Mazdutide for Weight Management and Gout in Adults With Obesity

Study Background and Rationale Gout is the most common form of inflammatory arthritis, and its prevalence is rising in parallel with the global obesity epidemic. Obesity is a major risk factor for gout, contributing to hyperuricemia through increased uric acid production and decreased renal excretion. While urate-lowering therapy (ULT) is the cornerstone of gout management, achieving target serum uric acid (SUA) levels and reducing flare frequency remains challenging in obese patients. Mazdutide is a novel, long-acting dual Glucagon-like Peptide-1 Receptor (GLP-1R) and Glucagon Receptor (GCGR) agonist. By simultaneously reducing energy intake and increasing energy expenditure, Mazdutide has demonstrated significant potential for weight reduction and metabolic improvement. This study is designed to investigate whether Mazdutide can reduce the frequency of gout flares in obese patients by addressing the underlying metabolic drivers of the disease.

Study Design and Objectives This is a single-arm, open-label, pre-post controlled exploratory clinical study. The primary objective is to evaluate the effect of 52 weeks of Mazdutide treatment on the Annualized Flare Rate (AFR) in adults with obesity and gout, by comparing it to the AFR in the 12 months prior to treatment. Each subject serves as their own control.

Secondary objectives include:

• Assessing the change in serum uric acid (SUA) levels and the proportion of subjects achieving the target SUA level (<6.0 mg/dL).
• Evaluating the time to the first gout flare during the treatment period.
• Measuring the change in body weight and the proportion of subjects achieving ≥5% and ≥10% weight loss.
• Analyzing changes in metabolic and inflammatory markers, including HbA1c, lipids, eGFR, IL-6, TNF-α, and hsCRP.
• Assessing health-related quality of life using the EQ-5D-5L questionnaire and pain using the Numerical Rating Scale (NRS).
• Evaluating the safety and tolerability of Mazdutide in this patient population. Study Population and Eligibility Criteria

The study will enroll 30 subjects who meet all of the following key criteria:

• Age and Gender: Male and female subjects aged 18 to 65 years (inclusive).
• Obesity Definition: Subjects must have a Body Mass Index (BMI) ≥ 30.0 kg/m².
• Gout Diagnosis: A confirmed diagnosis of gout based on the 2015 ACR/EULAR classification criteria.
• Disease Activity: Subjects must have a history of at least 2 gout flares in the past 6 months prior to screening.
• Background Therapy: Subjects must be on a stable dose of Urate-Lowering Therapy (ULT) for at least 8 weeks prior to enrollment, or have discontinued ULT for at least 8 weeks.

Intervention and Study Procedures All enrolled subjects will receive Mazdutide via subcutaneous injection once weekly for 52 weeks, followed by an 8-week follow-up period after discontinuation. The total study duration for each participant is 64 weeks.

The dosing regimen involves a stepwise escalation to improve tolerability:

Weeks 1-4: 2 mg once weekly. Weeks 5-8: 4 mg once weekly (if tolerated). Weeks 9-12: 6 mg once weekly (if tolerated). Weeks 13-52: 9 mg once weekly (if tolerated).

The dose may be adjusted or maintained at a lower level (e.g., 6 mg or 4 mg) based on individual tolerability, weight, and uric acid levels.

Subjects will attend regular study visits for safety and efficacy assessments. These visits include physical examinations, vital signs measurement, laboratory tests (hematology, biochemistry, lipids, SUA), and recording of any gout flares or adverse events. Gout flares will be defined and adjudicated according to a standardized protocol.

Statistical Analysis The primary endpoint, Annualized Flare Rate (AFR), will be analyzed by comparing the rate during the 52-week treatment period to the rate in the 12 months prior to treatment. A negative binomial regression model will be used to estimate the rate ratio and its 95% confidence interval. Secondary endpoints will be analyzed using appropriate statistical methods, such as mixed-effects models for repeated measures (MMRM) for continuous variables like SUA and body weight, and Kaplan-Meier analysis for time-to-event data.

