Lorcaserin: A review of its preclinical and clinical pharmacology and therapeutic potential
Introduction
At the turn of the current century, many Pharmaceutical Research and Development organisations had a significant investment in serotonin (5-HT) based research and drug discovery. Of the top 10 selling CNS drugs in Y2000, six had a mechanism of action that involved at least some pharmacological interaction with the serotonin system (https://www.drugtopics.com/drug-topics/content/top-200-drugs-retail-sales-2000). Some of these drugs (SSRI’s, atypical neuroleptics) acted on multiple 5-HT receptors (and in some cases other neurotransmitter targets) to exert their therapeutic effects. One exception was sumatriptan (Imigran®) a relatively selective 5-HT receptor subtype agonist that proved to be an important advance in the treatment of migraine. At that time it was a reasonable expectation that a wave of next generation serotonin-based therapies would be identified, based on a more selective modulation of 5-HT receptor function. Twenty-years later, apart from the multiple triptan follow-ons to sumatriptan, one of very few receptor selective drugs to emerge is the 5-HT2C receptor selective agonist lorcaserin (Belviq®).
Interest in the discovery of selective 5-HT2C receptor agonists was largely prompted by the clinical efficacy of a broadly acting serotonergic drug, the serotonin releaser/reuptake inhibitor (dex)fenfluramine. (Carvajal, García del Pozo, Martín de Diego, Rueda de Castro, & Velasco, 2000; Guy-Grand et al., 1989; Silverstone & Goodall, 1986). Marketed as Pondimin®/Redux®, (dex)fenfluramine reduced appetite and was an effective treatment for individuals wishing to lose weight. Unfortunately, (dex)fenfluramine was associated with side effects of cardiac valvulopathy and pulmonary hypertension which prompted its withdrawal from clinical use (Connolly et al., 1997; Gardin et al., 2000; Khan et al., 1998). Preclinical investigations identified the 5-HT2C receptor as a primary mediator of the effect of (dex)fenfluramine on appetite and weight gain (Rowland, Robertson, Lo, & Rema, 2001; Vickers, Dourish, & Kennett, 2001; Vickers, Clifton, Dourish, & Tecott, 1999, 2001b), and the 5-HT2B receptor as the primary mediator of its adverse cardiovascular effects (Fitzgerald et al., 2000; Hutcheson, Setola, Roth, & Merryman, 2011; Rothman et al., 2000).
A significant effort was directed towards the discovery and testing of selective 5-HT2C receptor agonists (Lee, Jung, & Lee, 2010; Monck & Kennett, 2008; Nilsson, 2006; Wacker & Miller, 2008). However, only one such drug has been approved for clinical use. This drug is lorcaserin, which was discovered and developed by Arena Pharmaceuticals. It was approved by the FDA in 2012 for weight management in conjunction with lifestyle modification and has been marketed in the US as Belviq® since 2013. Lorcaserin has also been approved in other territories such as South Korea, Brazil, Taiwan, Israel and Mexico, although to date approval has not been granted in additional larger markets such as the EU and Japan. In 2017, Eisai became solely responsible for all activities relating to global development and regulatory submissions, as well as global marketing for lorcaserin (Belviq®). Due to a variety of factors, not least a perception of modest efficacy, lorcaserin sales have been described as underwhelming (http://www.evaluate.com/node/13742/pdf).
This article reviews the preclinical and clinical pharmacology of lorcaserin and identifies potential therapeutic indications beyond obesity. Lorcaserin is the first selective 5-HT2C receptor agonist approved for use in humans, and due to its relatively recent approval, its full clinical potential is unknown. Precision medicine refers to the selection of treatments according to the individual characteristics of the patient, often in relation to genetics, environment or lifestyle (Frühbeck, Kiortsis, & Catalán, 2018; Hampel, Vergallo, Perry, Lista, & Alzheimer Precision Medicine Initiative (APMI), 2019; Menke, 2018). Further preclinical and clinical investigation of the effects of lorcaserin will identify the behavioural and physiological processes altered by this drug. In turn, a better understanding of these processes may help to identify specific patients, or subgroups of patients, that might benefit most from this drug. This raises the possibility of lorcaserin being used in a more directed way as a “precision medicine”.
