The next generation of weight loss drugs is rapidly approaching

The next generation of weight loss drugs is rapidly approaching

Published: Nov 20, 2023

By Amanda Heidt


The burgeoning weight loss industry, currently led by Novo Nordisk and Eli Lilly, looks set to grow in the near future to include earlier-stage contenders like AstraZeneca and Pfizer, making it one of the industry’s most aggressively expanding spaces.  

Last month, Novo Holdings CEO Kasim Kutay cited estimates that Novo’s Wegovy (active ingredient semaglutide) and similar drugs could generate returns exceeding $12 billion in coming years, while other analysts have placed the total global market at as high as $200 billion within the next decade.

“You can’t overstate the demand for these drugs, and there’s still a lot of room to grow,” said Jon Wolleben, a senior research analyst at JMP Securities who focuses on biotechnology. Roughly three-quarters of American adults are classified as obese or overweight, and the desire for weight loss products has far outstripped their supply. As manufacturing capabilities inevitably catch up and new players enter the space, “This could become the largest therapeutic class of drugs that the biopharma industry has ever seen,” Wolleben told BioSpace.

The success of offerings like Novo’s Ozempic and Wegovy or Lilly’s Mounjaro and newly approved Zepbound (active ingredient tirzepatide) may seem sudden, but they are, in fact, based on drugs developed throughout the 1970s and 80s as treatments for diabetes. Early iterations included glucose-dependent insulinotropic polypeptide (GIP) agonists that regulated insulin by stimulating its production in the body, followed later by dual agonists that also targeted glucagon-like peptide-1 (GLP-1) receptors. Together, the two work synergistically to improve glycemic control and induce weight loss. Semaglutide is a GLP-1 agonist, while tirzepatide combines both GIP and GLP-1 into a single peptide.

Allison Schneider, Novo’s director of media relations, told BioSpace that the reinvigorated interest in weight management and popularity of these drugs reflects not only technological advances but an evolving understanding that “obesity impairs health and requires long-term, holistic approaches to care and treatment.” Based on their success, she noted that there is plenty of territory left to explore.

The Next Generation

Moving forward, those companies looking to stake a claim in the therapeutic weight loss market—or to retain their competitive edge—are approaching drug development from three angles: layering on additional targets, interrogating new ways of delivery and refining their formulas to either dampen unwanted side effects or boost potential protective effects.

Lilly’s next candidate, retatrutide, leverages a “triple G” approach that binds and activates the GIP, GLP-1 and glucagon receptors. Together, the three receptors regulate insulin, decrease appetite and increase thermogenesis, and results for a mid-stage trial of the candidate showed that patients achieved weight loss of up to 24.2% after 48 weeks of treatment—the most compelling results yet reported for any weight loss drug. Earlier in the summer, Lilly also demonstrated that retatrutide induced an 86% decrease in liver fat over 48 weeks among 98 patients with nonalcoholic fatty liver disease.

“We have here the making of a new class of medicines, and there’s a lot to celebrate,” said Richard DiMarchi, a molecular biologist at Indiana University who previously spent decades at Eli Lilly overseeing endocrine research, including with glucagon, which he continues to pursue in his academic position. “We’re now achieving things that virtually no one thought were possible—weight loss that previously required surgical procedures.”

Among the next challenges will be shifting away from peptide-based injections toward something like an oral pill based on small molecule technology, which DiMarchi said will be cheaper to manufacture, driving down costs and improving accessibility. “What we hear today is patients vastly prefer a once-a-day pill,” he said. Wollenben agreed, noting, “I think you’re going to see more investment in the small molecule space,” with a goal of attaining similar efficacy.

AstraZeneca recently signed an exclusive license agreement with Eccogene, a China-based biotech developing a daily, oral GLP-1 agonist. Following an up-front payment of $185 million, Eccogene stands to net up to an additional $1.83 billion if the candidate hits future clinical, regulatory and commercial milestones. The molecule, called ECC5004, is currently being tested in a Phase I trial and has returned “promising” preliminary data, Sharon Barr, Astra’s executive vice president of biopharmaceuticals R&D, said in a statement at the time of the announcement.

Pfizer has taken a similar approach, partnering with the Japanese biopharmaceutical company Sosei Heptares on a small molecule–based oral GLP-1 agonist, PF-06954522, which is currently in Phase I trials. The candidate was discovered by Pfizer using Sosei Heptares’ proprietary stabilized receptor (StaR) technology.

Successful—But Not Satisfied

Hoping to push into new territory, Novo and Lilly have begun snapping up products and smaller companies with promising candidates to address the unwanted side effects of their drugs and bolster the medications’ other potential health benefits. In July, Lilly paid up to $1.9 billion to acquire Versanis and its lead asset, bimagrumab, a monoclonal antibody that aims to reduce fat without affecting muscle mass—a common complaint among patients taking semaglutide. Bimagrumab works by preventing proteins from binding to receptors that inhibit muscle growth and encourage fat mass to build. The candidate is currently being studied in combination with semaglutide to see if the pair can preserve or increase muscle mass concurrent with weight loss. In another study published this summer, an oral semaglutide formula was found to avoid the loss of muscle mass. 

For its part, Novo recently purchased the small molecule ocedurenone from KBP Biosciences for a potential $1.3 billion to advance its cardiovascular portfolio, which is increasingly being dovetailed with weight loss objectives. At the American Heart Association’s annual conference, held this month in Philadelphia, Novo presented early data showing that Wegovy led to a 20% risk reduction in major adverse cardiovascular events.

“If the clinical data bear out and these [next candidates] get approved, these are going to be drugs that almost everyone who’s obese can go on, and it’s going to be a really nice microcosm of drug development impacting health and how the system should work,” Wolleben said. “It’s going to be great for investors, for patients and for companies, so it’s going to be really fun to watch.”

Source: BioSpace