Semaglutide Injection Once‐Weekly for Weight Management in Adults: Results From A Randomized Phase III, Active‐Controlled Study

ABSTRACT

Aim

To evaluate and compare the efficacy, safety, and immunogenicity of a synthetic semaglutide injection (Test semaglutide) with Wegovy (Reference semaglutide) injection for weight management.

Materials and Methods

This randomized, Phase III, non‐inferiority study included adults with obesity or overweight with or without comorbidities from 21 centers in India. A total of 270 patients with body mass index ≥ 30 kg/m² or ≥ 27 kg/m² with the presence of at least one of the weight‐related comorbidities (hypertension, dyslipidemia or type 2 diabetes mellitus) were randomized (2:1) to receive either Test semaglutide (N = 177) or Reference semaglutide injection (N = 90) once weekly with dose escalation from 0.25 to 2.4 mg. The primary endpoint was percentage change in bodyweight from baseline to Week 24.

Results

Out of 267 randomized patients, 246 completed the study. At Week 24, mean percent weight change from baseline was −13.8% ± 4.28% in Test and −14.1% ± 4.11% in Reference groups with least‐squares mean difference of 0.26% (95% CI: −0.86% to 1.39%), meeting the criterion for non‐inferiority. The proportion of patients with ≥ 5% and ≥ 10% weight loss were 96.40% and 80.60% in Test, and 98.80% and 80.00% in Reference groups, respectively at Week 24. Improvements in body mass index, waist circumference, SF‐36 total score, and glycemic parameters were comparable between groups. Treatment‐emergent adverse events were reported in 72.30% and 76.70% in the Test and Reference groups, respectively, with gastrointestinal events being the most common.

Conclusions

Test synthetic semaglutide was found to be non‐inferior to Reference semaglutide in weight management with or without comorbidities.

Trial Registration

Prospectively registered on the Clinical Trials Registry—India, CTRI/2025/04/085487 [Registered on: 24/04/2025], https://ctri.nic.in/Clinicaltrials/pmaindet2.php?EncHid=MTIwNjMx&Enc=&userName=

1. Introduction

Overweight and obesity represent major global public health challenges, with a rising prevalence and a substantial burden of associated metabolic, cardiovascular, and psychosocial comorbidities [1, 2]. Excess adiposity is linked to type 2 diabetes mellitus (T2DM), dyslipidemia, hypertension, and cardiovascular disease [1, 2, 3].

Globally, the prevalence of overweight and obesity has increased markedly, with an estimated 1 billion men and 1.11 billion women living with overweight or obesity in 2021. China accounted for the largest number of affected adults, followed by India [4].

Consequently, several clinical guidelines and published literature recommend the use of pharmacotherapy as an adjunct to lifestyle intervention in individuals with a body mass index (BMI) ≥ 30 kg/m², or BMI ≥ 27 kg/m² in the presence of adiposity‐related complications. Semaglutide 2.4 mg administered once weekly has emerged as a recommended option to manage overweight and obesity [5, 6, 7, 8, 9, 10, 11, 12].

Semaglutide, a long‐acting glucagon‐like peptide‐1 (GLP‐1) receptor agonist, promotes weight loss through multiple mechanisms, including appetite suppression, delayed gastric emptying, and reduced energy intake [13]. Across global clinical trials, semaglutide demonstrated robust and sustained reductions in bodyweight and favorable effects on cardiometabolic risk factors [14, 15, 16, 17]. In addition, semaglutide also improves glycemic control in individuals with T2DM without increasing the risk of hypoglycemia, and reduces the risk of major adverse cardiovascular events in patients with established atherosclerotic cardiovascular disease [5, 18, 19, 20, 21, 22, 23, 24].

Individuals with overweight and obesity often exhibit heterogeneous metabolic profiles, particularly with respect to the presence or absence of diabetes, which may influence treatment response, safety, and clinical outcomes [14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25]. Comprehensive evaluation of weight loss efficacy, glycemic parameters, anthropometric measures and patient‐reported outcomes across these subgroups is therefore clinically important. As wider access to semaglutide remains a key need in obesity management, generic and cost‐effective formulations may improve treatment availability [26]. In this context, demonstration of non‐inferiority in weight reduction between formulations, alongside comparable safety and tolerability, is essential to establish therapeutic efficacy and support routine clinical use.

