Apitegromab targets lean mass loss during tirzepatide trial

apitegromab for – A randomized, double-blind phase 2 trial, EMBRAZE (NCT06445075), is testing whether apitegromab can help preserve lean body mass in adults taking tirzepatide. The study spans seven U.S. sites, uses DEXA scans as its primary measure at 24 weeks, tracks safety i

On day 1, after a 4-week screening period and written informed consent, participants in EMBRAZE were handed a choice that would be hidden from everyone but one pharmacist.

They either received apitegromab plus tirzepatide or a placebo plus tirzepatide. Apitegromab and placebo were administered intravenously, while tirzepatide was trained to be self-administered weekly using an injection pen. After that first dose. tirzepatide was increased by 2.5 mg every 4 weeks. up to a maximum maintenance dose of 15 mg per week—depending on treatment response and tolerability—over 24 weeks. Then came a 16-week safety period when study treatments were not administered.

The trial is designed around a single, urgent concern: weight loss treatments can reduce more than fat. The study’s primary endpoint measures whether apitegromab can slow the loss of lean body mass during tirzepatide-induced weight loss.

EMBRAZE is a randomized. double-blind. placebo-controlled phase 2 trial conducted at seven sites across the United States: ProSciento CRU in Chula Vista. California; AdventHealth Translational Research Institute in Orlando. Florida; Great Lakes Clinical Trials. LLC. dba Flourish Research in Chicago. Illinois; Tandem Clinical Research GI. LLC in Marrero. Louisiana; Alliance for Multispecialty Research. LLC in Norman. Oklahoma; Apex Mobile Clinical Research in Bellaire. Texas; and Clinical Trials of Texas. LLC. dba Flourish Research in San Antonio. Texas.

The protocol was approved by Advarra, a central institutional review board (IRB), along with IRBs at the participating sites. The trial adhered to the Declaration of Helsinki and Good Clinical Practice guidelines. Before the first participant was enrolled. the study protocol was amended from version 1 to version 2 to add tirzepatide as an incretin mimetic therapy and to designate adverse events of special interest: pancreatitis. liver injury. depression/suicidality. and creatine kinase elevations.

Participants were adults aged 18 to 65. To enter the study. they had to meet one of two eligibility tracks: either a BMI of at least 27.0 but less than 30.0 kg/m−2 with at least one weight-related comorbid condition. or a BMI of 30.0 to 45.0 kg/m−2. They also needed stable body weight within ±5 kg during the 90 days before screening and at least one self-reported unsuccessful dietary effort to lose weight.

Women of childbearing potential were required to have a negative pregnancy test and agree to use adequate birth control throughout trial participation. Everyone had to adhere to the study visit schedule and follow prespecified prohibitions and restrictions listed in the study protocol.

The trial excluded a long list of conditions—especially those that could make safety riskier or outcomes harder to interpret. People with a history of or active cardiovascular disease were ineligible. including clinically significant arrhythmias. congestive heart failure classified as New York Heart Association grades I−IV. mild. moderate or severe coronary artery disease or a history of angina. uncontrolled hyperlipidemia. myocardial infarction. stroke. coronary artery bypass graft surgery or percutaneous coronary intervention. valve disorders or defects. abdominal aortic aneurysm. or pulmonary hypertension.

They were also excluded for uncontrolled hypertension. defined using American Heart Association stage 1 or stage 2. plus a history of hypertensive crisis or treatment-resistant hypertension. Additional exclusions covered history of or active ischemic. hemorrhagic or anatomical neurovascular disease such as transient ischemic attack. cerebrovascular accident. arteriovenous malformation or brain aneurysm; peripheral vascular disease such as deep vein thrombosis/pulmonary embolism. chronic venous insufficiency. claudication or lymphedema; and active pulmonary disease including chronic obstructive pulmonary disease. pulmonary fibrosis. moderate-to-severe sleep apnea and moderate-to-severe asthma.

