Vanda's NEREUS Cuts Semaglutide-Induced Vomiting in Phase III Trial

Results of Study 3601

Study 3601 (VP-VLY-686-3601) was a randomized, placebo-controlled Phase III trial of NEREUS, an oral neurokinin-1 (NK-1) receptor antagonist, for preventing vomiting linked to GLP-1 receptor agonist therapy. According to Vanda, the primary endpoint was met: vomiting occurred in 43.0% of NEREUS-treated participants (61/142) compared with 58.5% on placebo (96/164), with p=0.006 adjusted for site. Vanda describes this as a 27% relative reduction.

The key secondary endpoint combined any vomiting with worst nausea of 3 or higher. It occurred in 33.1% of participants on NEREUS (47/142) versus 50.6% on placebo (83/164), with p=0.002, a 35% relative reduction.

Frequent and extreme vomiting

Vanda also reported exploratory analyses of higher-burden vomiting. Frequent vomiting, defined as more than 2 episodes on more than one day, occurred in 6.3% of the NEREUS group versus 15.9% on placebo (p=0.008), a 60% relative reduction. Extreme vomiting, defined as more than 10 total episodes, occurred in 2.8% versus 14.6% (p=0.0003), an 81% relative reduction.

The company states these analyses are post hoc and are presented as supportive evidence. It adds that a similar approximately 80% relative reduction in extreme vomiting was seen in the Phase II study.

On timing, almost all vomiting episodes in either group occurred by Day 2. Rates peaked on Day 1, and the gap between NEREUS and placebo was greatest on Days 1 and 2. Vanda concludes that early prevention, with dosing before initiation or dose escalation and in the first days afterward, is the most impactful window.

Study design and mechanism

Vanda says the trial was run under conditions that produce a high rate of vomiting. Participants received a single 1 mg dose of semaglutide without the gradual titration used in clinical practice, which the company calls a rigorous test of prevention. A pooled exposure-response analysis of Phase 2 and Phase 3 data showed that the reduction in vomiting probability stayed stable across the observed semaglutide concentration range, with no sign that the effect diminished at lower exposures. According to Vanda, this supports extrapolating the effect to real-world semaglutide dosing.

NEREUS acts at the vomiting center, including the area postrema and nucleus tractus solitarius, by blocking substance P signaling. Because of this mechanism, Vanda expects it to be applicable across all available GLP-1 receptor agonist therapies. The drug was approved in December 2025 for the prevention of motion-induced vomiting. On safety, the company reports it was generally well tolerated, with a profile consistent with earlier studies and no new safety signals.

Why it matters and what comes next

Vanda points to nausea and vomiting as among the most common reasons patients stop GLP-1 therapy or fail to reach therapeutic doses. Citing real-world studies, it says roughly half of patients discontinue within one year, with gastrointestinal side effects among the leading reasons. It also cites a global GLP-1 receptor agonist market of more than $50 billion and says better tolerability could help more patients start and stay on treatment.

Dr. Mihael H. Polymeropoulos, Vanda's President, CEO and Chairman, said the results "demonstrate that NEREUS can meaningfully reduce vomiting and frequent multi-day vomiting induced by GLP-1 therapy." Vanda intends to discuss the data from the Phase II and Phase III programs with the FDA and plans an sNDA for this use. The company's forward-looking statements note that FDA alignment and approval are not assured, and refer to an sNDA submission during 2027.