In addition, although the efficacy and safety of semaglutide for weight management have been well established in global clinical development programs, there remains a need for region‐specific evidence in the Indian population [14, 15, 16, 17].

We developed a synthetic Test formulation of semaglutide and conducted a single‐dose crossover bioequivalence study versus the Reference semaglutide. In this study, the ratios of least‐squares geometric means (90% confidence interval [CI]) of Test to Reference product were 96.83% (94.01–99.75) for AUC_0‐t , 96.73% (94.03–99.52) for AUC_0‐∞, and 95.24% (91.31–99.34) for C _max, confirming bioequivalence of the Test and Reference semaglutide formulations. Although the Test formulation cannot be classified as a biosimilar because it is manufactured by chemical synthesis rather than recombinant DNA (rDNA) technology, extensive analytical characterization supports its comparability to Reference semaglutide. Side‐by‐side comparative analyses, including ultra‐high‐performance liquid chromatography high‐resolution mass spectrometry (UPLC‐HRMS) peptide mapping (Glu‐C and chymotrypsin digestion) with full sequence coverage and < 10 ppm mass accuracy, confirmed identical primary molecular structure and fatty‐acid modification. Orthogonal physicochemical testing, in vitro bioassays, bioequivalence studies, and the Phase III clinical trial further demonstrated equivalence in potency, impurity profiles, therapeutic outcomes, and immunogenicity signals. These findings are fully consistent with the United States Food and Drug Administration principles for highly purified synthetic peptides referencing rDNA‐origin drugs and European Medicines Agency principles for the development and manufacture of synthetic peptides, while preserving full therapeutic interchangeability. The synthetic route eliminates recombinant process contaminants (e.g., host‐cell proteins, residual DNA, and endotoxins), which must be rigorously cleared and monitored in classical recombinant manufacturing [27, 28].

Chemical synthesis of peptide (short protein) is a well‐established process that uses advanced technologies to produce the desired molecular structure with effective control of impurities. The technological advancements have led to a continuous process with efficient couplings, washing, and temperature control, which eventually results in low consumption of amino acids, reagents, and solvents, making it viable for large‐scale production of semaglutide [29, 30, 31, 32].

Although recombinant manufacturing may offer media‐cost advantages at very large production scales, the synthetic route provides comparable product quality with well‐controlled peptide‐related impurities and impurity profiles that are free from biological contaminants [31, 32]. Furthermore, generic semaglutide offers a substantially more cost‐effective alternative to the originator product, regardless of the manufacturing route, thereby enhancing overall treatment affordability.

The present Phase III, randomized study was therefore designed to evaluate the efficacy and safety of synthetic‐origin Test semaglutide injection, a potentially more cost‐effective alternative, compared with Reference semaglutide injection for weight management in Indian adults who are obese or overweight.

2. Materials and Methods

2.1. Study Design

This randomized, open‐label, multicenter, parallel‐group, active‐controlled Phase III study was conducted across 21 centers in India to evaluate the efficacy, safety, and immunogenicity of Test semaglutide injection manufactured by Sun Pharmaceutical Industries Limited compared with Reference semaglutide injection (Wegovy) in patients with body mass index (BMI) ≥ 30 kg/m², or BMI of ≥ 27 kg/m² with at least one of the comorbidities, including hypertension, dyslipidemia and/or T2DM (CTRI/2025/04/085487).

The study included a screening period of up to 2 weeks, a 24‐week treatment period, and a post‐treatment safety follow‐up conducted at Week 28 (Figure 1). The study was conducted as per the principles of the Declaration of Helsinki [33, 34], International Council for Harmonization Good Clinical Practice guidelines [35], and other applicable regional regulatory requirements [36, 37]. Each participating center received approval from respective institutional ethics committee, and all patients provided written informed consent before screening.

FIGURE 1.

Flowchart of the study.

2.2. Study Population

Eligible patients were adults aged 18–65 years with a BMI ≥ 30 kg/m² or BMI ≥ 27 kg/m² with at least one weight‐related comorbidity, including hypertension, dyslipidemia, or T2DM. Patients were also required to have a history of at least one self‐reported unsuccessful dietary effort to lose bodyweight. Patients with T2DM at screening had specific eligibility requirements, including a T2DM diagnosis that had been at least 180 days before screening; a stable treatment with metformin, sulfonylurea, or metformin plus sulfonylurea for at least 90 days before screening, along with diet and exercise control; and glycated haemoglobin (HbA1c) 7.0%–10.0% at screening.