Inclusion criteria

• Informed consent is obtained before trial entry, and the subject fully understands the trial content, procedures, and potential adverse reactions; able to complete the study according to the protocol requirements.
• Subjects (including male subjects) have no plans for pregnancy, sperm donation, or egg donation from 14 days before screening until 3 months after trial completion, and voluntarily agree to use effective contraception.
• Aged 18 to 65 years (inclusive), male or female.
• Obesity: BMI ≥ 30.0 kg/m².
• Diagnosis of gout according to the 2015 ACR/EULAR classification criteria for gout, confirmed by the investigator; at least 2 gout flares in the past 6 months with supporting medical records/prescription documentation.
• Subjects must have been on a stable dose of urate-lowering therapy (ULT) for at least 8 weeks prior to enrollment: allowed agents include allopurinol, febuxostat, or other oral ULTs recognized by local guidelines; dose unchanged in the past 8 weeks; or discontinued ULT in the past 8 weeks; not taking colchicine for gout flare prophylaxis.
• Body weight change < 5% in the past 6 months controlled by diet and exercise alone.
• HbA1c ≤ 10.0%; background antidiabetic medications allowed: metformin, stable-dose insulin, sulfonylureas (SUs), SGLT2 inhibitors; prohibited: GLP-1 receptor agonists, DPP-4 inhibitors; background medications must be stable for ≥ 8 weeks prior to enrollment.
• Subjects have received standardized gout management or healthy lifestyle education for ≥ 6 months prior to enrollment, including but not limited to urate-lowering therapy, dietary modification, alcohol control, weight management, and gout-related behavioral interventions. These management measures have been stable for at least 2 months prior to enrollment without significant off-protocol changes. Subjects agree to maintain their previous lifestyle and disease management habits during the study, without actively changing dietary patterns, alcohol intake, exercise intensity, or other factors that may affect gout flares, unless deemed medically necessary by the investigator.

Exclusion criteria

• 1. Persistent or significant lifestyle changes in the 6 months prior to enrollment, including substantial adjustment in alcohol consumption, extreme dietary pattern changes, initiation or discontinuation of systemic urate-lowering therapy, initiation or discontinuation of diuretics/uricosuric agents, etc. If the investigator determines that such changes may have a clinically meaningful impact on gout flares or uric acid levels, the subject will be excluded.

• Average daily smoking ≥ 5 cigarettes in the 3 months prior to screening, or inability to stop using any tobacco products during the trial.

• History of specific allergies (asthma, urticaria, eczema, etc.), allergic constitution, or allergy to GLP-1/GCG dual receptor agonists and excipients. Subjects judged unsuitable for enrollment due to allergy to the study drug or its excipients. Subjects who participated in other clinical trial drug studies within 3 months prior to enrollment and are judged unsuitable by the investigator.

• History of heavy alcohol use and unwillingness to abstain from alcohol throughout the study period: > 14 units of alcohol per week (1 unit ≈ 10 mL alcohol, approximately 285 mL beer at 3.5%, 25 mL spirits at 40%, or 100 mL wine at 10%).

• Body weight change > 5.0% (self-reported) in the 12 weeks prior to screening controlled by diet and exercise alone.

• ULT dose adjustment within 8 weeks prior to screening, or expected need for ULT adjustment during the study. Acute gout flare within 2 weeks prior to enrollment. Inability to maintain stable ULT dose during the study.

7.Medication History:

• Use of any clinical trial drug within 3 months prior to enrollment.
• Use of other urate-lowering or uric acid-affecting drugs (e.g., lesinurad) within 2 weeks prior to randomization, or inability to discontinue other urate-lowering or uric acid-affecting drugs during the study.
• Use of aspirin > 325 mg daily within 2 weeks prior to enrollment, or unstable aspirin dosing, or expected use during the study.
• Use of any diuretics within 2 weeks prior to enrollment, or expected use during the study.
• Unstable dosing of medications for comorbid conditions within 4 weeks prior to enrollment, or expected adjustment of treatment regimen during the study.
• Use of any other prescription drugs, over-the-counter drugs, traditional Chinese medicine, or health supplements within 1 week prior to enrollment or within 5 drug half-lives (whichever is longer).
• Use of drugs or treatments that may cause significant weight gain or loss within 3 months:

• Corticosteroids (short-term use < 7 days or topical, inhaled, intraocular, or intranasal administration excluded);

• Tricyclic antidepressants, atypical antipsychotics, and mood stabilizers (e.g., imipramine, chlorpromazine, amitriptyline, mirtazapine, clozapine, olanzapine, paroxetine, phenelzine, thioridazine, valproic acid and derivatives, lithium);

• Orlistat, GLP-1 receptor agonists, or other weight-loss treatments beyond diet and exercise (e.g., weight-loss teas, traditional Chinese medicine weight-loss products, acupuncture for weight loss);

• Other drugs or treatments that may significantly affect weight or uric acid (e.g., SGLT2 inhibitors). If SGLT2 inhibitors are used, dose adjustment must not exceed the stable dose at enrollment.

• Patients with secondary hyperuricemia (e.g., due to renal disease, hematologic malignancy, chemotherapy, or drug-induced) or history of idiopathic uricaciduria (e.g., Lesch-Nyhan syndrome, phosphoribosylpyrophosphate (PRPP) synthetase hyperactivity, familial juvenile hyperuricemic nephropathy, congenital hereditary hyperuricemia); or history of xanthinuria.

