Weight loss produced by tesofensine in patients with Parkinson's or Alzheimer's disease. — VialBase Research

Summary

Tesofensine is a norepinephrine, dopamine, and serotonin reuptake inhibitor, and this meta-analysis is the paper that turned an unsuccessful neurology drug into an obesity candidate. The authors pooled four randomized, double-blind, multicenter trials — two in Parkinson’s disease and two in Alzheimer’s disease — that compared tesofensine (n = 740) with placebo (n = 228), examining the weight changes that occurred incidentally over 14 weeks of once-daily oral dosing without any accompanying weight loss program. Results were adjusted for baseline values, age, and study. Obesity was present in 14% of the placebo group and 21% of the tesofensine group. Across the total cohort, weight change at 14 weeks was +0.5% on placebo versus -0.5%, -0.9%, -1.8%, and -2.8% on tesofensine 0.125, 0.25, 0.5, and 1.0 mg (P = 0.015 for the dose effect). Within the obese subgroup the corresponding figures were -0.2%, -1.7%, -1.6%, -1.5%, and -3.7%, and the proportion of obese patients achieving at least 5% weight loss rose from 2.1% on placebo to 8.2%, 14.1%, 20.9%, and 32.1% across ascending doses (P < 0.001 for 0.25, 0.5, and 1.0 mg versus placebo on both endpoints). Alongside the weight effect came a clear, dose-dependent cardiovascular signal: heart rate changed by -0.4, 2.1, 4.2, 6.0, and 6.8 bpm at 14 weeks, statistically significant versus placebo from the 0.25 mg dose upward, although no effect on blood pressure was observed. The authors concluded that tesofensine produced roughly 4% placebo-subtracted weight loss over more than 14 weeks with no diet or lifestyle therapy — comparable to sibutramine but without sibutramine’s blood pressure effect — and that on this basis tesofensine was now being developed for obesity management.

Key Findings

• Pooled analysis of four randomized, double-blind, multicenter trials in Parkinson’s or Alzheimer’s disease: tesofensine n = 740, placebo n = 228, 14 weeks of once-daily oral dosing, no weight loss program
• Total-cohort weight change at 14 weeks: +0.5% (placebo), -0.5% (0.125 mg), -0.9% (0.25 mg), -1.8% (0.5 mg), -2.8% (1.0 mg); P = 0.015 for dose effect
• Obese subgroup weight change: -0.2%, -1.7%, -1.6%, -1.5%, -3.7% across the same dose ladder; responders achieving at least 5% weight loss rose from 2.1% on placebo to 32.1% at 1.0 mg (P < 0.001 for the 0.25, 0.5, and 1.0 mg doses)
• Dose-dependent heart rate increase of -0.4, 2.1, 4.2, 6.0, and 6.8 bpm at 14 weeks, significant versus placebo from 0.25 mg upward; no effect on blood pressure was observed
• Placebo-subtracted weight loss of approximately 4% over more than 14 weeks, described by the authors as similar to sibutramine — a drug later withdrawn in multiple markets over cardiovascular concerns

Relevance to Tesofensine

This is the strongest genuinely quantitative dataset behind Tesofensine as a weight-loss agent, and it should be cited with three facts attached. First, the weight data are a post-hoc pooled observation from trials designed for Parkinson’s and Alzheimer’s disease, not from a purpose-built obesity trial — the participants were neurology patients, mostly non-obese, receiving no diet or lifestyle support. Second, the effect is real and dose-dependent, with roughly 4% placebo-subtracted loss at the top of the dose range. Third, and most often omitted in marketing copy, the same dose-response produced heart rate increases up to 6.8 bpm at 1.0 mg, significant from 0.25 mg upward. A triple monoamine reuptake inhibitor that raises resting heart rate in a dose-dependent way carries an obvious cardiovascular question, and the authors’ own comparator — sibutramine — was subsequently withdrawn from several markets over cardiovascular outcomes. Any honest summary of tesofensine’s benefit must present the heart rate number in the same breath as the weight number.

Citation

Astrup A, Meier DH, Mikkelsen BO, et al. Weight loss produced by tesofensine in patients with Parkinson’s or Alzheimer’s disease. Obesity (Silver Spring, Md.). 2008;16(6):1363-9. doi:10.1038/oby.2008.56.

See Also

• Parent compound: Tesofensine