Beyond that. individuals with hepatic. pancreatic. neuromuscular and/or psychiatric disease were ineligible. as were those with active malignancy (except local subcutaneous squamous cell and basal cell carcinomas) or a history of immunosuppressive. chemotherapeutic or radiation treatment within 12 months prior to screening. People with a history of type 1 or type 2 diabetes were excluded. while type 2 diabetes resolved for more than 12 months and prediabetes managed with lifestyle and diet were not exclusions.

The study also ruled out participants with a history of gastroparesis; gastric or peptic ulcer; active gastritis or esophagitis; uncontrolled gastroesophageal reflux disease; or severe inflammatory bowel disease. Other exclusions included uncontrolled thyroid disease. severe endocrine disorders such as Cushing’s disease. hypogonadism and growth hormone deficiency. autoimmune or inflammatory disorders that may cause muscle wasting such as myasthenia gravis. rheumatoid arthritis. lupus. polymyositis or dermatomyositis. and neuromuscular disorders that may cause muscle wasting such as muscular dystrophy. spinal muscular atrophy or amyotrophic lateral sclerosis.

Neurologic diseases such as epilepsy, dementia, Parkinson’s disease or Bell’s palsy were also disqualifiers. So were acute or chronic pancreatitis (or being at high risk for pancreatitis). clinically significant abnormal lipase and/or amylase. taking medications that may cause serious damage to the pancreas such as valproic acid. history of or active acute or chronic liver disease. uncontrolled psychiatric disease. severe coagulopathy. and chronic kidney disease stages 1−5. Active infection—or treatment of infection within 6 months prior to screening—also excluded enrollment.

People could not have undergone bariatric surgery or used gastric balloons or other gastric volume reduction devices. The trial also excluded those who donated or lost at least 500 ml (1 pint) of blood within 8 weeks prior to screening or donated plasma of at least 600 ml within 14 days prior to screening.

Anyone with a history of apitegromab treatment was ineligible. Medication-related exclusions included using antiobesity medications. nutritional supplements or over-the-counter products for weight loss within 3 months prior to screening; using antidiabetic medications. nutritional supplements or over-the-counter products for lowering blood sugar within 3 months prior to screening; and using medications known to induce weight gain within 3 months prior to screening.

The protocol also prohibited therapies with potentially significant muscle effects—including androgens. insulin-like growth factor. growth hormone. systemic beta-agonists. neurotoxins or muscle relaxants or muscle-enhancing supplements—within 3 months prior to screening. Systemic corticosteroids within 60 days before screening were excluded. and intraarticular corticosteroid injections were excluded as well (while inhaled or topical steroids were allowed). Medications that impede coagulation or platelet aggregation were also prohibited.

History of alcoholism or illicit drug use or the use of inhaled vasoconstrictive tobacco or cannabis or synthetic products—such as vape pens, pipes, cigars and cigarettes—was prohibited.

Even if someone met the medical criteria on paper. they could still be excluded if they had contraindications to study treatment or. in the investigator’s opinion. any other medical condition. clinically significant laboratory result or electrocardiogram findings that might compromise safety or compliance. preclude successful study completion. or interfere with interpreting results.

Before randomization, baseline characteristics were collected through standard assessments and a complete physical examination. Demographic information such as age, sex, race and ethnicity was self-reported by participants.

Sex was not used in the study design, but it was used as a covariate in data analysis as described in the statistical methods section. A post hoc subgroup analysis of the primary endpoint by sex was also planned on an exploratory basis.

All participants received standard care counseling on lifestyle recommendations including diet, physical activity and behavior modification. Reporting on these variables was not mandated or monitored.

Randomization happened in a 1:1 ratio via an interactive web response system managed by an independent vendor. without blocking or stratification factors. The site pharmacist remained unblinded for the duration of the trial. while the sponsor. participants. investigators and site personnel—except the pharmacist—were blinded to assignments. DEXA scans were performed and assessed by blinded personnel. and statistical analyses were planned prior to unblinding at the end of the treatment period.

The primary endpoint looks at change from baseline in lean body mass at 24 weeks, assessed by whole-body DEXA scans. Participants in the apitegromab group are compared with those receiving tirzepatide alone. Each DEXA scan includes bilateral arms, bilateral legs and trunk, including the body organs. Cross-calibration between DEXA systems was not warranted.

