Tesofensine

A drug that found its indication by accident. Tesofensine was developed by NeuroSearch as a triple monoamine reuptake inhibitor for Parkinson's and Alzheimer's disease. It did not work for either. What the trials did show was weight loss: pooling four randomised trials, weight change at 14 weeks was +0.5% on placebo against -0.5%, -0.9%, -1.8% and -2.8% at 0.125, 0.25, 0.5 and 1.0 mg, and among the obese participants 32.1% at the top dose lost 5% or more against 2.1% on placebo [1].

The obesity trial. A phase 2 trial in five Danish centres randomised 203 patients with a BMI of 30-40 to tesofensine 0.25, 0.5 or 1.0 mg or placebo for 24 weeks, all on an energy-restricted diet. Placebo produced 2.0% weight loss; 0.25 mg produced 4.5% and 0.5 mg produced 9.2%. Heart rate rose 7.4 beats per minute in the 0.5 mg group; blood pressure did not change significantly at 0.25 or 0.5 mg. The authors concluded tesofensine 0.5 mg might produce twice the weight loss of the drugs then approved, and that phase 3 confirmation was needed [2].

The expression of concern. In April 2013 the Lancet issued an expression of concern about that trial over under-reporting of adverse effects; the authors replied in July 2013. The notice has not been withdrawn [2]. Anyone weighing this drug should weigh that: the headline efficacy number comes from a trial whose adverse-effect reporting the journal publicly questioned.

Phase 3 never happened for obesity in the major markets, and tesofensine is not approved in the United States, the European Union or the United Kingdom.

Hypothalamic obesity. This is the more interesting current use. Damage to the hypothalamus - usually from a craniopharyngioma or its treatment - causes rapid, intractable weight gain that responds poorly to everything. A randomised trial gave 21 adults Tesomet (tesofensine 0.5 mg with metoprolol 50 mg) or placebo for 24 weeks. Tesomet produced 6.3% more weight loss than placebo, and 8 of 13 reached 5% weight loss against 1 of 8. Sleep disturbance affected 50% against 13%, dry mouth 43% against 0% and headache 36% against 0%; heart rate and blood pressure did not differ significantly between groups, which was the point of adding the beta-blocker [3].

Abuse potential. Given that it blocks dopamine reuptake, this was examined directly. In recreational stimulant users, tesofensine's subjective effects were not distinguishable from placebo and were lower than dextroamphetamine 30 mg on every measure; the authors concluded its abuse potential is no greater than placebo [4].

Tesofensine blocks the presynaptic transporters for noradrenaline, dopamine and serotonin, raising synaptic concentrations of all three [2]. Appetite suppression follows from the combined monoaminergic tone - noradrenergic and serotonergic signalling both reduce food intake, and dopaminergic signalling is implicated in food reward.

The rat work adds a mechanistic wrinkle: in diet-induced obese rats, tesofensine reduced food intake and body weight and reduced striatal D2/D3 receptor availability [5] - a change in the reward system rather than only in hunger signalling.

The human appetite study is the most informative. Appetite sensations were suppressed while weight was actively falling; when the drug was reintroduced in a weight-reduced state, it suppressed them again [6]. That matters because the body defends a reduced weight by raising hunger, and a drug that still works against that defence is doing something useful.

The cardiovascular liability comes from the same mechanism. Raising noradrenergic tone raises heart rate; that is why the hypothalamic-obesity product pairs tesofensine with a beta-blocker [3]. It is also why a monoamine-based obesity drug carries history: sibutramine, a noradrenaline and serotonin reuptake inhibitor, was withdrawn over cardiovascular outcomes.

An oral tablet, once daily. Tesomet is the fixed combination with metoprolol 50 mg, formulated specifically so that the beta-blocker offsets the sympathomimetic heart-rate effect - and in the hypothalamic obesity trial it did, with no significant heart rate or blood pressure difference against placebo [3].

Start with the expression of concern. The pivotal obesity trial's adverse-effect reporting was publicly questioned by the Lancet in 2013, the authors responded, and the notice stands [2]. Every tolerability statement drawn from that trial should be read with that in mind.

What the trials report. In the obesity trial, the most frequent adverse 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 [2]. In the pooled neurology trials, heart rate rose significantly from 0.25 mg upwards [1]. In the hypothalamic obesity trial, sleep disturbance affected 50% against 13% on placebo, dry mouth 43% against 0%, and headache 36% against 0% [3].

Abuse potential was formally assessed and found no greater than placebo in recreational stimulant users [4], which is a more reassuring result than a dopamine reuptake inhibitor might warrant on first principles.

What is missing is the thing that matters most for this drug class: cardiovascular outcome data. No phase 3 obesity trial was completed and no outcome trial exists. Sibutramine looked acceptable on blood pressure and heart rate too, until SCOUT measured events.

No formal interaction studies appear in the available literature, but the pharmacology dictates caution. Combining a triple monoamine reuptake inhibitor with an MAO inhibitor risks hypertensive crisis and serotonin syndrome; combining it with SSRIs, SNRIs or other serotonergic drugs raises serotonin syndrome risk; combining it with stimulants compounds the cardiovascular effects.

The one documented combination is deliberate: metoprolol, added to blunt the heart rate rise [3].