Study Overview
A new phase 2 clinical trial, called EMBRAZE, has demonstrated that the investigational drug apitegromab can significantly preserve lean body mass in adults with overweight or obesity who are taking tirzepatide for weight loss. The findings, published in Nature Medicine, address a growing concern with incretin mimetic therapies: the loss of lean mass in proportion to total weight loss, which may adversely affect health and physical function.
Background: The Problem of Lean Mass Loss
Tirzepatide, a dual GIP and GLP-1 receptor agonist, is highly effective for weight reduction. However, like other incretin-based therapies, it leads to a reduction in lean mass that accounts for about 20-40% of total weight loss. This loss of muscle and other lean tissue can potentially impair metabolic health, physical performance, and quality of life, especially in older adults or those with sarcopenia. Preserving lean mass during weight loss is therefore a critical therapeutic goal.
How Apitegromab Works
Apitegromab is a fully human monoclonal antibody that selectively inhibits the activation of myostatin, a protein that naturally limits muscle growth. By blocking myostatin, apitegromab promotes an increase in muscle mass. It is currently under investigation for conditions associated with muscle loss, such as spinal muscular atrophy. The EMBRAZE study is the first to test its potential in the context of pharmacologically induced weight loss.
Trial Design and Participants
The EMBRAZE study was a randomized, double-blind, placebo-controlled phase 2 trial. It enrolled 102 adults with overweight or obesity (body mass index ≥27 kg/m²). Participants were randomized 1:1 to receive tirzepatide plus either apitegromab (at a dose of 10 mg per kg of body weight) or a placebo. The treatment period lasted 24 weeks. The primary endpoint was the change in lean body mass, measured by dual-energy X-ray absorptiometry (DXA).
Key Results
At week 24, the group receiving apitegromab lost significantly less lean mass compared to the placebo group. The least square mean difference in lean mass loss was 1.9 kg (80% confidence interval: 1.2 to 2.7 kg; P = 0.001), representing a 54.9% retention of lean mass relative to placebo. Importantly, total body weight loss was similar between the two groups, indicating that apitegromab specifically preserved lean tissue without blunting overall weight reduction.
Pharmacodynamic analysis showed that trough concentrations of apitegromab and total latent myostatin, a marker of target engagement, increased over time and reached a plateau after approximately 16 weeks, consistent with sustained myostatin inhibition.
Safety and Tolerability
The incidence of adverse events was generally similar between groups: 76% (39 of 51) in the apitegromab group and 71% (36 of 51) in the placebo group. Serious adverse events occurred in one participant (2%) in each arm. The safety profile was considered acceptable, supporting further development.
Implications and Next Steps
These proof-of-concept results suggest that selective myostatin inhibition with apitegromab could be a valuable adjunct to incretin-based weight loss therapies, helping to preserve muscle mass and potentially improve body composition outcomes. Larger and longer-term studies are needed to confirm these findings, assess functional benefits, and evaluate the impact on health outcomes such as physical performance and metabolic health.
The study was registered at ClinicalTrials.gov under identifier NCT06445075. The authors note that while the results are promising, the sample size was modest, and the trial duration was relatively short. Future research should explore optimal dosing, combination regimens, and effects in diverse populations.
Conclusion
The EMBRAZE study provides the first clinical evidence that adding a myostatin inhibitor to tirzepatide can significantly reduce lean mass loss during weight loss. This approach could address a key limitation of current obesity pharmacotherapy, potentially leading to healthier weight loss with preserved muscle function.
This article is based on reporting by Nature Medicine. Read the original article.
Originally published on nature.com
