Neurogastrx presented proof-of-concept data from its placebo-controlled Phase 2 clinical study of NG101 (metopimazine mesylate) at ObesityWeek® 2025, demonstrating significant reductions in nausea and vomiting associated with GLP-1 receptor agonist use. The oral, peripherally restricted dopamine D2 receptor antagonist represents a first-in-class therapy targeting a major barrier to GLP-1 treatment adherence.
Clinical Trial Results
The study enrolled 90 participants aged 18-55 who received a single subcutaneous dose of semaglutide (0.5 mg) along with either NG101 20 mg twice daily or placebo for five days. Compared to placebo, NG101 achieved statistically significant improvements across multiple endpoints:
- Nausea incidence: 40% reduction (p=0.0203)
- Vomiting incidence: 67% reduction (p=0.0274)
- Discrete vomiting episodes: 56% reduction (p=0.0238)
- Symptom duration: Significantly reduced (p=0.0063), with events lasting more than one day occurring in 22% versus 51% of participants
- Nausea severity: 70% reduction as reported by participants (p=0.0138)
The treatment also demonstrated an improved safety profile, with substantially fewer adverse events when semaglutide was co-administered with NG101 compared to placebo.
Patient-Reported Outcomes Highlight Treatment Burden
Participant-reported outcomes revealed a greater symptom burden than clinical assessments suggested. While clinicians graded fewer than five incidents of nausea and vomiting as moderate or severe, 70 of the 90 patients rated themselves as having moderate or severe symptoms at some point during the study. NG101 reduced the maximum nausea rating of moderate-severe nausea by 31% (p=0.0225).
"The real-world incidence of nausea and vomiting reported by patients is far more significant and disruptive than the investigator-reported events in clinical trials," said Jim O'Mara, president and CEO of Neurogastrx. The FDA prioritizes patient-reported outcome measures for nausea and vomiting as they more accurately reflect the participant experience.
Addressing a Major Market Challenge
GLP-1 receptor agonists face significant adherence challenges, with only 30% of patients who start these medications for weight loss continuing treatment after one year. A study published in JAMA Network Open in January showed the one-year discontinuation rate of GLP-1 receptor agonists for patients without type 2 diabetes was 64.8%, with gastrointestinal events being the most frequently cited reason.
"GLP-1 agonists can be life-changing for individuals with obesity. Yet for so many, the common GI side effects of nausea and vomiting are often unbearable, leading to patients discontinuing treatment or being unable to reach optimal doses," said Sean Wharton, MD, PharmD, Medical Director at Wharton Medical Clinic for Weight and Diabetes Management in Ontario, Canada.
With the global GLP-1 market estimated at $63 billion in 2025, the sector faces substantial revenue losses due to treatment discontinuation. More importantly, patients miss out on the clear benefits of weight loss on overall health, including improvements in metabolic and cardiovascular diseases associated with obesity.
Mechanism of Action
NG101 works by selectively targeting the Area Postrema (AP), a brain region located outside the blood-brain barrier that is rich in dopamine D2 receptors. GLP-1 agonists activate two distinct brain areas: the Nucleus of the Tractus Solitarius (NTS), which causes satiety and leads to weight loss, and the AP, which triggers nausea and vomiting.
Since the NTS resides inside the brain and is inaccessible to NG101, the peripherally restricted compound can block nausea and vomiting symptoms without interfering with the weight loss benefits of GLP-1 therapy. By blocking D2 receptors in the AP, NG101 specifically addresses the unwanted gastrointestinal side effects while preserving therapeutic efficacy.
The company plans to evaluate NG101 with multiple GLP-1 treatments in future clinical development programs, potentially expanding access to sustainable and tolerable obesity treatments for millions of patients worldwide.