Secondary endpoints include change from baseline in body weight, total fat mass, and DEXA parameters on body composition at week 24. Body weight was obtained using a calibrated scale in a fasted state at each visit from screening through the last trial visit.

For DEXA-based primary and secondary endpoints, scans were taken within 7 days prior to participants’ initial dose of apitegromab or placebo and repeated at 24 weeks.

Exploratory endpoints extend beyond that point: change from baseline in DEXA measurements at week 32; physical function using force production with handheld dynamometry and the number of repetitions in the chair sit-to-stand test at weeks 24 and 32; and cardiometabolic markers such as hemoglobin A1C (HbA1C) at weeks 24 and 32.

Pharmacokinetics and pharmacodynamics were assessed through the treatment and safety follow-up periods. Apitegromab and tirzepatide trough samples were collected every 4 weeks during the treatment period and during safety follow-up visits. and end-of-infusion samples of apitegromab were collected on day 1. week 12 and week 20. Trough concentrations of latent myostatin were collected through 24 weeks and during the safety follow-up period.

Safety outcomes tracked adverse events. clinical laboratory tests. vital signs. electrocardiogram measurements and psychiatric evaluations reported through the last study visit. Data were reviewed throughout the study in a blinded manner by medical monitors and the sponsor to ensure participant safety. The presence of serum ADAs against apitegromab was also assessed. Safety data were collected through week 40.

The trial’s statistical plan defines the primary efficacy population as all randomized participants who completed treatment and had evaluable DEXA lean body mass data at baseline and at the scheduled week 24 visit—designated as the completer population in the statistical analysis plan. Most efficacy analyses were repeated on the ITT population (all randomized participants) and the modified ITT population (all randomized participants with evaluable baseline and one postbaseline lean body mass measurement. regardless of timing). Safety analyses included all dosed participants, and pharmacokinetics/pharmacodynamics analyses included all participants with quantifiable data.

Analyses were conducted using SAS version 9.4 software. All efficacy, safety and pharmacokinetics/pharmacodynamics endpoints were summarized descriptively by treatment group. Least square means with 80% CIs and the difference between groups in change from baseline at week 24 in lean body mass were estimated using a linear regression model controlling for baseline weight. baseline lean body mass. age and sex. The same regression model was used for changes in other DEXA parameters and change in weight.

A two-sided significance level of 0.20 was selected for this phase 2 study, and all P values are nominal with no adjustment for multiplicity, meaning the confidence intervals should be interpreted in that context.

The sample size was planned assuming a standard deviation of 4.6 kg. With 43 participants per study arm (evaluable). the study was set to yield about 75% power to detect an effect size of 2 kg for the primary lean body mass change at week 24. Anticipating about 13% might not be evaluable, the total planned enrollment was 50 participants per arm.

There was one key treatment detail embedded in the trial’s structure: no participants received semaglutide as a treatment assignment due to lack of drug availability at the time the EMBRAZE study initiation began, a situation that lasted throughout the study duration.

Within the protocol. concomitant therapies or interventional procedures medically indicated as part of standard supportive care were allowed at the discretion of the investigator. Antiobesity medications. antidiabetic medications or medications associated with serious risk to the pancreas (including valproic acid and diuretics). and therapies with potentially significant muscle anabolic or catabolic effects or weight gain were prohibited.

EMBRAZE was planned with multiple layers of monitoring and controlled conditions. Baseline and DEXA assessments were controlled through blinded personnel. randomization used an interactive web response system without blocking or stratification factors. and statistical analyses were planned prior to unblinding.

In the tight space between weight loss and preserved strength. the trial’s design makes one question central: can apitegromab help protect lean body mass while people take tirzepatide?. The study answers that question in numbers—lean mass measured by whole-body DEXA scans at week 24. backed by safety tracking through week 40—while tightening the safety net around specific risks including pancreatitis. liver injury. depression/suicidality and creatine kinase elevations.

apitegromab tirzepatide lean body mass DEXA phase 2 trial EMBRAZE NCT06445075 randomized double-blind placebo-controlled muscle preservation safety follow-up