Lorcaserin: A review of its preclinical and clinical pharmacology and therapeutic potential

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Abstract

The selective 5-HT2C receptor agonist lorcaserin, in conjunction with lifestyle modification, was approved by the FDA in 2012 for weight management. It has been marketed in the US as Belviq® since 2013. This article provides a review of the preclinical and clinical pharmacology of lorcaserin, including its pharmacokinetic and safety profiles. Preclinical studies with lorcaserin initially focused on simple measures of food intake and body weight gain, but have now expanded to include studies on its effects on appetitive aspects of feeding behaviour and models of binge-eating. A significant number of studies have also shown that lorcaserin alters behaviours related to drug use and addiction, in rodents and non-human primates. Potential clinically-relevant effects of lorcaserin have also been reported in models of pain and seizure-like activity. Not surprisingly, the majority of clinical work with lorcaserin has focused on its effects on weight gain, and on physiological processes related to energy intake. However, results of clinical trials and experimental laboratory studies involving lorcaserin are now appearing which describe effects on a range of other behaviours and physiological functions. These include smoking cessation, cocaine self-administration, and behavioural and brain responses to food cues. All of this work suggests that lorcaserin may have therapeutic potential for a variety of disorders and conditions beyond obesity. Based on clinical experience, including the outcomes from several, large, well-powered clinical obesity trials at the approved 10 mg BID dose both pre and post approval, a priori concerns about cardiac valvulopathy have largely been allayed. However, as with any recently approved first-in-class pharmacotherapy, there may be yet-unknown risks, as well as benefits, associated with use of lorcaserin. Nonetheless, the current safety profile and an expanding post approval safety data base should encourage further experimental laboratory-based and clinical trial-based research with lorcaserin in targeted populations to investigate its full 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.

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