New agent may help halt weight gain caused by antipsychotic drug
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Key takeaways:
- Olanzapine plus an intestinal microsomal triglyceride transfer protein inhibitor lowered postprandial triglycerides by 82%.
- This combined treatment also resulted in lower weight gain vs. olanzapine alone.
SAN ANTONIO —An intestinal microsomal triglyceride transfer protein inhibitor reduced postprandial triglycerides and halted weight gain in patients treated with the antipsychotic olanzapine, according to results of a pilot study.
RDX-002 (Response Pharmaceuticals) is a first-in-class, potent and selective inhibitor of intestinal microsomal triglyceride transfer protein. A preclinical study from 2019 suggested that upregulation of intestinal microsomal triglyceride transfer protein may play a role in antipsychotic-induced weight gain by increasing the uptake of dietary lipids, according to William J. Sasiela, PhD, chief medical officer at Response Pharmaceuticals.
“RDX-002 is specifically designed to work only in the intestine. It’s non-systemic. There’s little to no drug found in patients,” Sasiela said during a presentation at ObesityWeek. “In prior phase 2 trials, RDX-002 demonstrated reductions in LDL [cholesterol], HbA1c in patients with type 2 diabetes and body weight.”
Sasiela and colleagues conducted a single-center, open-label 15-day study with 20 healthy participants (mean age, 28.1 years) currently treated with olanzapine to assess if RDX-002 reduced dietary fat and body weight gain. During the first week of treatment, all patients received olanzapine 10 mg alone with the addition of RDX-002 200 mg twice daily for 13 patients at week 2.
The primary outcome was postprandial triglyceride area under the curve on day 1, 8 and 15 after a standardized meal. Secondary outcomes included body weight changes, fasting lipids, olanzapine peak plasma concentration and safety.
Compared with day 1, by day 8, postprandial triglycerides rose by 54% with olanzapine treatment alone (P = .009). By day 15, compared with day 8, patients treated with olanzapine plus RDX-002 demonstrated a significant reduction in postprandial triglyceride area under the curve (–81.6%; P < .001) compared with those only treated with olanzapine (–18.8%).
Patients treated with olanzapine alone had a mean 1.6 kg increase in body weight after 1 week of treatment, rising to 1.7 kg by week 2 (P = .016). Conversely, patients treated with olanzapine plus RDX-002 had a mean 0.4 kg increase in body weight by 2 weeks (P = .443), Sasiela said.
In a post hoc analysis, at week 2, researchers observed the greatest absolute reduction in triglyceride area under the curve among patients with RDX-002 treatment added.
At 2 weeks, those assigned olanzapine alone had a 24.8% increase in LDL (P = .016), while those assigned olanzapine and RDX-002 had no significant change in LDL, Sasiela said.
Neither group had changes in fasting glucose level, while the olanzapine and RDX-002 group had a slight decrease in HDL cholesterol (–6.3%) compared with a slight increase for the olanzapine alone group (+3.6%), he said.
RDX-002 was associated with some mild to moderate gastrointestinal adverse events such as diarrhea and flatulence. No serious adverse events or discontinuations were reported.
More studies are underway evaluating RDX-002 in this patient population, including a phase 2 proof-of-concept clinical study in those who discontinued GLP-1 receptor agonists after weight loss for obesity, Sasiela said.
“In this ongoing trial, we’re going to be enrolling 40 patients who are in the process of discontinuing their GLP-1 agonist for treatment for obesity,” Sasiela said. “Our primary endpoints is going to be the same mean change in postprandial triglyceride area under the curve, but we’ll also look at the effects of this GLP discontinuation alone and explore changes in body weight, fasting lipids and glycemic parameters.”
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Sasiela WJ. Oral-026. Presented at: ObesityWeek; Nov. 3-6, 2024; San Antonio.
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