Turning the Page for Obesity Therapies — Addressing Tolerability and Delivery

Weight management remains a popular topic in our society. This doesn’t come as a surprise, as reports indicate that obesity affects nearly 43% of adults in the U.S. alone. Obesity is more than a number on a scale – it’s a major driver of chronic diseases like diabetes, cardiovascular disease, sleep apnea, and even certain cancers. Physicians and hospitals are seeing a direct correlation between the percentage of obese individuals and their visits to the emergency room. 

While many individuals are taking weight management head-on through diet, exercise, and lifestyle changes, some still need other treatments for weight loss. Studies have found that even modest weight loss — just 5-10% of body weight — can lead to meaningful health improvements.  

It’s obvious to see why many people think the GLP-1 class of drugs are a brand-new option for treating obesity, but in fact, they’ve actually been around for a little over a decade now. The FDA approved Saxenda (liraglutide) as the first-ever GLP-1 for weight loss back in 2014. Still, it wasn’t until 2021 that word of mouth took off, with Wegovy (semaglutide) receiving approval from the FDA for the same indication. 

The current GLP-1s on the market are once-weekly subcutaneous injections that suppress appetite and have created a treatment pathway that didn’t exist before. They have made significant progress in the obesity field, and individuals have been able to lose weight quickly. Still, there have been challenges that have become increasingly clear over the last few years, including gastrointestinal (GI) issues that create a barrier to users feeling well enough to participate in life’s daily activities.

Tolerability remains the biggest challenge for GLP-1s, as many patients experience adverse events and discomfort. Approximately 20-30% of patients undergoing GLP-1 therapy discontinue usage due to GI and GI related issues, and around 70% drop out after a year, factoring in these side effects along with economic reasons. While weight loss is possible with these medicines, the quality of life becomes questionable. 

As the obesity epidemic continues to increase, we’re at a turning point in public health. It’s clear that the latest scientific breakthroughs need to rise to the challenge of tackling the obesity crisis. Biotech and pharmaceutical companies are turning to alternative pathways to address tolerability head-on. 

New wave of obesity treatments

We are starting to see a switch within the industry, with more research and development funneled into a weight-loss treatment involving a GLP-1/glucagon dual agonist. While the switch is being made, this concept, similar to GLP-1, isn’t new. Development of this concept has been happening since the mid-2010s. One company was able to progress to Phase 2 for type 2 diabetes before failing to meet endpoints. Those efforts were not wasted, as they show scientists and researchers that the ratio between GLP-1 and glucagon activity is essential for success. It works because GLP-1 lowers glucose, while glucagon tends to increase it. Adding too much of one will shift the balance and cancel out the other. 

We are seeing multiple ratios being tested throughout the industry. Preclinical testing has shown that some companies are studying a completely balanced 1:1 ratio. Altimmune is a prime example of this, where they used a 1:1 ratio with pemvidutide, where it was evident that there was no significant glucose control. On the other hand, there are companies that are testing heavier GLP-1 weightings, like 6:1 or 8:1, which haven’t been successful in delivering proportional glucose-lowering effects in clinical testing. The industry is realizing that more GLP-1 itself doesn’t mean better outcomes; the better outcomes result from finding the right balance. 

Delivery method

While strides are being made in innovation to fix the tolerability challenge, significant progress is also being made in the delivery method of the treatments. As mentioned, current GLP-1 therapies on the market are once-weekly subcutaneous injections. Biotech and Pharmaceutical companies realize that not only are weekly injectables not favorable, but they aren’t the most convenient. 

One delivery method currently being explored is long-acting injectables. These monthly injections could improve patient adherence, but the injections would also have to show sustained efficacy and tolerability. If the formulation were effective without adverse events, this delivery method would be a significant advancement for the obesity market. 

Another delivery method being explored and becoming the more popular option is oral versions of GLP-1 drugs. If successful, this method would be a game-changer for patient convenience, but a lot has to happen for this to happen. Turning injectable peptides into effective oral formulations is challenging and a big undertaking. Many biotech and pharmaceuticals, though, are up for the challenge, and we may see the first oral GLP-1 medicine approved by the FDA. 

Complete harmony

There have been great strides that have been made within the obesity market with GLP-1s. The research and development have certainly paved the way for this new era of weight loss therapies. As scientists and researchers figure out the right balance of GLP-1 to glucagon ratio and a better drug delivery method, we are beginning to turn the page for the many individuals suffering from obesity. Making treatments more tolerable, cost-effective, and accessible will give individuals the ability to lose weight without the burden of severe side effects, ultimately enabling them to maintain a healthier lifestyle.

Photo: Peter Dazeley, Getty Images

Mr. Hyung Heon Kim is the Chief Executive Officer and President of MetaVia and has served on its Board since July 2021. Before this role, he was General Counsel and Senior Vice President at Dong-A ST and Dong-A Socio Group, a Korean pharmaceutical and medical device conglomerate. From 2018 to 2020, he was Executive Director of Dong-A ST and previously led International Legal Affairs at Dong-A Socio Holdings. Since April 2021, he has also served as a director at AnaPath Services GmbH, a Swiss-based R&D services provider. Earlier in his career, Mr. Kim was legal counsel to SK Energy Co., Ltd. and SK Innovation Co., Ltd. He holds a Bachelor of Law degree from Soongshil University in Korea and a Juris Doctor from Washington University School of Law.

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