Development

Novo Nordisk's oral semaglutide achieves 21.6% weight loss in early responders in Phase III obesity trial

Edited by Robert McTiernan··4 min read

New sub-analyses from the Phase III OASIS 4 trial show that oral semaglutide 25 mg (Wegovy pill) produced 21.6% weight loss in early responders by week 64, with nearly eight in ten participants with poor physical function achieving clinically meaningful functional improvement. The data were presented by Novo Nordisk (Copenhagen: NOVO B) at the European Congress on Obesity 2026 in Istanbul.

OASIS 4 is a randomized, double-blind, placebo-controlled Phase III trial evaluating oral semaglutide 25 mg once daily versus placebo in adults with obesity (BMI ≥30 kg/m²) or overweight (BMI ≥27 kg/m²) with at least one weight-related comorbidity, excluding those with type 2 diabetes, with participants randomized 2:1 over 64 weeks and a total enrollment of 307.

The ECO2026 data focused on two post hoc analyses of OASIS 4. In the early-responder analysis, 28.8% of participants on the Wegovy oral semaglutide achieved at least 10% weight loss by week 16, with that subgroup reaching a mean 13.2% reduction at that point and 21.6% by week 64. Participants who did not meet the early-response threshold still achieved 11.5% weight loss by trial end, a figure the company described as clinically meaningful. In a separate physical function analysis, 77.3% of participants with poor baseline physical function who received the semaglutide pill achieved clinically meaningful improvements in function scores — encompassing range of motion and stamina — compared with 42.9% in the placebo group.

These results extend the primary OASIS 4 findings, previously published in the New England Journal of Medicine, in which oral semaglutide 25 mg produced an average 17% weight loss versus 2.7% with placebo across the full trial population.

Competitive positioning

The ECO2026 Novo Nordisk presentation also included two analyses positioned explicitly against orforglipron, Eli Lilly's investigational oral nonpeptide GLP-1 receptor agonist. An indirect treatment comparison, designated ORION, reported that the Wegovy pill demonstrated greater mean weight loss than orforglipron 36 mg, and that orforglipron was associated with approximately 14 times higher odds of discontinuation due to gastrointestinal adverse effects. A separate patient preference study, OPTIC, found that 84% of survey respondents favored a treatment profile consistent with oral semaglutide over that of orforglipron.

These comparisons carry important methodological constraints. Neither ORION nor OPTIC is a head-to-head randomized trial; the indirect comparison relies on cross-trial data, and the preference study reflects survey responses rather than clinical outcomes. Cross-trial comparisons are limited by differences in trial populations, dosing schedules, titration protocols, and outcome definitions, and should not be interpreted as equivalent to direct evidence.

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Wegovy pill physical function findings

The physical function findings from the ECO2026 semaglutide pill results add a dimension to the OASIS 4 dataset that goes beyond body weight alone. The 77.3% versus 42.9% response rate in participants with poor baseline function — assessed using validated tools measuring range of motion and stamina — suggests that weight reduction achieved with oral semaglutide may translate into improvements in day-to-day physical capacity in a population where functional limitation is common.

This type of patient-reported and performance-based outcome is gaining traction as a regulatory and commercial consideration in obesity, reflecting a broader shift in how the field defines treatment benefit beyond the scale. Whether these functional improvements are mediated primarily through weight loss or through additional mechanisms of GLP-1 receptor agonism remains an open question that the current sub-analyses do not resolve.

The early-responder stratification is also clinically instructive. The identification that nearly three in ten patients achieve rapid and pronounced weight loss — and that this early trajectory predicts substantially greater long-term outcomes — has practical implications for dose escalation decisions and patient counseling. The finding that non-early responders still achieve meaningful weight reduction by week 64 supports continued treatment in patients who do not show early dramatic responses, though the post hoc nature of this analysis limits the strength of that inference.

Novo Nordisk has indicated that the EMA review of the Wegovy pill for obesity remains ongoing, with a regulatory decision representing the next material milestone for the oral semaglutide program outside the US.

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