Key exclusion criteria were type 1 diabetes mellitus; prior exposure to semaglutide; treatment with any GLP‐1 receptor agonist within 180 days before screening; a self‐reported bodyweight change > 5 kg within 90 days before screening; use of pharmacological treatments for obesity or other medications known to affect bodyweight (except oral contraceptives) within 90 days before screening; a history of bariatric surgery or weight‐loss devices unless such interventions had been completed and reversed > 1 year before screening. Participants with clinically significant endocrine or metabolic disorders, including uncontrolled thyroid disease, a history or presence of pancreatitis, elevated calcitonin levels, or a personal or first‐degree family history of multiple endocrine neoplasia type 2 or medullary thyroid carcinoma, were excluded. Individuals with a history or current severe psychiatric disorders, including major depressive disorder within 2 years before screening; history of suicidal behavior or ideation within 30 days before screening; or a history of suicide attempt were also ineligible. Additional exclusions were clinically significant renal or hepatic impairment, recent major cardiovascular events or symptomatic heart failure, HbA1c levels ≥ 6.5% in patients without diabetes, and history or current uncontrolled diabetic retinopathy or maculopathy in patients with diabetes.

2.3. Randomization and Treatment

A computer‐generated randomization sequence was created by the statistician. Eligible participants were enrolled by investigators and randomized in a 2:1 ratio through an interactive web response system to receive Test or Reference for a treatment period of 24 weeks. Randomization was stratified by the presence of diabetes and baseline BMI category (27 to < 35 kg/m² and ≥ 35 kg/m²). Participants received a total of 24 once‐weekly subcutaneous injections administered in the abdomen, thigh, or upper arm, starting at 0.25 mg, with stepwise dose escalation to a target maintenance dose of 2.4 mg by Week 16 (0.25 weekly for 4 weeks, followed by 0.5 weekly for 4 weeks, followed by 0.75 weekly for 4 weeks, followed by 1.7 weekly for 4 weeks). If dose reduction was required, the previous lower dose was continued until symptoms were resolved. Patients received maintenance dose of 2.4 mg for 8 weeks. For diabetic patients taking sulfonylurea to mitigate the risk of hypoglycemia, sulfonylurea doses were allowed to be reduced by 50% at randomization as per investigator discretion.

The study was designed as open‐label considering the objective primary endpoint. The study drug was self‐administered at home, with on‐site administration and training provided during scheduled visits. All participants received standardized lifestyle intervention, including dietary counselling targeting an approximately 500 kcal/day caloric deficit from calculated total energy expenditure (TEE) and encouragement of at least 150 min of physical activity per week, with adherence monitored using patient diaries reviewed at each visit.

2.4. Efficacy Assessments

The primary efficacy endpoint was the percentage change in bodyweight from baseline to Week 24. Secondary efficacy endpoints included the proportion of patients having bodyweight reduction of ≥ 5% and ≥ 10%, and changes from baseline in BMI, waist circumference, and 36‐item short form health survey (SF‐36) total score. Percentage changes in bodyweight from baseline at timepoints earlier than 24 weeks were also evaluated as secondary endpoints.

Other secondary efficacy assessments were changes from baseline in HbA1c, fasting blood glucose (FBG), and postprandial blood glucose (PPBG) evaluated by subgrouping patients with and without diabetes. FBG and PPBG analyses were based on samples collected at scheduled site visits for all participants. Fasting samples were obtained after a minimum 8‐h overnight fast, and PPBG was measured 2 h following a meal. Waist‐to‐height ratio was also analyzed as additional efficacy analysis.

2.5. Safety and Immunogenicity Assessments

Safety assessments were performed throughout the study and included monitoring of treatment‐emergent adverse events (TEAEs). Adverse events (AEs) were coded using the Medical Dictionary for Regulatory Activities (MedDRA) version 28.0 and assessed for severity and relationship.

Immunogenicity was evaluated using validated assays to assess the proportion of patients with anti‐drug antibodies (ADA) and neutralizing antibodies (Nab) at baseline and at Week 24.

2.6. Statistical Analysis

Guidelines define 5%–10% weight loss as clinically important. Therefore, we have kept the non‐inferiority margin to below this minimum clinically important difference. Assuming a non‐inferiority margin of 4.5%, standard deviation of 11, power of 80% and a level of significance of 2.5% (one‐sided) and a randomization ratio of 2:1 (Test: Reference), the study required 213 (Test 142; Reference 71) patients. Allowing for 20% dropout, the total sample size was 267 (Test 178; Reference 89) [38].

