Vanda Pharmaceuticals reports a 27% relative reduction in vomiting with tradipitant in Phase 3 Study 3601, although real-world efficacy remains uncertain.
Written By: Neha Vishwakarma, PharmD
Reviewed By: Pharmacally Editorial Team
Vanda Pharmaceuticals announced on October 27, 2026, that its Phase 3 Study 3601 met its primary endpoint, showing that NEREUS™ (tradipitant) reduced the incidence of vomiting associated with semaglutide compared with placebo. Vomiting occurred in 43.0% of participants receiving tradipitant versus 58.5% receiving placebo, representing a 27% relative reduction (p=0.006).
The findings support further evaluation of tradipitant for managing vomiting associated with glucagon-like peptide-1 (GLP-1) receptor agonist therapy. However, the study used a single semaglutide dose without gradual titration, limiting conclusions about the treatment’s effectiveness under routine clinical conditions.
Study 3601 Evaluated Vomiting Prevention Under High-Risk Conditions
Study 3601 (VP-VLY-686-3601) was a randomized, placebo-controlled Phase 3 trial evaluating tradipitant, an oral neurokinin-1 (NK-1) receptor antagonist, for preventing vomiting associated with GLP-1 receptor agonist treatment.
The study enrolled 306 participants, of whom 142 received tradipitant and 164 received placebo. All participants received a single 1 mg dose of semaglutide without gradual dose titration. This differs from routine clinical practice, in which semaglutide is introduced and escalated gradually.
Vanda designed the study to create conditions associated with a high incidence of vomiting, providing a stringent test of preventive efficacy. Nevertheless, the resulting event rates may not reflect those observed during routine treatment.
Primary and Secondary Endpoints Showed Reduced Vomiting
The primary endpoint, the incidence of any vomiting, occurred in 61 of 142 participants receiving tradipitant (43.0%), compared with 96 of 164 receiving placebo (58.5%). The difference was statistically significant (p=0.006, adjusted for site).
The key secondary endpoint combined any vomiting with a worst nausea score of at least 3. This outcome occurred in 33.1% of participants receiving tradipitant versus 50.6% receiving placebo, representing a 35% relative reduction (p=0.002, adjusted for site).
The absolute difference in the incidence of any vomiting was 15.5 percentage points. Under the study conditions, this corresponds to an approximate number needed to treat of seven to prevent vomiting in one additional participant. This estimate should not be extrapolated directly to routine clinical use, where gradual titration may produce different baseline event rates.
Exploratory Analyses Suggested Fewer High-Burden Episodes
Vanda also reported two exploratory, post hoc analyses examining more frequent or extreme vomiting.
Frequent multi-day vomiting, defined as more than two episodes on more than one day, occurred in 6.3% of participants receiving tradipitant versus 15.9% receiving placebo, a 60% relative reduction (p=0.008).
Extreme vomiting, defined as more than 10 total episodes, occurred in 2.8% versus 14.6%, respectively, representing an 81% relative reduction (p=0.0003).
These findings suggest a potential reduction in higher-burden vomiting episodes. However, because the analyses were exploratory and post hoc, they should be interpreted as supportive rather than confirmatory evidence. The study did not establish whether tradipitant reduces dehydration, healthcare utilization, or discontinuation of GLP-1 therapy.
Early Vomiting Patterns May Inform Future Use
According to Vanda, almost all vomiting in both groups occurred by Day 2, with rates peaking on Day 1. The largest separation between treatment groups occurred during the first two days.
A pooled exposure-response analysis of Phase 2 and Phase 3 data also found that the reduction in vomiting probability remained stable across the observed semaglutide concentration range. Vanda considers this supportive of potential applicability to routine dosing, although evidence from studies using gradual titration would be needed to establish the effect under usual clinical conditions.
Tradipitant blocks NK-1 receptors involved in central vomiting pathways, including the area postrema and nucleus tractus solitarius, by interfering with substance P signaling. Although this mechanism provides a rationale for investigating its use across GLP-1 therapies, Study 3601 evaluated semaglutide only. Efficacy with other agents, including tirzepatide, remains unestablished.
Safety and Regulatory Outlook
Vanda described tradipitant as generally well tolerated, with a safety profile consistent with earlier studies and no new safety signals. However, the announcement did not provide detailed adverse-event rates, serious adverse events, or discontinuation data, limiting an independent assessment of the benefit-risk profile.
The company plans to discuss the Phase 2 and Phase 3 findings with the U.S. Food and Drug Administration (FDA) before pursuing a supplemental New Drug Application (sNDA) for preventing GLP-1-related vomiting.
The results establish a statistically significant reduction in vomiting under the trial’s specific conditions, but they do not yet demonstrate improved treatment persistence, weight-loss outcomes, or long-term tolerability. Evidence from studies using gradual dose titration, alongside fuller safety reporting, will be important in determining the potential clinical value of tradipitant in this setting.
NEREUS is approved for prevention of motion-induced vomiting. Its proposed use for GLP-1-associated vomiting remains subject to regulatory review and is not established by these results alone.
Reference
Vanda Pharmaceuticals Announces Positive Results from Study 3601 of NEREUS™ (tradipitant) for Prevention of GLP-1-Induced Vomiting. Vanda Pharmaceuticals Inc, October 27, 2026.
A Study to Evaluate Tradipitant on Treating Nausea and Vomiting Induced by GLP-1R Agonist Use, ClinicalTrials.gov ID NCT07446439
About the Writer
Neha Vishwakarma (LinkedIn) is a Pharm.D professional with experience in clinical pharmacy, pharmacovigilance, and clinical research. She has hands-on experience in ADR assessment, ICSR processing, medication safety, and clinical data evaluation. Her research background in surgical site infections and antibiotic use supports her focus on evidence-based healthcare writing.