, the success of incretin drugs has reignited interest in the weight-loss treatment market. Other pharma, like Eli Lilly, Amgen and Astra Zeneca are looking to develop similar drugs. The next wave of GLP-1 weight-loss drugs will also aim at improving efficacy, convenience or tolerability.
Various companies are generally trying to improve efficacy by increasing the number of targets beyond GLP-1 to other incretins. Eli Lilly’s injectable diabetes drug, Mounjaro (tirzepatide) targets not just GLP-1 but also another obesity related hormone called glucose-dependent insulinotropic polypeptide (GIP), and in April 2023, was announced to induce greater weight loss than Wegovy. Eli Lilly even has a “triple G” drug, retatrutide, injected once a week and targeting GLP-1, GIP and the hormone, glucagon, surpassing other weight loss drugs to-date.
To improve convenience, both Novo Nordisk and Eli Lilly are developing oral pill formulations. In June 23rd 2023, Eli Lilly announced Phase 2 trial results showing that its oral drug, Oforglipron, caused an incredible 14.7% mean weight reduction after 36 weeks. This announcement caused Eli Lilly’s share price to jump 1.9%, a USD$7.6 billion increase in value. However, it remains to be seen whether the pill will be cheaper and whether the side effects remain the same.
The boom in interest in obesity and the success and commercial prospects of GLP-1 drugs has led many groups to develop drugs targeting other hormones and signaling molecules, aiming to achieve or surpass the efficacy of Wegovy while doing away with the negative side effects.
One such company is Rivus Pharmacueticals. Their candidate, HU6, is a Phase 2 drug seeks to tackle obesity by increasing resting energy expenditure via the activation of mitochondria, the energy factories in cells. This encourages increased use of sugars and fats. The drug appears to target visceral fat, in particular fat within the liver. Rivus closed a US$132 million Series B financing round in September 2022, led by RA Capital, and aims to IPO in 2024 if the readouts from their ongoing two Phase 2 trials are positive.
Another example is Versanis Bio, whose antibody drug candidate functions by blocking activin type II receptors found in both fat and muscle cells, aiming to reduce fat mass while increasing lean muscle. Their antibody is in a Phase 2b trial as a monotherapy and in combination with semaglutide. Eli Lilly recently acquired Versanis for US$1.9 billion to boost their obesity portfolio.
Kallyope’s approach is to harness the gut-brain axis to treat obesity, with two oral compounds identified by their proprietary discovery platform in Phase I trials.
Aardvark Therapeutics has a novel drug candidate that targets bitter taste receptors (TAS2Rs) in the gut, where they trigger the release of appetite suppressing hormones like GLP-1, GIP, PYY and CCK. Their compound, ARD-101, is one of the most bitter compounds known to man. Most bitter substances are toxic to humans, and ARD-101 may work by tricking the body into thinking it is being challenged by a toxin and mobilizing the body’s response to suppress hunger for treating obesity.
The drug, which just completed Phase 2 trials, has an exceptional safety profile and has anti-inflammatory and metabolic effects with significant reductions in hunger observed. This effect on hunger is largely modulated by ARD-101’s effect on regulating hormone, CCK.
Here, it is important to recognize that hunger is distinct from appetite. Hunger is a physiological cue represented by discomfort indicating the body’s need for food, and appetite is a psychological drive to eat. We often conflate both concepts in common language, saying we are “hungry for a burger” when in fact we have an appetite for it. This distinction is particularly important when it comes to weight loss because when we shed pounds, we also trigger mechanisms that make us hungrier and need to eat more. This is a known issue with GLP-1 drugs, that patients who stop taking them quickly regain the weight they lost.
The human body lacks the ability to effectively regulate weight as it doesn’t signal discomfort when we indulge in overeating, but we do experience uncomfortable hunger sensations when we undereat. This absence of feedback can easily lead to a gradual and persistent weight gain. In this context, appetite plays a significant role in weight gain, as it drives our desire to eat. On the other hand, mastering hunger control is crucial when endeavoring to lose weight. By managing hunger and understanding the signals our body sends, we can work towards effective weight management. Aardvark believes that controlling CCK is a key component in achieving hunger regulation.
ARD-101 was recently granted Orphan Drug Designation by the FDA in Prader-Willi Syndrome (PWS), a rare genetic disease characterized by extreme and unabated hunger with no treatment options. In the Phase 2 trial, ARD-101 caused such a huge and unprecedented decrease in food seeking behavior in PWS patients that the drug is being considered for compassionate use prior to approval.
Drugs like ARD-101 that are safe and mobilize a different mechanism of action to incretin drugs could be used in combination with GLP-1 drugs to enhance weigh loss effects.
As societies get richer and people continue to live longer and eat more, the prevalence of obesity epidemic will continue to grow, and treatment of this disease will remain vital for decades to come. We are just at the beginning of understanding and making a dent on the problem. To preserve the health of the public and the economy, it is crucial that we continue to invest in investigating and developing the multiple treatments and combinations that are likely be needed to manage this complex condition.