Baseline characteristics were assessed in the intention‐to‐treat (ITT) population (all randomized patients); per‐protocol (PP) population was used as the primary efficacy population (patients who completed the study without major protocol deviations), and safety analyses included all participants who received at least 1 dose. Protocol deviations were reviewed by the investigator and sponsor's medical monitor and were classified as major or minor based on impact analysis prior to database lock, and patients with major protocol deviations were excluded from the PP population.

The efficacy analysis results were also analyzed in the ITT population, as supporting evidence.

The primary analysis used a mixed model for repeated measures (MMRM) with percentage change in bodyweight as the dependent variable and treatment, visit, treatment‐by‐visit interaction, and stratification factors as fixed effects, with baseline bodyweight as a covariate. Least‐squares means, standard errors, 95% CIs, and p‐values for treatment differences (Test minus Reference) were reported. Model parameters were estimated using restricted maximum likelihood with Kenward‐Roger degrees of freedom and an unstructured covariance matrix; alternative covariance structures were applied if required. Baseline comparisons were performed using a two‐sample t‐test. Non‐inferiority was concluded if the upper bound of the two‐sided 95% confidence interval for the treatment difference was below the prespecified margin of 4.5%. Missing primary endpoint data were handled using multiple imputation, with sensitivity analyses conducted using MMRM. Within‐group changes were assessed using repeated‐measures analysis of variance.

Continuous secondary endpoints were summarized descriptively and analyzed using MMRM with the same model specification as the primary analysis; within‐group changes were assessed using repeated‐measures analysis of covariance. Categorical variables were compared using Cochran‐Mantel‐Haenszel tests stratified by diabetes status and baseline BMI category, with corresponding 95% CIs.

In non‐diabetic participants, changes in glycemic parameters were analyzed using analysis of covariance adjusted for treatment, stratification factors, and baseline values.

Safety analyses summarized TEAEs coded using the medical dictionary for regulatory activities by system organ class and preferred term, severity, relationship, outcome and action taken, with incidences presented as counts and percentages. Laboratory parameters, vital signs and physical examination findings were summarized using descriptive statistics.

3. Results

A total of 319 patients were screened, of whom 267 were randomized to receive either the Test semaglutide or Reference semaglutide injection. Overall, 246 patients completed the study (Figure 2). The study was conducted between April 26, 2025, and November 19, 2025.

FIGURE 2.

Patient disposition. AE, adverse event; ITT, intention‐to‐treat; PP, per‐protocol; SAE, serious adverse event; †, one participant in the Reference arm who completed the study was excluded from the PP population due to a major protocol deviation, as the patient was incorrectly randomized. Patient did not have T2DM but was stratified to the T2DM population.

3.1. Baseline Demographic and Clinical Characteristics

Baseline demographic and clinical characteristics were comparable between the two treatment groups. Mean age, height, bodyweight, BMI and waist circumference were comparable between groups.

Among the 71 patients with diabetes mellitus included in this study, 58 were receiving metformin (500–1500 mg), 5 were receiving combination therapy with metformin and glimepiride, and 8 were receiving glimepiride monotherapy; a total of 10 patients with diabetes mellitus had co‐existing hypertension. At baseline, the median (IQR) duration of diabetes was comparable between the Test group and the Reference group (p = 0.5000) (Table 1).

TABLE 1.

Baseline demographics and clinical characteristics.

Parameters	Test semaglutide injection (N = 177)	Reference semaglutide injection (N = 90)	p a
Gender			0.3212
Male, n (%) b	92 (52.0%)	41 (45.6%)
Female, n (%) b	85 (48.0%)	49 (54.4%)
Age c , years	40.84 ± 10.04	42.57 ± 10.31	0.1896
Height c , cm	164.7 ± 9.50	162.7 ± 9.31	0.1063
Weight c , kg	93.82 ± 14.39	92.96 ± 14.37	0.6421
Body mass index c , kg/m2	34.56 ± 4.19	35.14 ± 4.67	0.3107
Waist circumference c , cm	112.6 ± 15.82	113.1 ± 15.23	0.7753
HbA1c c , %
Patients with T2DM	8.43 ± 0.75	8.36 ± 0.71	0.6971
Patients without T2DM	5.51 ± 0.47	5.50 ± 0.43	0.9083
Duration of diabetes, median (IQR), months	38.5 (8.3–37.3)	32.2 (8.2–37.4)	0.5000

Abbreviation: T2DM, Type 2 diabetes mellitus.

