New hormone-based therapies poised to expand obesity treatment options
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SAN DIEGO — Multiple new anti-obesity medications currently in the pipeline could expand treatment options for the disease in the coming years, according to a speaker at ObesityWeek 2022.
Ania M. Jastreboff, MD, PhD, associate professor of medicine and pediatrics (endocrinology) at Yale University School of Medicine, director of weight management and obesity prevention at the Yale Stress Center, and co-director of the Yale Center for Weight Management, described the FDA’s approval of semaglutide 2.4 mg (Wegovy, Novo Nordisk) in June 2021 — based on the large, sustained weight reduction seen in clinical trials — as an important milestone for obesity treatment.
Semaglutide is just the start, however, according to Jastreboff. A slew of new agents, most of which are nutrient-stimulated hormone-based therapies, are currently in development and could greatly expand the number of options available for obesity treatment in the near future, she said.
“In terms of moving beyond filling the treatment gap, what we really focused on over time is body weight reduction,” Jastreboff said during a presentation. “Clearly, these molecules are fulfilling that and even beyond, especially when used in combination [therapy], synergistically and with bariatric surgery. But when we think about treating obesity, we have to move beyond weight reduction. We have to focus on treating obesity.”
Semaglutide, tirzepatide paving the way
As Healio previously reported, semaglutide 2.4 mg was approved in June 2021 for chronic weight management in adults with obesity. The latest data on semaglutide revealed the agent can be a long-term therapy option for adults with obesity. In findings from the STEP 5 trial, participants receiving semaglutide maintained a 16.7% loss in body weight at 2 years. The next data expected on semaglutide will be cardiovascular outcomes in the SELECT trial, which is scheduled to be completed in September 2023, Jastreboff said.
Tirzepatide (Mounjaro, Eli Lilly) may soon join semaglutide as a therapy for treating obesity. As Healio previously reported, tirzepatide, a dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonist, was approved by the FDA for treatment of type 2 diabetes in adults in May. While the agent is not yet approved for treating obesity, the FDA granted tirzepatide a fast track designation in October following findings from the SURPASS-1 clinical trial published in The New England Journal of Medicine in July. In the trial, participants taking the highest dose of 15 mg tirzepatide had a 22.5% reduction in body weight, and nearly 40% of participants in the highest dose group lost 25% or more body weight.
Next steps will be to examine findings from the phase 3 SURMOUNT-2 clinical trial of adults with type 2 diabetes and obesity, which could be available in April. FDA approval could potentially come shortly after the SURMOUNT-2 results are released, according to Jastreboff.
New therapies in the pipeline
Cagrilintide (Novo Nordisk), an amylin analogue, is another agent currently in the pipeline for obesity treatment. In findings from a phase 2 trial published in 2021, adults receiving the highest dose of 4.5 mg cagrilintide for 26 weeks had a 10.6% reduction in body weight.
An even greater reduction in body weight was observed when cagrilintide was combined with semaglutide. In findings from a phase 1b trial, adults receiving 2.4 mg cagrilintide combined with 2.4 mg semaglutide once weekly had a 17.1% reduction in body weight at 20 weeks. Combination cagrilintide and semaglutide will be compared with the two agents alone in the REDEFINE 1 trial, which is scheduled to begin this month. The trial will analyze weight change in adults with obesity over 68 weeks. In addition, the REDEFINE 2 trial, scheduled to begin in 2023, will analyze the effect of combined cagrilintide and semaglutide in adults with obesity and type 2 diabetes.
Several other drugs in the pipeline are currently in phase 2 trials, including the glucagon/GLP-1 receptor agonists pemvidutide (Altimmune) and BI 456906 (Boehringer Ingelheim); a triple GIP/glucagon/GLP-1 receptor agonist retatrutide (Eli Lilly), and two oral GLP-1 receptor agonists, danuglipron (Pfizer) and LY-3502970 (Eli Lilly). A third oral option is an oral form of semaglutide, which is currently in a phase 3 trial.
Jastreboff noted there are options beyond nutrient-stimulated hormone-based therapies, such as bimagrumab (Novartis), a monoclonal antibody infusion that blocks activin type II receptors. In a study published in JAMA Network Open in 2021, adults who received bimagrumab every 4 weeks for 48 weeks lost 20.5% of fat mass and gained 3.6% in lean mass.
Moving forward
There are plenty of promising therapies on the horizon for treating obesity, but clinicians must look beyond just reducing weight, Jastreboff said.
“We need to target the neurometabolic pathophysiology of obesity,” Jastreboff said. “We need to target different mechanisms, focusing on the heterogeneity of response and knowing there are different types of obesity and that they will respond differently to therapies. We need to individualize combination therapies to target different mechanisms, combining various anti-obesity medications as well as metabolic bariatric surgery.”
Additionally, Jastreboff said the quality of weight reduction must be a focus moving forward, with a greater emphasis on preserving and increasing lean mass. Above all, she said, access and affordability to anti-obesity medications must be a priority.
References:
- Garvey WT, et al. Nat Med. 2022;doi:10.1038/s41591-022-02026-4.
- Heymsfield SB, et al. JAMA Netw Open. 2021;doi:10.1001/jamanetworkopen.2020.33457.
- Jastreboff AM, et al. N Engl J Med. 2022;doi:10.1056/NEJMoa2206038.
- Lau DCW, et al. Lancet. 2021;doi:10.1016/S0140-6736(21)01751-7.
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Jastreboff AM. New developments in anti-obesity pharmacotherapy. Presented at: ObesityWeek; Nov. 1-4, 2022; San Diego.
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