Fat Loss Without Muscle Loss: Can These Next-Gen Weight-Loss Therapies Become Blockbuster Drugs?

▎Edited by the WuXi AppTec content team

Recently, Eli Lilly and Company's glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor dual agonistZepbound(Tirzepatide) Receives U.S. FDA Approval to Help Obese or Overweight Adult Patients Control Weight. In clinical trials, it canReduce patient weight by more than 20%With the success of Eli Lilly and Company's Zepbound and Novo Nordisk's Wegovy (semaglutide) in safely and effectively reducing weight, the development of weight-loss drugs has become one of the hotspots for industry investment. According to statistics from the industry media STAT, there are currently about70 Weight Loss Therapies Enter Clinical Development Stage.Among these new-generation weight-loss therapies, besides those targeting gut hormones that have already been clinically validated,Therapies that preserve muscle mass while promoting weight loss are gaining increasing attention.

Image Source: 123RF

The Impact and Potential Risks of Weight Loss Therapy on Health

The already approved weight-loss therapies Wegovy and Zepbound have demonstrated breakthrough results in reducing body weight. Moreover, clinical trial results from Novo Nordisk show,Semaglutide not only reduces body weight, but alsoSignificantly reduce patients' heart failure symptoms

Since obesity is associated with various cardiovascular and metabolic diseases, treatments targeting obesity have the potential to reduce the risk of multiple diseases.

However, as Wegovy and Zepbound are being more widely used in the weight loss field, their potential risks are also gaining more attention. An article recently published in the academic journal *Nature* pointed out that studies show,In addition to gastrointestinal reactions, the potential side effects of GLP-1 receptor agonists also include muscle tissue loss, which is a concern in the industry.

Regeneron Chief Scientific Officer Dr. George Yancopoulos in an interview with industry media EndpointsInterview

He said that currently, weight-loss drugs mainly work by making people stop eating to lose weight. Patients lose not only fat but also muscle. Many people, after reaching their desired weight loss level, stop taking the medication because they don't like it, and then their weight rebounds. However, when they lose weight, they lose both fat and muscle, and when the weight rebounds, they only regain fat. So, they have to start losing weight again. If you cycle through weight loss attempts, it will slowly change your body composition, replacing muscle with fat.

In this context, the new generation of weight loss therapies focuses not only on enhancing weight reduction efficacy and patient convenience but also on minimizing potential side effects and preserving muscle mass. Encouragingly, several therapies under investigation have already shown promising results in reducing fat without muscle loss and have entered clinical development stages.

Innovative Mechanism of Fat Reduction Without Muscle Loss

Eli Lilly and Company, which has multiple approved and investigational weight-loss therapies, recently announced that it will invest up to approximately $1.9 billion.Acquisition of Versanis

, acquiring its investigational therapy bimagrumab. Bimagrumab is a potential "first-in-class" monoclonal antibody targeting activin receptor type 2 (ActRII). ActRII is an activin receptor expressed in both fat and muscle cells. Activation of ActRII receptor signaling can lead to muscle atrophy and accumulation of fat in adipose tissue; thus, targeting this pathway has the potential to drive fat loss while increasing muscle composition in patients. In a 48-week Phase 2 clinical trial involving overweight or obese patients with type 2 diabetes, compared to placebo, bimagrumab resulted in approximately a 22% reduction in fat mass and a 4.5% increase in lean body mass.

Eli Lilly and Company is expected to launch clinical trials next year to evaluate the potential of bimagrumab in combination with other weight-loss therapies to reduce body weight while preserving muscle tissue.

Biohaven's R&D PipelineTaldefgrobep alfa is a myostatin antagonist and activin type 1 receptor inhibitor.Myostatin is a natural protein that restricts the growth of skeletal muscle. Myostatin inhibitors are expected to serve as a therapeutic strategy to enhance muscle mass and strength in patients. Biohaven initially developed taldefgrobep alfa for the treatment of spinal muscular atrophy.However, in healthy volunteers, it also showed the effect of reducing fat while increasing muscle mass.

▲Taldefgrobep alfa increases muscle mass while reducing intramuscular fat (Image source:

Biohaven Official Website)

The company is currently conducting a proof-of-concept clinical trial to evaluate the efficacy of taldefgrobep alfa in obese and overweight populations.

Rivus Pharmaceuticals' Investigational TherapyHU6 is a type of Controlled Metabolic Accelerator (CMAs)., an innovative approach that activates mitochondrial uncoupling to a limited extent. Mitochondrial uncoupling is a natural process by which the body regulates and expends energy. By transporting protons out of the mitochondrial membrane gap,CMAs can increase the oxidation of sugar and fat while maintaining the production level of adenosine triphosphate (ATP) unchanged. Activation of this process leads to a reduction in fat accumulation and prevents additional systemic fat buildup.