^a p‐values were computed using a two‐sample t‐test for continuous variables and the chi‐square test for categorical variables to assess differences between treatment groups.

^b n (%): n stands for number of patients, and percentages were computed using N provided in the column header.

^c Data presented as mean ± standard deviation.

3.2. Primary Efficacy Outcome

3.2.1. Percentage Change in Bodyweight From Baseline to Week 24

A comparable reduction in percentage change in bodyweight was observed between the Test and Reference groups at Week 24 (−13.8% ± 4.28% in Test and −14.1% ± 4.11% in Reference groups, p = 0.6421) in the PP population (Figure 3A). The changes from baseline in both groups at Week 24 were statistically significant (p < 0.0001 each). The estimated least‐squares mean difference (95% CI) between treatments was 0.26% (−0.86% to 1.39%). The upper bound of the CI was below the predefined non‐inferiority margin of 4.5%, thereby demonstrating non‐inferiority of the Test to the Reference semaglutide injection.

FIGURE 3.

Change in bodyweight (A) percentage change from baseline, (B) proportion of patients with ≥ 5% reduction from baseline, and (C) proportion of patients with ≥ 10% reduction from baseline.

Similar results were obtained in the ITT population, with a comparable reduction in percentage change in bodyweight observed between the Test and Reference groups at Week 24 (−13.6% ± 4.45% in Test and −13.7% ± 4.59% in Reference groups, p = 0.7417). The changes from baseline in both groups at Week 24 were statistically significant (p < 0.0001 each). The estimated least‐squares mean difference (95% CI) between treatments was 0.19% (−0.95% to 1.33%).

3.3. Secondary Efficacy Outcomes

3.3.1. Percentage Change in Bodyweight From Baseline to Weeks 4, 8, 12, 16 and 20

A comparable percentage change in bodyweight was observed between the Test and Reference groups at Weeks 4, 8, 12, 16, and 20 (p ≥ 0.05 each). The changes from baseline in both groups at all timepoints were statistically significant (p < 0.0001 each) (Figure 3A).

3.3.2. Proportion of Patients With Bodyweight Reduction ≥ 5% and ≥ 10% From Baseline to Weeks 4, 8, 12, 16, 20, and 24

The weight reduction by ≥ 5% and ≥ 10% results were comparable between the Test and Reference groups at Weeks 8, 12, 16, 20 and 24 (p ≥ 0.05 each) (Figure 3B), with almost 80.6% (in Test group) and 80.0% (in Reference group) achieving ≥ 10% weight loss (Figure 3C).

3.3.3. Changes in BMI and Waist Circumference From Baseline to Weeks 4, 8, 12, 16, 20, and 24

The changes from baseline in BMI and waist circumference in both groups at all timepoints were statistically significant at all visits (p < 0.0001 each) (Table 2). Comparable reductions in BMI and waist circumference were observed between the Test and Reference groups at these visits (p ≥ 0.05 each).

TABLE 2.

Change in body mass index, waist circumference, and SF‐36 total score from baseline.

Visits	Body mass index* (mean ± SD)			Waist circumference* (mean ± SD)			SF‐36 total score* (mean ± SD)
	Test	Reference	p	Test	Reference	p	Test	Reference	p
Week 4	−0.67 ± 0.42	−0.68 ± 0.50	0.9266	−1.68 ± 3.41	−2.44 ± 7.54	0.3383	3.12 ± 7.73	1.96 ± 3.72	0.2091
Week 8	−1.39 ± 0.64	−1.43 ± 0.66	0.8855	−3.08 ± 4.08	−3.81 ± 7.63	0.3887	7.32 ± 13.89	4.47 ± 11.83	0.0872
Week 12	−2.25 ± 0.83	−2.35 ± 0.86	0.5114	−5.15 ± 4.29	−5.73 ± 7.86	0.5244	9.93 ± 15.83	7.41 ± 13.07	0.1876
Week 16	−3.01 ± 1.01	−3.17 ± 1.17	0.3314	−6.84 ± 4.61	−7.48 ± 8.29	0.4961	15.68 ± 17.75	13.15 ± 19.30	0.2744
Week 20	−3.88 ± 1.28	−4.06 ± 1.43	0.3634	−8.91 ± 5.27	−9.57 ± 8.76	0.5264	19.35 ± 18.96	17.60 ± 20.51	0.4787
Week 24	−4.73 ± 1.45	−4.94 ± 1.53	0.3386	−10.7 ± 5.75	−11.6 ± 9.30	0.3946	23.73 ± 18.89	22.51 ± 21.10	0.6221

Note: *p < 0.05. A significant improvement from baseline at all visits in each parameter.