• Past and Current Medical History - any of the following will exclude:

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• Other joint diseases that may confound gouty arthritis diagnosis, such as rheumatoid arthritis, septic arthritis, traumatic arthritis, psoriatic arthritis, etc.
• History of malignant tumors (regardless of cure status).
• Active infection at screening, serious infection requiring IV antimicrobial therapy or hospitalization within 12 weeks prior to randomization, or any infection requiring oral antibiotic therapy within 2 weeks prior to randomization.
• Gastrointestinal dysfunction such as peptic ulcer, irritable bowel syndrome, inflammatory bowel disease; history of conditions affecting gastric emptying (e.g., gastric bypass, pyloric stenosis), or prior gastrointestinal surgery (except procedures with minimal effect on GI motility such as polypectomy, appendectomy, and hemorrhoid surgery); history of acute or chronic pancreatitis; history of acute cholecystitis or symptomatic/requiring-treatment chronic cholecystitis or gallstones (subjects with prior cholecystectomy may be enrolled if judged suitable by the investigator); history of chronic malabsorption syndrome or cholestasis.
• Major surgery within 3 months prior to randomization, bariatric surgery (except liposuction > 1 year prior); planned surgery during the study.
• Myocardial infarction, unstable angina, percutaneous coronary intervention, coronary artery bypass grafting, stroke, intracerebral hemorrhage, subarachnoid hemorrhage, or transient ischemic attack within 12 months prior to randomization.
• Unstable hypertension within 1 month prior to screening, defined as: systolic BP ≥ 160 mmHg and/or diastolic BP ≥ 100 mmHg (if on antihypertensive medication, must be stable for 1 month).
• Other unstable cardiovascular, hepatic, renal, gastrointestinal, immune, hematologic, endocrine, metabolic, psychiatric, and/or psychological conditions that may affect study participation.
• Blood donation (or blood loss) ≥ 400 mL within 3 months prior to randomization, or receipt of blood transfusion.
• Endocrine diseases or history that may significantly affect weight (e.g., Cushing's syndrome, hypothyroidism or hyperthyroidism), except hypothyroidism if thyroid hormone replacement dose has been stable for at least 3 months.

• History of severe hypoglycemia or recurrent symptomatic hypoglycemia (≥ 2 episodes in 6 months); secondary obesity due to disease or medication, including: elevated cortisol (e.g., Cushing's syndrome), obesity due to pituitary and hypothalamic injury, obesity due to weight-loss drug withdrawal/discontinuation; history of or screening evidence of retinopathy; history of or screening evidence of malignant tumors (except cured skin basal cell carcinoma and cervical carcinoma in situ).

• Clinically significant 12-lead ECG abnormalities at screening: second- or third-degree atrioventricular block, long QT syndrome, or QTcF > 450 ms in males or > 470 ms in females; left or right bundle branch block, pre-excitation syndrome, or other clinically significant arrhythmias (sinus arrhythmia excluded); or heart rate < 50 bpm or > 100 bpm.

• Any screening laboratory abnormality meeting the following criteria (re-measurement within one week allowed if clinically justified, with documentation): serum calcitonin ≥ 20 ng/L (pg/mL); ALT ≥ 3.0 × ULN and/or AST ≥ 3.0 × ULN and/or total bilirubin ≥ 1.5 × ULN; eGFR < 60 mL/min/1.73 m²; thyroid dysfunction (TSH > 6 mIU/L or < 0.4 mIU/L); fasting triglycerides ≥ 5.64 mmol/L (500 mg/dL); serum amylase or lipase > 2.0 × ULN; INR above the upper limit of normal range; hemoglobin < 110 g/L (males) or < 100 g/L (females).

• Use of any of the following within 3 months prior to screening: GLP-1 receptor agonists, GLP-1R/GCGR agonists, GIPR/GLP-1R agonists, or GIPR/GLP-1R/GCGR agonists; drugs affecting weight, including systemic corticosteroids (IV, oral, or intra-articular), tricyclic antidepressants, psychotropic or sedative medications (e.g., imipramine, amitriptyline, mirtazapine, paroxetine, phenelzine, chlorpromazine, thioridazine, clozapine, olanzapine, valproic acid, valproic acid derivatives, lithium); weight-affecting traditional Chinese medicines, health supplements, meal replacements; past or current use of weight-loss medications such as sibutramine, orlistat, phentermine, phenylpropanolamine, fenfluramine, phendimetrazine, bupropion, lorcaserin, phentermine/topiramate combination, naltrexone/bupropion combination; use of any alcohol-containing products within 48 hours prior to dosing, or positive alcohol screening.

• Positive hepatitis B surface antigen, positive hepatitis C antibody, positive HIV antibody, or positive syphilis screening.

• Positive drug abuse screening, history of drug abuse within the past 5 years, or drug use within 3 months prior to the trial.

• Pregnant or lactating females, or positive pregnancy test. 17. Subjects unable to participate for their own reasons. 18. Any other factors, in the investigator's judgment, that may affect the efficacy or safety evaluation of this study and render the subject unsuitable for participation.