A report published in 2023, estimates that over 40% of adults in the U.S. have obesity, defined as a body mass index (BMI) of over 30 kg/m 2. While not everyone in this group is unwell, there is no doubt that obesity increases the risk of associated health conditions such as type 2 diabetes, cardiovascular disease, osteoarthritis, sleep apnea, and many others.
The biotech and pharma industry has been trying to develop effective medications to treat obesity for many years. A combined treatment for obesity containing the two appetite suppressants fenfluramine and phentermine (known as fen-phen) was approved and widely used in the early 1990s, but was subsequently withdrawn from the market in 1997 when it became apparent that fenfluramine was causing potentially fatal pulmonary hypertension and heart valve problems.
Over a quarter of people who took fen-phen for longer periods (up to 24 months) had abnormal echocardiograms and a lawsuit led to approximately $13 billion damages being paid out to claimants by American Home Products (subsequently renamed Wyeth), which produced the drug.
The fen-phen scandal inevitably had a negative impact on investment in the obesity space and development of new medications. For example, Contrave (naltrexone/bupropion), a weight loss drug that targets the mesolimbic system and the hedonic system to control both hunger and cravings, took almost five years to finally achieve FDA approval in late 2014 due to extra checks and testing requested by the FDA.
Glucagon-like peptide-1 (GLP-1) receptor agonists were initially developed to treat type 2 diabetes. Exenatide, a synthetic version of a peptide found in the venom of the Gila monster lizard, was the first GLP-1 agonist to be approved by the FDA in 2005. These drugs act by slowing gastric emptying, inhibiting glucagon release, and triggering insulin release. This allows them to lower blood glucose, but also reduce food intake, which in turn lowers body weight.
It did not take long for manufacturers of GLP-1 agonists, such as Danish pharma company Novo Nordisk, to recognize the anti-obesity potential of these drugs. The approval of Novo Nordisk’s GLP-1 agonist Wegovy (semaglutide) for weight loss in 2021 and Eli Lilly’s combined GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) agonist Zepbound (tirzepatide) in 2022 has boosted the obesity treatment field enormously. The two drugs are very effective and can induce 12–20% weight loss in people who are prescribed them, depending on their personal medical profile.
Liraglutide, an earlier generation GLP-1 receptor agonist developed by Novo Nordisk to treat type 2 diabetes, was also approved for treatment of obesity by the FDA in 2021, but is not as effective or long-lasting as semaglutide.
“The introduction of GLP-1 agonists is exciting and really represents what I think could be a sea change in the way that obesity is treated over time,” said George Hampton, CEO of Currax Pharmaceuticals, which produces Contrave.
Although the approval of both Wegovy and Zepbound for weight loss is important, obesity is a very variable condition and has different triggers in different people. GLP-1 agonists do not work for everyone and a precision medicine approach involving biomarker testing and use of the right drug for the right patient is needed to have the biggest impact on this widespread condition.
With the approval of Wegovy and Zepbound for weight loss revolutionizing the space, many biotech and pharma companies are looking to the future to bring out additional treatments for obesity.
To date, the GLP-1 receptor agonists used to treat obesity are injected, but oral formulations optimized for treating obesity are being developed. Novo Nordisk already has an approved oral formulation of semaglutide to treat type 2 diabetes and it is now aiming to do the same for obesity.
Another approach several companies are developing is to combine GLP-1 agonists with other entero-pancreatic hormones that can help boost efficacy such as GIP, glucagon, and amylin. Altimmune is one such company. The Maryland-based biotech has a combined GLP-1 receptor agonist and glucagon therapy in development called pemvidutide.
“Glucagon helps because it raises resting energy expenditure. You take in fewer calories, but you’re also burning the ones that you have on board more quickly,” Scot Roberts, PhD, Altimmune’s chief scientific officer, told Inside Precision Medicine.
“The liver is replete with glucagon receptors, and glucagon acts there to change the metabolism. It brings down low density lipoprotein cholesterol, which is associated with cardiovascular risk. [Obesity] also lowers the amount of fat in your liver.”
For this reason, Altimmune hopes that, if approved, pemvidutide could be a good option for people with obesity who also have high levels of low-density lipoprotein (LDL) cholesterol. The company is also testing the drug in a separate series of trials to treat metabolic dysfunction-associated steatohepatitis (MASH), also known as nonalcoholic fatty liver disease.
“Ultimately, even to get reimbursement for these drugs, it’s going to be critical that we’re able to show a real benefit to the patient,” said Altimmune CEO Vipin Garg.
“Weight loss is great, but that’s a cosmetic benefit, we have to go beyond that and show what the drug is able to do in terms of … cardiovascular health. People don’t die because they’re [have obesity], they die because of cardiovascular outcomes resulting from obesity.”
The company announced good topline results for the Phase II Momentum trial of pemvidutide for treating obesity in November last year and now hopes to move forward to Phase III. On the highest dose of pemvidutide, patients lost 15.6% of their body weight on average and loss of lean muscle mass was less than seen with other GLP-1 agonists, which Altimmune hopes will give its candidate an edge against competitors.
Eli Lilly, Hanmi Pharmaceutical, and Boehringer Ingelheim all have candidate therapies in development that are GLP-1 plus glucagon agonists, so it remains to be seen if Altimmune can be successful with pemvidutide. As a smaller biotech company, they are looking to partner with a larger pharma company or other investor to help them carry out Phase III trials and progress towards market approval.