Abbreviations: Reference, Reference semaglutide injection (N = 80); SD, standard deviation; SF‐36, 36‐item short form health survey; Test, Test semaglutide injection (N = 165).

3.3.4. Change in SF‐36 Total Score From Baseline to Weeks 4, 8, 12, 16, 20 and 24

Quality of life is improved as assessed by changes in quality of life based on SF‐36 total score in both study groups as treatment is continued during the study and the results were comparable between the Test and Reference groups at all visits (p ≥ 0.05 each) (Table 2).

3.3.5. Changes in Glycemic Parameters in Patients With Diabetes and Without Diabetes

Significant reductions in HbA1c, FBG and PPBG were observed during the study in patients with diabetes in both groups, with comparable results within both study arms. However, the changes in glycemic parameters in non‐diabetic patients were not clinically significant (Appendix S1).

3.4. Other Outcomes

A comparable reduction in waist‐to‐height ratio was observed between the Test and Reference groups at Weeks 4, 8, 12, 16 and 20 (p ≥ 0.05 each). The changes from baseline in both groups at all timepoints were statistically significant (p < 0.0001 each) (Appendix S2).

3.5. Safety

A total of 289 TEAEs in 128 (72.3%) patients were reported in the Test group, and 192 TEAEs in 69 (76.7%) patients were reported in the Reference group. 59.9% TEAEs in the Test group and 71.1% TEAEs in the Reference group were related to the study drug. The most common TEAEs reported were vomiting (21.5%), followed by diarrhea (17.5%) and nausea (16.4%) in the Test group, and diarrhea (30.0%), followed by vomiting (22.2%) and nausea (21.1%) in the Reference group (Appendix S3). Most AEs were mild‐to‐moderate in severity, with only one severe AE (spinal osteoarthritis).

Three events, one event of spinal osteoarthritis in the Test group and one event each of gastritis and acute pancreatitis in the Reference group, were reported as SAE due to hospitalization. The SAE in the Test group was severe in intensity and was unrelated to the study drug, while the SAEs in the Reference group were of moderate intensity and were reported as probably related to the study drug. Of the 481 TEAEs, 477 TEAEs were reported as resolved by the investigators (286 in Test group and 191 in Reference group).

There was discontinuation of study drug in one patient in the Test group and 4 patients in the Reference group. TEAE leading to study drug discontinuation in the Test group was macular edema and TEAEs in the Reference group were one event of acute pancreatitis, two events of gastritis, and one event of gastroenteritis. All events resolved after discontinuation of study drug.

The study drug was interrupted in one patient in the Test group due to TEAE of nausea and vomiting. This patient missed one dose of the study drug, that is, the 1 mg dose at Week 9. Subsequently, the patient recovered from the event and could take the rest of the doses.

There were no clinically significant changes in laboratory parameters, including the serum calcitonin levels, during the study.

3.6. Immunogenicity

No patients in either treatment group were found to be positive for ADA at baseline or at Week 24. As no binding antibodies were detected, confirmatory Nab testing was not required.

4. Discussion

In this Phase III randomized study, Test synthetic semaglutide injection demonstrated clinically significant weight reduction and an acceptable safety profile that was comparable to the Reference semaglutide injection in adults with overweight or obesity, with or without comorbidities. The findings of the study support the non‐inferiority of Sun's Semaglutide compared to Wegovy in weight reduction when used in overweight or obesity. The efficacy of both the formulations used in the study is consistent with the established therapeutic effects of once‐weekly semaglutide reported across the global STEP clinical development program [14, 15, 16, 17, 39, 40].

Weight loss observed in this study was comparable to the results in STEP 1 and STEP 11 studies [41, 42]. The consistency of weight‐loss efficacy observed in the present trial reinforces the usefulness of semaglutide across populations.

