Vanda Pharmaceuticals has announced positive results from Study 3601 (VP-VLY-686-3601), a phase 3 randomised, placebo-controlled study evaluating NEREUS (tradipitant), an oral neurokinin-1 (NK-1) receptor antagonist, for the prevention of vomiting associated with GLP-1 receptor agonist therapy. The study showed significant reduction in overall vomiting episodes (27 percent p=0.006 as well as reduction of frequent (60 percent p=0.008) and extreme vomiting (81 percent p=0.0003) episodes.

Based on the totality of data from the phase 2 and phase 3 programs, Vanda intends to discuss the results with the US Food and Drug Administration (FDA) and is planning a supplemental New Drug Application (sNDA) to support the use of NEREUS for the prevention of vomiting associated with GLP-1 receptor agonist therapy.

NEREUS reduced the incidence of any vomiting. Vomiting occurred in 43 percent of NEREUS-treated participants (61/142) compared with 58.5 percent on placebo (96/164) (p=0.006, adjusted for site), a 27 percent relative reduction.

The key secondary endpoint of any vomiting together with worst nausea ≥3 occurred in 33.1 percent of participants on NEREUS (47/142) versus 50.6 percent on placebo (83/164) (p=0.002, adjusted for site), a 35 percent relative reduction.

Exploratory analyses examined higher-intensity vomiting patterns. The proportion of participants with frequent vomiting—defined as more than 2 episodes on more than 1 day—was 6.3 percent with NEREUS versus 15.9 percent with placebo (p=0.008, site-adjusted), a 60 percent relative reduction.

The proportion with extreme vomiting (greater than 10 total episodes) was 2.8 percent with NEREUS versus 14.6 percent with placebo (p=0.0003, site-adjusted), corresponding to an 81 percent relative reduction. These analyses are post hoc and are presented as supportive evidence of a reduction in higher-burden vomiting. A similar approximately 80 percent relative reduction in extreme vomiting was observed in the phase 2 study.

Almost all vomiting episodes in either group occurred by day 2. Vomiting rates peaked on day 1, and the absolute separation between NEREUS and placebo was greatest on days 1 and 2. After day 2, few additional participants began vomiting. These observations indicate that early prevention—dosing prior to initiation or dose escalation and in the first days after dosing of the GLP-1 analog—is the most impactful window for reducing vomiting.

The phase 3 study tested NEREUS 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. This design provides a rigorous test of prevention when the emetogenic stimulus is strong. A pooled exposure–response analysis of the phase 2 and phase 3 data showed that the reduction in vomiting probability with NEREUS remained stable across the observed semaglutide concentration range, with no evidence that the treatment effect diminished at lower exposures, supporting extrapolation of the effect to real-world dosing of semaglutide.

NEREUS is an NK-1 receptor antagonist that acts at the vomiting center, including the area postrema (AP) and Nucleus Tractus Solitarius (NTS). By blocking substance P signaling in these central pathways, NEREUS is expected to be applicable across all available GLP-1 receptor agonist therapies.

Nausea and vomiting are among the most common reasons patients discontinue or fail to reach therapeutic doses of GLP-1 receptor agonists. Real-world studies show that roughly half of patients discontinue GLP-1 therapy within 1 year, with gastrointestinal side effects among the leading reasons. The global GLP-1 receptor agonist market exceeds USD 50 billion and continues to expand. Improving tolerability could enable more patients to initiate and remain on therapy.

Vanda plans to discuss the results with the FDA and intends to submit an sNDA for NEREUS for the prevention of vomiting associated with GLP-1 receptor agonist therapy.

NEREUS was generally well tolerated, with a safety profile consistent with previous studies. No new safety signals were observed.

Dr. Mihael H Polymeropoulos, President, CEO and Chairman, Board of Vanda Pharmaceuticals, said, "These results demonstrate that NEREUS can meaningfully reduce vomiting and frequent multi-day vomiting induced by GLP-1 therapy, which are key contributors to treatment discontinuation. The consistency and magnitude of the effects observed across this program could offer significant benefit to the millions of people seeking or using GLP1 therapies."