▲CMAs can increase the oxidation of sugar and fat while maintaining ATP production levels unchanged (Image source: Rivus official website)

Already publishedPhase 2a Clinical TrialThe results showed that, in obese participants with elevated liver fat levels, after 8 weeks of treatment,HU6 significantly reduced liver, abdominal, and total body fat in participants while preserving skeletal muscle mass, leading to notable weight loss.Recently, the company announced that the first patient has been randomized in the Phase 2b clinical trial of HU6. This randomized, double-blind, placebo-controlled clinical trial will evaluate the effects of HU6 in approximately 280 obese patients with type 2 diabetes.

Veru's Pipeline TherapiesEnobosarm is a selective androgen receptor modulator (SARM) that, by activating androgen receptors, has the effects of increasing muscle mass and physical function, stimulating lipolysis, and inhibiting adipogenesis.The company plans to launch a Phase 2b clinical trial to evaluate the effect of enobosarm in combination with semaglutide or tirzepatide on weight loss while preserving muscle mass.

▲Mechanism of Action of Enobosarm in Reducing Fat and Improving Muscle and Bone Mass (Image Source:

Veru Official Website）

BioAge Labs' Potential "First-in-Class" TherapyBGE-105 (azelaprag) is an apelin receptor agonist. Apelin is a peptide secreted during exercise that regulates metabolism and promotes muscle regeneration through its interactions with skeletal muscle, the heart, and the central nervous system.Phase 1 clinical trial results showed that, in healthy elderly individuals over 65 years old who require strict bed rest,BGE-105 Significantly Prevents Muscle Atrophy and Maintains Muscle Protein SynthesisThe company has announced a collaboration with Eli Lilly to initiate a Phase 2 clinical trial evaluating the efficacy of BGE-105 in combination with tirzepatide for the treatment of obesity.

Regeneron's Chief Scientific Officer, Dr. George Yancopoulos, also pointed out in an interview,Combining GLP-1 receptor agonists with muscle-protecting biologics can lead to greater weight loss, but almost entirely through fat reduction, which would represent a substantial advancement in weight-loss therapies.

One of the Highlights of Biomedical Innovation in 2023

Recently, the renowned venture capital firm Atlas Venture pointed out in its 2023 retrospective report that,In the future, obesity may become the most prevalent indication. Moreover, treating obesity can save substantial resources for global public health by reducing the risks of multiple related cardiovascular and metabolic diseases.In the company's annual review, the development of the obesity R&D pipeline was one of the highlights of innovation in the pharmaceutical field in 2023, including not only multiple therapies targeting mechanisms of action that have already been validated, but alsoMany drugs target emerging mechanisms of action, including CB1,GPR75、GPR40、TAS2R, D5D, MOGAT2 andINHBEInnovative targets such as.

We look forward to the continuous prosperity of research in the field of obesity, which can change society's cognitive bias towards obesity, enabling us to better understand and support those who are striving hard in the difficult battle of losing weight. At the same time, we also hope for more breakthroughs in the development of corresponding therapies, providing more treatment options for obese patients who truly need drug assistance.