“GLP-1 analogs are effective overall, but some people cannot tolerate the side effects or don’t achieve adequate weight loss, so it’s important to have additional options in our treatment armamentarium,” said Elizabeth Lawson, MD, a neuroendocrinologist and associate professor of medicine at Harvard Medical School.
A number of non-GLP-1 drugs for treatment of obesity are available or in development. For example, orlistat is an oral medication that has been approved by the FDA for weight loss since 1999. It only has limited efficacy and can trigger gastrointestinal side effects like many other weight loss drugs.
After the fen-phen scandal, it became clear that although fenfluramine caused significant adverse effects, phentermine could still be beneficial. A new combination therapy called phentermine/topiramate, brand name Qsymia, was approved in the U.S. in 2012. It can be effective at triggering weight loss in some people with obesity in combination with diet and exercise, but is also linked to addiction due to its similarity to amphetamine, so needs to be prescribed with caution.
Another option that is already on the market is Contrave, combining bupropion, an antidepressant, and naltrexone, an opioid antagonist.
“It’s in a class of its own,” explained Hampton, whose company develops and markets Contrave. “It works on the ‘reward’ system of the brain. Certain patients with obesity eat when they’re stressed, upset, angry, or even happy. They eat, and food provides a dopamine response, a high that drives eating even when you’re not hungry. Contrave works on both the mesolimbic system and the hedonic system to control both hunger and cravings.”
Some rare genetic disorders cause extreme weight gain. Setmelanotide, brand name Imcivree, was approved by the FDA in late 2020. It was developed and approved for treating children (older than 6 years) or adults with one of three genetic conditions that cause obesity: pro-opiomelanocortin deficiency, proprotein convertase subtilisin/kexin type 1 deficiency, and leptin receptor deficiency, confirmed by genetic testing. In 2022, the additional indication of obesity due to Bardet-Biedl Syndrome was also approved by the FDA.
Prader-Willi syndrome is another genetic disorder that can cause obesity. Tonix Pharmaceuticals, in collaboration with Elizabeth Lawson and colleagues at Massachusetts General Hospital, is working on a new treatment for this condition based on oxytocin, which is currently at Phase II.
“Children with Prader-Willi syndrome manifest initially as failure to thrive, meaning they don’t eat enough … but in adolescence and adulthood, they develop hyperphagia, or impulsive over eating behavior,” explained Seth Lederman, MD, co-founder and CEO at Tonix.
“One of the things that got us attracted to oxytocin and Prader-Willi is that experiments in a mouse knockout model … have shown that oxytocin treatment around the time of birth looks like it reverses all of the effects of Prader-Willi. Animals develop normally, it’s really a dramatic change.”
Lawson has also been testing oxytocin for treatment of other forms of obesity. Results from a recent randomized, double-blind, placebo-controlled trial testing intranasal oxytocin in adults with obesity did not succeed in reducing body weight over eighte weeks, but Lawson says she doesn’t think the results should signal an end to testing oxytocin for obesity management.
“The overall data showing that oxytocin regulates eating behavior and metabolism are compelling, and our trial results can guide us in developing and testing new oxytocin-based therapeutic strategies,” she emphasized.
“We should explore different ways to increase oxytocin signaling to modulate energy balance, including alternative drug formulations; longer-acting medications that act at the oxytocin receptor; and interventions to increase one’s own release of oxytocin.”
“Precision or personalized medicine is a medical model that proposes the customization of healthcare, with decisions and treatments tailored to each patient. This approach can be particularly effective in targeting obesity,” said Fatima Cody Stanford, MD, an obesity medicine physician scientist at Massachusetts General Hospital and Harvard Medical School.
Obesity has varying causes and physiology, and factors such as a person’s genetics also play a role. This means that the same medications or treatment plan will not work for everyone.
“Personalized medicine can empower patients to take a more active role in their health management. By understanding their genetic predispositions, patients may be more motivated to adhere to prescribed treatment plans,” noted Stanford.
Andres Acosta, MD, PhD, is an associate professor and consultant in the department of gastroenterology and hepatology at the Mayo Clinic in Minnesota. He is also a co-founder of Phenomix Sciences, a biotech company focusing on obesity phenotyping and biomarker testing.
“More than 120 million people qualify for obesity medications. If we look worldwide, it is a billion people,” explained Acosta. “When we have such a high burden of disease, we need to find out who we need to treat first and how. We need to find out who will be the best responders and who will not respond, so we can actually give them something cost effective.”
Acosta and his team at the Mayo Clinic have developed genetic risk score tests, licensed by Phenomix Sciences, to phenotype individuals with obesity and predict the drug that is most likely to work for them.
They have broadly defined obesity into four types. Hungry brain, which involves consuming too many calories without feeling full; hungry gut, where people feel hungry again shortly after eating; emotional hunger, when food consumption triggers a dopamine reward; and slow burn, when people have a slow metabolism and do not burn calories they consume effectively.
The tests they have developed show that different medications work best for different types of obesity. For example, people with the “hungry brain” type of obesity do well on phentermine/topiramate extended release, those with the “emotional hunger” type do better on Contrave, and those with the “hungry gut” type have the best results using GLP-1 receptor agonists, while people with the “slow burn” type have a good response to low-dose phentermine plus
