SUN-151 - Rationale for Cendifensine, A Broad-Spectrum Monoamine Modulator, to Treat Vasomotor and Other Symptoms in Menopause

Introduction/Background
During menopause, loss of estrogenic modulation decreases dopamine (DA) and serotonin (5-HT) signaling while enhancing norepinephrine (NE) activity, disrupting neural circuits that regulate thermoregulation, mood, sleep, and appetite among other domains. These changes give rise to hallmark menopausal symptoms, including vasomotor symptoms (hot flashes and night sweats, VMS), insomnia, fatigue, weight gain, emotional dysregulation, and attention and concentration deficits.
Hormone replacement therapy (HRT) has been the primary treatment for moderate-to-severe VMS; however, a proportion of menopausal women elect not to or cannot receive HRT. Approved or off-label non-HRT treatments (SSRIs and SNRIs, NK1/3 antagonists) offer modest efficacy or require increased monitoring. Recently approved NK1/3 antagonists deliver a substantial reduction in VMS symptoms however lack broader effects due to their specificity for the thermoregulatory zone.
Cendifensine (NOE-115), a broad-spectrum monoamine modulator, blocks 5-HT, NE as well as DA transporters. Directly modulating DA levels in addition to NE and 5-HT represents a novel therapeutic approach in VMS. Cendifensine increases extracellular levels of 5-HT, NE, and DA, thereby enhancing neurotransmission in multiple brain regions, in particular the hypothalamus. By restoring monoaminergic tone, cendifensine has the potential to normalize thermoregulatory signaling and reduce VMS by directly modulating warm sensing hypothalamic neurons.
By also influencing mood, sleep, fatigue, and appetite, cendifensine’s pharmacological profile suggests broader therapeutic potential beyond thermoregulation.
Methods &

Results:
In preclinical studies, cendifensine reduced immobility time in both the rat forced swim test (10 mg/kg PO) and the mouse tail suspension test (1 – 10 mg/kg PO) demonstrating antidepressant-like properties. The compound was wake-promoting in rats with a dose-dependent increase in wake time (3 – 10 mg/kg PO). Cendifensine reduced both regular (5 – 20 mg/kg PO) and palatable food intake (10 – 20 mg/kg PO) in rats, and reduced body weight (15 mg/kg/day PO) and body fat mass (3 – 15 mg/kg/day PO) in diet-induced obese rats; these effects are consistent with modulation of DA pathways that govern appetite and reward.

Conclusion:
Taken together, beyond the direct reduction of VMS as observed in the completed phase 2 clinical trial (NOE-PMM-201, NCT06385795), these data show that, by having a direct effect on all three monoamine levels, cendifensine has beneficial effects on mood, sleep and fatigue as well as weight and appetite regulation. In the NOE-PMM-201 trial, cendifensine demonstrated large, meaningful, and significant reductions in VMS frequency, VMS severity, and improved co-occurring VMS symptoms.

The studies were funded by Roche and Noema Pharma.

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