.data_color_scheme_dark{--weui-ORANGERED: #ff6146;--weui-BG-0: #111;--weui-BG-1: #1e1e1e;--weui-BG-2: #191919;--weui-BG-3: #202020;--weui-BG-4: #404040;--weui-BG-5: #2c2c2c;--weui-FG-0: rgba(255, 255, 255, .8);--weui-FG-HALF: rgba(255, 255, 255, .6);--weui-FG-1: rgba(255, 255, 255, .5);--weui-FG-2: rgba(255, 255, 255, .3);--weui-FG-3: rgba(255, 255, 255, .1);--weui-FG-4: rgba(255, 255, 255, .15);--weui-FG-5: rgba(255, 255, 255, .1);--weui-RED: #fa5151;--weui-REDORANGE: #ff6146;--weui-ORANGE: #c87d2f;--weui-YELLOW: #cc9c00;--weui-GREEN: #74a800;--weui-LIGHTGREEN: #3eb575;--weui-BRAND: #07c160;--weui-BLUE: #10aeff;--weui-INDIGO: #1196ff;--weui-PURPLE: #8183ff;--weui-WHITE: rgba(255, 255, 255, .8);--weui-LINK: #7d90a9;--weui-TEXTGREEN: #259c5c;--weui-FG: #fff;--weui-BG: #000;--weui-TAG-TEXT-RED: rgba(250, 81, 81, .6);--weui-TAG-BACKGROUND-RED: rgba(250, 81, 81, .1);--weui-TAG-TEXT-ORANGE: rgba(250, 157, 59, .6);--weui-TAG-BACKGROUND-ORANGE: rgba(250, 157, 59, .1);--weui-TAG-TEXT-GREEN: rgba(6, 174, 86, .6);--weui-TAG-BACKGROUND-GREEN: rgba(6, 174, 86, .1);--weui-TAG-TEXT-BLUE: rgba(16, 174, 255, .6);--weui-TAG-BACKGROUND-BLUE: rgba(16, 174, 255, .1);--weui-TAG-TEXT-BLACK: rgba(255, 255, 255, .5);--weui-TAG-BACKGROUND-BLACK: rgba(255, 255, 255, .05)}.data_color_scheme_dark{--weui-BTN-ACTIVE-MASK: rgba(255, 255, 255, .1)}.data_color_scheme_dark{--weui-BTN-DEFAULT-ACTIVE-BG: rgba(255, 255, 255, .126)}.data_color_scheme_dark{--weui-DIALOG-LINE-COLOR: rgba(255, 255, 255, .1)}.data_color_scheme_dark{--weui-BG-COLOR-ACTIVE: #373737}.data_color_scheme_dark{--weui-BG-6: rgba(255, 255, 255, .1);--weui-ACTIVE-MASK: rgba(255, 255, 255, .1)}.rich_media_content{color:#000000e5;font-size:17px;font-size:var(--articleFontsize);overflow:hidden;text-align:justify}.rich_media_content{color:#ffffffa6;color:var(--weui-FG-HALF)}.rich_media_content{position:relative;z-index:0}.wxw-img{vertical-align:bottom}.rich_media_content p{clear:both;min-height:1em}td p{margin:0;padding:0}a{color:#576b95;text-decoration:none;-webkit-tap-highlight-color:#0000}a{color:#7d90a9;color:var(--weui-LINK)}a,button{cursor:pointer}:root{--articleFontsize: 17px}:root{--sab: env(safe-area-inset-bottom)}:root{--wxBorderAvatarRatio: 3}:root{--discussPageGap: 16px}:root{--appmsgPageGap: 20px}body,.wx-root,page{--weui-BTN-HEIGHT: 48;--weui-BTN-HEIGHT-MEDIUM: 40;--weui-BTN-HEIGHT-SMALL: 32}.wx-root,body{--weui-BTN-ACTIVE-MASK: rgba(0, 0, 0, .1)}.wx-root,body{--weui-BTN-DEFAULT-ACTIVE-BG: #e6e6e6}.wx-root,body{--weui-DIALOG-LINE-COLOR: rgba(0, 0, 0, .1)}.wx-root,body{--weui-BG-COLOR-ACTIVE: #ececec}body,.wx-root{--weui-FG-1: rgba(0, 0, 0, .55);--weui-ORANGERED: #ff6146;--weui-BG-0: #ededed;--weui-BG-1: #f7f7f7;--weui-BG-2: #fff;--weui-BG-3: #f7f7f7;--weui-BG-4: #4c4c4c;--weui-BG-5: #fff;--weui-FG-0: rgba(0, 0, 0, .9);--weui-FG-HALF: rgba(0, 0, 0, .9);--weui-FG-1: rgba(0, 0, 0, .5);--weui-FG-2: rgba(0, 0, 0, .3);--weui-FG-3: rgba(0, 0, 0, .1);--weui-FG-4: rgba(0, 0, 0, .15);--weui-FG-5: rgba(0, 0, 0, .05);--weui-RED: #fa5151;--weui-REDORANGE: #ff6146;--weui-ORANGE: #fa9d3b;--weui-YELLOW: #ffc300;--weui-GREEN: #91d300;--weui-LIGHTGREEN: #95ec69;--weui-BRAND: #07c160;--weui-BLUE: #10aeff;--weui-INDIGO: #1485ee;--weui-PURPLE: #6467f0;--weui-WHITE: #fff;--weui-LINK: #576b95;--weui-TEXTGREEN: #06ae56;--weui-FG: #000;--weui-BG: #fff;--weui-TAG-TEXT-RED: rgba(250, 81, 81, .6);--weui-TAG-BACKGROUND-RED: rgba(250, 81, 81, .1);--weui-TAG-TEXT-ORANGE: #fa9d3b;--weui-TAG-BACKGROUND-ORANGE: rgba(250, 157, 59, .1);--weui-TAG-TEXT-GREEN: #06ae56;--weui-TAG-BACKGROUND-GREEN: rgba(6, 174, 86, .1);--weui-TAG-TEXT-BLUE: #10aeff;--weui-TAG-BACKGROUND-BLUE: rgba(16, 174, 255, .1);--weui-TAG-TEXT-BLACK: rgba(0, 0, 0, .5);--weui-TAG-BACKGROUND-BLACK: rgba(0, 0, 0, .05)}body,.wx-root{--weui-BG-6: rgba(0, 0, 0, .05);--weui-ACTIVE-MASK: rgba(0, 0, 0, .05)}@media(prefers-color-scheme:dark){.wx-root:not([data-weui-theme=light]),body:not([data-weui-theme=light]){--weui-ORANGERED: #ff6146;--weui-BG-0: #111;--weui-BG-1: #1e1e1e;--weui-BG-2: #191919;--weui-BG-3: #202020;--weui-BG-4: #404040;--weui-BG-5: #2c2c2c;--weui-FG-0: rgba(255, 255, 255, .8);--weui-FG-HALF: rgba(255, 255, 255, .6);--weui-FG-1: rgba(255, 255, 255, .5);--weui-FG-2: rgba(255, 255, 255, .3);--weui-FG-3: rgba(255, 255, 255, .1);--weui-FG-4: rgba(255, 255, 255, .15);--weui-FG-5: rgba(255, 255, 255, .1);--weui-RED: #fa5151;--weui-REDORANGE: #ff6146;--weui-ORANGE: #c87d2f;--weui-YELLOW: #cc9c00;--weui-GREEN: #74a800;--weui-LIGHTGREEN: #3eb575;--weui-BRAND: #07c160;--weui-BLUE: #10aeff;--weui-INDIGO: #1196ff;--weui-PURPLE: #8183ff;--weui-WHITE: rgba(255, 255, 255, .8);--weui-LINK: #7d90a9;--weui-TEXTGREEN: #259c5c;--weui-FG: #fff;--weui-BG: #000;--weui-TAG-TEXT-RED: rgba(250, 81, 81, .6);--weui-TAG-BACKGROUND-RED: rgba(250, 81, 81, .1);--weui-TAG-TEXT-ORANGE: rgba(250, 157, 59, .6);--weui-TAG-BACKGROUND-ORANGE: rgba(250, 157, 59, .1);--weui-TAG-TEXT-GREEN: rgba(6, 174, 86, .6);--weui-TAG-BACKGROUND-GREEN: rgba(6, 174, 86, .1);--weui-TAG-TEXT-BLUE: rgba(16, 174, 255, .6);--weui-TAG-BACKGROUND-BLUE: rgba(16, 174, 255, .1);--weui-TAG-TEXT-BLACK: rgba(255, 255, 255, .5);--weui-TAG-BACKGROUND-BLACK: rgba(255, 255, 255, .05)}}@media(prefers-color-scheme:dark){.wx-root:not([data-weui-theme=light]),body:not([data-weui-theme=light]){--weui-BTN-ACTIVE-MASK: rgba(255, 255, 255, .1)}}@media(prefers-color-scheme:dark){.wx-root:not([data-weui-theme=light]),body:not([data-weui-theme=light]){--weui-BTN-DEFAULT-ACTIVE-BG: rgba(255, 255, 255, .126)}}@media(prefers-color-scheme:dark){.wx-root:not([data-weui-theme=light]),body:not([data-weui-theme=light]){--weui-DIALOG-LINE-COLOR: rgba(255, 255, 255, .1)}}@media(prefers-color-scheme:dark){.wx-root:not([data-weui-theme=light]),body:not([data-weui-theme=light]){--weui-BG-COLOR-ACTIVE: #373737}}@media(prefers-color-scheme:dark){.wx-root:not([data-weui-theme=light]),body:not([data-weui-theme=light]){--weui-BG-6: rgba(255, 255, 255, .1);--weui-ACTIVE-MASK: rgba(255, 255, 255, .1)}}@media(prefers-color-scheme:dark){body:not([data-weui-theme=light]).appmsg_skin_default.rich_media_empty_extra{background-color:#191919}}@media(prefers-color-scheme:dark){body:not([data-weui-theme=light]).my_comment_empty_data{background-color:#111}}h1,h2,h3,h4,h5,h6{font-weight:400;font-size:16px}@media(prefers-color-scheme:dark){body:not([data-weui-theme=light]) .rich_media_content img:not(.wx_img_placeholder){filter:brightness(.8)}}*{margin:0;padding:0}.rich_media_content *{max-width:100%!important;box-sizing:border-box!important;-webkit-box-sizing:border-box!important;word-wrap:break-word!important}