STEP 6 study conducted in the Asian population included patients with comorbidities, including diabetes, wherein it was demonstrated that semaglutide produces substantial weight loss regardless of diabetes status, while additionally improving glycemic control in individuals with T2DM without increasing the risk of hypoglycemia in those without diabetes [14, 43]. The findings from the current study are consistent with these observations, supporting the broad applicability of semaglutide‐based therapy across metabolically diverse populations.

The change in HbA1c observed in the current study is also similar to changes observed in the STEP 2 study conducted in patients with diabetes with overweight or obesity [44].

Safety and tolerability outcomes in this trial were consistent with the established profile of GLP‐1 receptor agonists [11]. Gastrointestinal AEs, including nausea, vomiting, and diarrhea, were the most reported events and were mild to moderate in severity and transient in nature. About 57.3% of the AEs that occurred in the trial were gastrointestinal AEs. This mirrors AEs reported across STEP 1 to STEP 5 [15, 16, 17, 41, 44]. While no binding ADAs were detected during the study, thereby precluding the need for confirmatory Nab testing, the limited duration of exposure warrants cautious interpretation of the immunogenicity findings.

Importantly, the present study included patients with heterogeneous metabolic profiles, including individuals without any comorbidity or with comorbidities of diabetes, hypertension, and/or dyslipidemia. This is clinically relevant, as obesity frequently coexists with metabolic dysregulation, and treatment responses may differ across subgroups. While this heterogeneity enhances the clinical relevance of the study by reflecting real‐world populations, it may also introduce variability in treatment response that could attenuate the ability to detect subtle differences between the Test and Reference formulations. Variability in response to GLP‐1 receptor agonists, including semaglutide, across metabolic subgroups has been well documented [45]. Therefore, the inclusion of patients with and without obesity‐related comorbidities, while a strength from a generalizability perspective, may have reduced sensitivity for detecting small between‐group differences in a non‐inferiority setting.

Semaglutide has demonstrated favorable effects on cardiometabolic risk factors, including waist circumference, blood pressure, and glycemic indices, as well as cardiovascular outcomes in high‐risk populations. Prior large‐scale studies have shown reductions in major adverse cardiovascular events among individuals with established atherosclerotic cardiovascular disease, reinforcing the broader clinical value of semaglutide beyond weight loss alone [5, 18, 19, 20, 21, 22, 23, 24]. With Test synthetic semaglutide demonstrated comparable efficacy and safety indicate that similar clinical benefits may be anticipated to Reference semaglutide injection.

The need for region‐specific comparative evidence is important given known differences in metabolic risk profiles and treatment response across Asian and non‐Asian populations [14, 46]. The present study adds to this growing body of evidence by providing head‐to‐head comparative data, supporting regulatory decision‐making and clinical confidence while potentially expanding access to semaglutide.

5. Limitations

This study has several limitations that should be considered when interpreting the findings. First, the open‐label design may have introduced expectation and reporting bias, particularly in subjective secondary endpoints such as health‐related quality of life (SF‐36 scores) and AE reporting. Although the primary efficacy endpoint (bodyweight) is objective and less susceptible to observer bias, the absence of blinding remains a methodological constraint. Blinding was also operationally challenging due to differences in delivery devices between the study treatments (single‐dose prefilled pen vs. multi‐dose prefilled pen). Future studies may consider blinded outcome assessment, where feasible, to minimize such biases.

Second, the 24‐week study duration is relatively short in the context of obesity pharmacotherapy, where longer‐term data are typically required to evaluate the durability of weight loss, long‐term safety, and cardiometabolic outcomes. While this duration was sufficient to capture the primary phase of treatment response, given that clinical evidence with Semaglutide indicates that the majority of weight loss and associated body composition changes occur within the first 16–24 weeks, caution is warranted in extrapolating these findings beyond the study period. Longer‐duration studies are needed to better characterize sustained effects, maintenance of weight loss, and potential rebound weight gain following treatment discontinuation. Notably, the Test formulation demonstrated an identical primary molecular structure to the Reference formulation and met bioequivalence criteria in a dedicated pharmacokinetic study; in the absence of structural or pharmacokinetic differences either before treatment or during the 24‐week comparative trial, substantial divergence in long‐term efficacy or safety beyond the studied period appears unlikely, although confirmatory longer‐term data would remain valuable.

