For GLP-1 Medication Users, Investigational NK-1 Agent May Quell GI Side Effects by Half

Vanda Pharmaceuticals reported positive topline results from a randomized controlled trial of tradipitant, an oral neurokinin (NK)-1 receptor antagonist, for preventing nausea and vomiting associated with GLP-1 receptor agonist treatment for obesity. Specifically, treatment with the investigational drug reduced vomiting by half, according to a November 17 statement from Vanda.

The phase 2 study (VP-VLY-686-2601) enrolled 116 overweight or obese adults (body mass index [BMI] 25–40 kg/m²) without prior GLP-1 exposure and pretreated participants with tradipitant 85 mg twice daily or placebo before administering a 1 mg dose of semaglutide (Wegovy), a dose that typically requires 9 weeks of titration.

Vomiting, the study's primary endpoint, occurred in 29.3% of participants treated with tradipitant (17/58) compared with 58.6% who received placebo (34/58) (P =.002), a 50% relative reduction. The key secondary endpoint, defined as vomiting plus worst nausea (3 or greater on a 0–5 scale), was reported in 22.4% of tradipitant recipients (13/58) vs 48.3% taking placebo (28/58) (P =.004). According to the company, the tradipitant safety profile was consistent with previous studies of the drug with no new signals reported.

"These results demonstrate tradipitant's potential to mitigate GLP-1 induced nausea and vomiting which are key contributors [to] the 30–50% real-world discontinuation rates for GLP-1 agonists, often before therapeutic doses are reached," Mihael H. Polymeropoulos, MD, presiden and CEO and chairman of Vanda said in a statement. "Tradipitant's effect in reducing nausea and vomiting could significantly improve GLP-1 agonist adherence enabling more people to receive the full therapeutic benefit."

Real-World Consequences of GLP-1 Discontinuation

Falling short of the full benefit of GLP-1 therapy as a result of discontinuation has been documented in the literature. In a large retrospective cohort study of nearly 8000 adutls with overweight or obesity, Gasoyan et al reported significant differences in weight loss based on medication persistence. Participants who discontinued semaglutide early lost only 3.6% of their weight, compared to 10.9% among those who continued treatment. For tirzepatide, early discontinuation resulted in 3.6% weight loss versus 15.3% for those who persisted. Overall the study found that individuals lost an average of 8.7% of baseline body weight after 1 year of treatment, compared to the 14.9% to 20.9% weight reductions demonstrated in phase 3 clinical trials with the GLP-1-based receptor agonists.² Early discontinuation exacts a cost both on individuals and on payors, adding stress to the health care system still mostly at odds with the cost of the antiobesity medications.

According to the Vanda statement, the findings align with previous data the company has reported in motion sickness where tradipitant reduced vomiting by more than 50% across randomized trials including more than 800 participants. .

Vanda plans to advance tradipitant into phase 3 trials in the first half of 2026 and will evaluate regulatory pathways for its use as an adjunct to GLP-1 therapy. Tradipitant is also under FDA review for motion sickness with a PDUFA date of December 30, 2025.

References

1. Vanda Pharmaceuticals reports positive results for tradipitant in preventing GLP-1 induced nausea and vomiting. News release. Vanda Pharmaceuticals. November 17, 2025. Accessed November 18, 2025. https://www.prnewswire.com/news-releases/vanda-pharmaceuticals-reports-positive-results-for-tradipitant-in-preventing-glp-1-induced-nausea-and-vomiting
2. Halsey G. High discontinuation rates of GLP-1 RA-based drugs linked to weight loss far below phase 3 clinical trials. Patient Care. June 12, 2025. Accessed November 18, 2025. https://www.patientcareonline.com/view/high-discontinuation-rates-of-glp-1-ra-based-drugs-linked-to-weight-loss-far-below-phase-3-clinical-trials