Tesofensine

Also known as: NS-2330, NS2330, NS 2330

Evidence: Clinical

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Overview

Small-molecule triple monoamine reuptake inhibitor, not a peptide. In a 24-week phase 2 trial (n=203), 0.5 mg daily gave 9.2% weight loss versus 2.0% with placebo plus diet.

Tesofensine (NS2330) was developed by NeuroSearch for Parkinson's and Alzheimer's disease, where effects were modest; a pooled analysis of four 14-week trials (n=968) found dose-related weight loss (Astrup 2008, Obesity). In a Danish phase 2 obesity trial (n=203), 0.25, 0.5 and 1.0 mg daily with diet gave 4.5%, 9.2% and 10.6% weight loss over 24 weeks versus 2.0% with placebo (Astrup 2008). The Lancet issued an expression of concern in 2013 over under-reported adverse events, and the authors published a correction (Astrup 2013). Mechanism studies showed raised satiety, lower appetite and higher fat oxidation (Sjödin 2010; Gilbert 2012). A Mexican phase 3 trial (n=372) was reported by press release in 2018 but not in a peer-reviewed journal (Chakhtoura 2023). Combined with metoprolol (Tesomet) it was tested in hypothalamic obesity (Huynh 2022). No FDA or EMA approval.

Benefits

Weight loss (human RCT, 24 weeks), increased satiety and reduced appetite (human RCT), higher 24-hour fat oxidation (human, 2 weeks)

Dosing reference

Research dose: 0.25 to 0.5 mg once daily by mouth (phase 2 and phase 3 obesity doses; 1.0 mg was also tested)
Range: 250 to 500 mcg, 1x daily

Oral, once daily. The phase 2 obesity trial tested 0.25, 0.5 and 1.0 mg for 24 weeks with an energy-restricted diet (Astrup 2008); the Mexican phase 3 used 0.25 and 0.5 mg. The Tesomet combination used 0.5 mg with metoprolol 50 mg (Huynh 2022). With a half-life near 10 days, steady state takes weeks.

Mechanism

Tesofensine inhibits presynaptic reuptake of noradrenaline, dopamine and serotonin. In overweight men it raised satiety and fullness, lowered prospective food intake, raised 24-hour fat oxidation by 18 g and raised night-time energy expenditure 4.6%, so appetite suppression is the main driver of weight loss with a small energy-expenditure component (Sjödin 2010). Appetite effects were dose-dependent over 24 weeks (Gilbert 2012). Its major metabolite M1 circulates even longer (Lehr 2007). Hypothalamic and dopamine-reward pathways are proposed from rodent work.

Evidence

Clinical: at least one published human trial or an approved drug

24-week phase 2 trial (n=203): 4.5%, 9.2% and 10.6% weight loss at 0.25, 0.5 and 1.0 mg versus 2.0% with placebo plus diet; heart rate rose 7.4 bpm at 0.5 mg (Astrup et al., 2008)
The Lancet placed an expression of concern on the 2008 trial in 2013 for under-reported adverse events; the authors published the missing data (Astrup et al., 2013)
2 weeks of treatment raised satiety and 24-hour fat oxidation and gave 1.8 kg weight loss over placebo in overweight men (Sjödin et al., 2010)
Tesofensine 0.5 mg with metoprolol 50 mg gave 6.3% additional weight loss over placebo in 21 adults with hypothalamic obesity (Huynh et al., 2022)
Human-trial status: phase 3 in Mexico (n=372) reported only by press release (Chakhtoura et al., 2023); Parkinson's and Alzheimer's programmes not pursued; not approved by FDA or EMA

References

Side effects

In the 24-week phase 2 trial the most common effects were dry mouth, nausea, constipation, hard stools, diarrhoea and insomnia; heart rate rose 7.4 bpm at 0.5 mg, while blood pressure did not rise significantly at 0.25 or 0.5 mg (Astrup 2008). Adverse events in that trial were later found under-reported (Astrup 2013). With metoprolol, sleep disturbance, dry mouth and headache were common and one case of worsened anxiety led to withdrawal (Huynh 2022). It is cleared by CYP3A4; itraconazole raised exposure in a PK study. Mood effects, irritability and stimulant-like effects are commonly reported (anecdotal).

Storage

Storage: Room temperature, dry (general small-molecule guidance; no compound-specific CoA located)
Lyophilized: 12+ months

Pharmacology

Half-life: ~234 h, with active metabolite M1 ~374 h (oral, population PK in Alzheimer's patients; Lehr 2007)
Bioavailability: Oral; absolute bioavailability not located in published sources. Long half-life supports once-daily dosing (Lehr 2007)
Molecular weight: 328.3 Da