Section snippets
Primary pharmacology
The 5-HT2 receptor class is comprised of the 5-HT2A, 5-HT2B and 5-HT2C receptor subtypes. This grouping is based on close amino-acid sequence homology (46–50%) and a preferential coupling to Gq/11. Activation of this G-protein increases the hydrolysis of inositol phosphates and elevates intracellular Ca2+ levels (Hoyer et al., 1994; Palacios, Pazos, & Hoyer, 2017).
Because of associations between 5-HT2A receptor activation and hallucinogenic activity (Geyer & Vollenweider, 2008; Nichols, 2016),
Pre-FDA approval
Lorcaserin entered clinical Phase 1 testing in 2004. Lorcaserin was shown to have consistent and highly predictable pharmacokinetic properties, in healthy subjects and in the target population of overweight and obese adults. Pharmacokinetic properties were independent of sex and race. In a single dose study over the dose range of 10 mg–40 mg, lorcaserin Cmax and AUC increased proportionally with dose, with no change in Tmax (∼2 h). Cmax values were approximately 30 ng/mL, 60 ng/ml and 145 ng/ml at
Lorcaserin – what next?
Since the approval of lorcaserin by the FDA in 2012, and market entry the following year for obesity with lifestyle modification, sales measured in terms of prescriptions have been generally described as modest (http://seekingalpha.com/article/3915896). However, one area of advancement is in the area of safety perception. Based on outcomes from the large CAMELLIA-TIMI trial and the BLOOM, BLOSSOM, and BLOOM-DM trials, at the approved 10 mg BID dose, concerns about valvulopathy have been largely
Disclosures
WRS is a share holder in Arena Pharmaceuticals. GAH and PJF declare no conflict of interest to this work.
References (326)
The study of food addiction using animal models of binge eating
Appetite
(2010)- et al.
Agonist-directed signaling of serotonin 5-HT2C receptors: Differences between serotonin and lysergic acid diethylamide (LSD)
Neuropsychopharmacology
(1999) - et al.
Body mass correlates inversely with inhibitory control in response to food among adolescent girls: An fMRI study
Neuroimage.
(2010) - et al.
d-Fenfluramine and lorcaserin inhibit the binge-like feeding induced by μ-opioid receptor stimulation of the nucleus accumbens in the rat
Neuroscience Letters
(2018) Serotonin manipulations and the structure of feeding behaviour
Appetite
(1986)- et al.
Design and rationale for the cardiovascular and metabolic effects of Lorcaserin in overweight and obese patients-thrombolysis in myocardial infarction 61 (CAMELLIA-TIMI 61) trial
American Heart Journal
(2018) - et al.
Effect of lorcaserin on prevention and remission of type 2 diabetes in overweight and obese patients (CAMELLIA-TIMI 61): A randomised, placebo-controlled trial
Lancet
(2018) - et al.
RS-102221: A novel high affinity and selective, 5-HT2C receptor antagonist
Neuropharmacology
(1997) - et al.
Dextromethorphan interactions with histaminergic and serotonergic treatments to reduce nicotine self-administration in rats
Pharmacology, Biochemistry, and Behavior
(2016) - et al.
Lorcaserin improves glycemic control via a melanocortin neurocircuit
Molecular Metabolism
(2017)
Involvement of 5-HT2C receptors in mediating the discriminative stimulus properties of m-chlorophenylpiperazine (mCPP)
European Journal of Pharmacology
The use of the reinstatement model to study relapse to palatable food seeking during dieting
Neuropharmacology.
Support for 5-HT2C receptor functional selectivity in vivo utilizing structurally diverse, selective 5-HT2C receptor ligands and the 2,5-dimethoxy-4-iodoamphetamine elicited head-twitch response model
Neuropharmacology.
Safety Pharmacology assessment of drugs with biased 5-HT(2B) receptor agonism mediating cardiac valvulopathy
Journal of Pharmacological and Toxicological Methods
The behavioral pharmacology and therapeutic potential of lorcaserin for substance use disorders
Neuropharmacology.
Feeding and reward: Perspectives from three rat models of binge eating
Physiology & Behavior
IV nicotine self-administration in rats using a consummatory operant licking response: Sensitivity to serotonergic, glutaminergic and histaminergic drugs
Progress in Neuro-psychopharmacology & Biological Psychiatry
Impulsivity, compulsivity, and top-down cognitive control
Neuron
mCPP-induced hyperactivity in 5-HT2C receptor mutant mice is mediated by activation of multiple 5-HT receptor subtypes
Neuropharmacology.