Third, dedicated body composition assessments (e.g., dual‐energy X‐ray absorptiometry‐ or computed tomography‐based evaluation of muscle mass and visceral adiposity), including fat mass and lean body mass, were not pre‐specified or performed in this study. As a result, the relative contributions of fat loss versus lean mass changes to overall weight reduction with Semaglutide could not be determined. Future studies incorporating detailed body composition analyses would provide greater insight into the quality and clinical implications of weight loss.

Finally, as all participants were recruited from Indian centers, the generalizability of these findings to non‐Indian or non‐Asian populations may be limited. This is particularly relevant given known differences in body composition, adiposity distribution, and metabolic risk profiles across ethnic groups. However, this study also provides important population‐specific evidence of Semaglutide in an Indian cohort, which is underrepresented in global STEP trials. Further multi‐ethnic studies are warranted to confirm the broader applicability of these findings. While the results provide supportive comparative evidence for its use in weight management, long‐term and multi‐ethnic studies would be valuable to further confirm the durability of effect and broader generalizability.

6. Conclusions

This Phase III study demonstrates that Test synthetic semaglutide injection is non‐inferior to the Reference semaglutide injection in weight reduction in Indian adults with overweight or obesity, with or without comorbidities, and exhibits a safety and tolerability profile consistent with established semaglutide data. These findings support its use as an effective therapeutic option for weight management and contribute meaningful comparative evidence to inform clinical practice.

Author Contributions

Unnikrishnan Ambika Gopalakrishnan, Ameya Joshi, Harish Kumar, Richa Giri, Sanjiv Maheshwari, Valluri Satya Prasad, Jitendra Shukla, Rekha M. Chowdaiah, Nutan Kumar Agrawal, Yogesh Rasal, Banshidhar Sahoo, Shweta Bhandari, Ambanna Gowda, Uday Phadke, Pravin Supe, Niranjan Pathak, Ambrish Chandrappa, Ashutosh Sonawane, Yash Bahulikar, Amit Bhaskar, and Arunkumar Radhakrishnan were involved in the conduct of the study. Supriya Sonowal, Dipak Patil, Pravin Ghadge, and Suyog Mehta were involved in the study design, data analysis and interpretation. Sucheta Pandit was involved in clinical study operations. Priyanka Yadav, Supriya Sonowal, and Dipak Patil were involved in manuscript finalization.

Funding

The study was funded by Sun Pharmaceutical Industries Limited, which contributed to the study design, data analysis, and manuscript preparation. To ensure analytical rigor and minimize potential bias, all statistical analyses were conducted according to a pre‐specified statistical analysis plan (SAP), with all endpoints, analysis populations, and statistical methods defined a priori and not modified after study initiation. All authors had full and unrestricted access to the complete dataset and were responsible for the interpretation of data and the decision to submit the manuscript for publication. Analyses were performed using validated statistical methods, and the study relied primarily on objective and standardized outcome measures to further mitigate bias.

Conflicts of Interest

Unnikrishnan Ambika Gopalakrishnan, Ameya Joshi, Harish Kumar, Richa Giri, Sanjiv Maheshwari, Valluri Satya Prasad, Jitendra Shukla, Rekha M. Chowdaiah, Nutan Kumar Agrawal, Yogesh Rasal, Banshidhar Sahoo, Shweta Bhandari, Ambanna Gowda, Uday Phadke, Pravin Supe, Niranjan Pathak, Ambrish Chandrappa, Ashutosh Sonawane, Yash Bahulikar, Amit Bhaskar, and Arunkumar Radhakrishnan were the study investigators, and they received grant from the sponsor for conducting the study at their respective sites. Priyanka Yadav, Sucheta Pandit, Supriya Sonowal, Dipak Patil, Pravin Ghadge, and Suyog Mehta are full‐time employees of Sun Pharma Laboratories Limited.

Supporting information

Appendix S1: dom71069‐sup‐0001‐AppendixS1‐S3.docx.

Appendix S2: dom71069‐sup‐0001‐AppendixS1‐S3.docx.

Appendix S3: dom71069‐sup‐0001‐AppendixS1‐S3.docx.

Ambika Gopalakrishnan U., Joshi A., Kumar H., et al., “Semaglutide Injection Once‐Weekly for Weight Management in Adults: Results From A Randomized Phase III, Active‐Controlled Study,” Diabetes, Obesity and Metabolism 28, no. 9 (2026): 8602–8612, 10.1111/dom.71069.

Data Availability Statement

The data sets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.