Discriminative stimulus properties of the novel serotonin (5-HT)2C receptor agonist, RO 60-0175: A pharmacological analysis
Neuropharmacology.
Impulsive choice and impulsive action predict vulnerability to distinct stages of nicotine seeking in rats
Biological Psychiatry
Role of serotonin(2C) receptors in the control of brain dopaminergic function
Pharmacology, Biochemistry, and Behavior
Biochemical and electrophysiological evidence that RO 60-0175 inhibits mesolimbic dopaminergic function through serotonin(2C) receptors
Brain Research
Persistent attenuation of nicotine self-administration in rats by co-administration of chronic nicotine infusion with the dopamine D1 receptor antagonist SCH-23390 or the serotonin 5-HT2C agonist lorcaserin
Pharmacology, Biochemistry, and Behavior
5-HT2C receptors in the ventral tegmental area, but not in the arcuate nucleus, mediate the hypophagic and hypolocomotor effects of the selective 5-HT2C receptor agonist AR231630 in rats
Behavioural Brain Research
Ligand-directed serotonin 5-HT2C receptor desensitization and sensitization
European Journal of Pharmacology
Reward circuit function in high BMI individuals with compulsive overeating: Similarities with addiction
Neuroimage.
Pharmacotherapy for neuropathic pain in adults: A systematic review and meta-analysis
The Lancet Neurology
Messenger RNA editing of the human serotonin 5-HT2C receptor
Neuropsychopharmacology
Characterizing the effects of 5-HT2C receptor ligands on motor activity and feeding behaviour in 5-HT2C receptor knockout mice
Neuropharmacology.
Impulsive action induced by amphetamine, cocaine and MK801 is reduced by 5-HT(2C) receptor stimulation and 5-HT(2A) receptor blockade
Neuropharmacology.
Genetic and pharmacological evidence that 5-HT2C receptor activation, but not inhibition, affects motivation to feed under a progressive ratio schedule of reinforcement
Pharmacology, Biochemistry, and Behavior
Precision medicine: Diagnosis and management of obesity
The Lancet Diabetes & Endocrinology
Brain circuits regulating energy homeostasis
Regulatory Peptides
Diagnostic and statistical manual of mental disorders (DSM-5®)
Functional status of the serotonin 5-HT2C receptor (5-HT2CR) drives interlocked phenotypes that precipitate relapse-like behaviors in cocaine dependence
Neuropsychopharmacology
Serotonin (5-HT) 5-HT2A receptor (5-HT2AR):5-HT2CR imbalance in medial prefrontal cortex associates with motor impulsivity
ACS Chemical Neuroscience
FDA briefing document. Lorcaserin hydrochloride. NDA 22-529. 13th August 2010
FDA briefing document. Lorcaserin hydrochloride. NDA 22-529. 6th April 2012
Safety and efficacy of lorcaserin: A combined analysis of the BLOOM and BLOSSOM trials
Postgraduate Medicine
Independent neuronal origin of seizures and behavioral comorbidities in an animal model of a severe childhood genetic epileptic encephalopathy
PLoS Genetics
Weight gain in smokers after quitting cigarettes: Meta-analysis
BMJ.
Repeated 7-Day treatment with the 5-HT2C agonist lorcaserin or the 5-HT2A antagonist pimavanserin alone or in combination fails to reduce cocaine vs food choice in male Rhesus monkeys
Neuropsychopharmacology
The application of the 5-choice serial reaction time task for the assessment of visual attentional processes and impulse control in rats
Nature Protocols
High impulsivity predicts the switch to compulsive cocaine-taking
Science.
Behavioural evidence for functional interactions between 5-HT-receptor subtypes in rats and mice
British Journal of Pharmacology
Involvement of 5-HT1C-receptors in drug-induced penile erections in rats
Psychopharmacology.
Signal transduction differences between 5-hydroxytryptamine type 2A and type 2C receptor systems
Molecular Pharmacology
Effector pathway-dependent relative efficacy at serotonin type 2A and 2C receptors: Evidence for agonist-directed trafficking of receptor stimulus
Molecular Pharmacology
RNA-editing of the 5-HT2C receptor alters agonist-receptor-effector coupling specificity
British Journal of Pharmacology
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