Has the bloom gone out of lorcaserin following the CAMELLIA-TIMI61 trial?

KEYWORDS:

• Diabetes risk
• food appetite
• serotonin 5HT2c receptor
• Belviq

1. Introduction

Lorcaserin is a selective serotonin 5-HT2c receptor agonist that has shown efficacy for weight loss, as documented by the BLOOM, BLOSSOM and CAMELLIA-TIMI 61 trials [1–4]. While these trials have shown that lorcaserin does not induce the pattern of cardiovascular complications which have plagued other weight loss drugs that activate serotonin-dependent satiety signaling, the FDA asked the manufacturer to continue post-approval monitoring. In the CAMELLIA-TIMI 61 cohort, a small increase in cancer was noted in the treatment group, which has led the FDA to request Eisai, the manufacturer, to voluntarily withdraw the drug from the US market in February this year [5].

2. Brief history of lorcaserin

Many drugs that influence appetite have stimulated neurotransmitter pathways that influence the signaling of appetite and satiety by the central nervous system. Unfortunately, most have had to be withdrawn or had severe restrictions on their use due to a range of side-effects that include life-threatening psychological and cardiovascular events. Earlier drugs such as fenfluramine increased the release of serotonin and activated a range of receptors such as the 5-HT2c receptor, which has a key role in stimulating hypothalamic signaling of satiety. However, the use of fenfluramine by itself and in combination with other drugs was found to cause heart valve damage, cardiac fibrosis and pulmonary hypertension, which resulted in the banning and withdrawal of drugs of this class. These undesirable side-effects are thought to be mediated by serotonin 5-HT2a and 2b receptors. Subsequent pharmaceutical refinement focused on discovering molecules that selectively bind to the 5-HT2c receptor, and lorcaserin, a full 5-HT2c agonist, (with low activity at 5-HT2a and 2b receptors) was shown to have consistent effects on weight loss, without inducing significant side-effects on the cardiovascular system. Through a series of multi-center trials involving about 5 thousand patients, lorcaserin received approval for marketing and use in the USA in 2012, while continuing post-market evaluation of safety [6].

3. Clinical trial evaluation

The multi-center BLOOM (Behavioral Modification and Lorcaserin for Overweight and Obesity Management) trial showed that lorcaserin (10 mg twice daily) as an adjunct treatment to diet and exercise induced significant and sustained weight loss of >5% compared to placebo. A further study BLOSSOM (Behavioral Modification and Lorcaserin Second Study) compared two doses of lorcaserin (10 mg/d and 10 mg bd) to placebo and showed that both treatment groups experienced greater weight loss than placebo. There was no evidence of an increased rate of valvulopathy, which was the main safety concern of the FDA, and approval was granted in 2012. Post hoc analysis of participant results from the BLOOM + BLOSSOM and a diabetic sub-group (BLOOM-DM) revealed that there was no difference in echocardiographic diagnosis of valvulopathy between the treatment and placebo groups after 1 year [6]. However, ongoing monitoring was a condition of FDA approval. The manufacturer sponsored the CAMELLIA-TIMI-61 trial (Cardiovascular and Metabolic Effects of Lorcaserin in Overweight and Obese Patients – Thrombolysis in Myocardial Infarction 61) in a cohort of 12,000 patients who were at high risk of developing cardiovascular disease due to having either atherosclerotic cardiovascular disease or multiple cardiovascular risk factors. About 93% of participants completed the trial and the median follow-up period was 3.3 years [7]. Weight loss of >5% occurred in 53.3% of participants treated with lorcaserin, which was significantly greater than placebo (22.2%). Importantly, new or worsening valvulopathy was not significantly increased in the treatment group (1.8%) relative to placebo (1.3%) [7].

The incidence of hypoglycemia has also been raised as a potential serious adverse event associated with lorcaserin. Post-hoc analysis of the BLOOM + BLOSSOM and BLOOM-DM trials [8] showed that percentage of patients with greater than 5 and 10% weight loss was higher in subjects who were older than 36 years old. The level of weight loss was not as high in patients with type 2 diabetes (T2D) and 7.4% more subjects in the treatment group self-reported hypoglycemic events (not requiring hospitalization), in comparison to the placebo group. While some concern was raised around the increase in the number of hypoglycemic events in the treatment group, it was noted that successful weight loss in a diabetic cohort would be expected to increase insulin sensitivity and this could be managed by reducing the dosage of insulin and insulin-sensitizing medications at the outset of lorcaserin therapy [9]. Eisai also conducted a grouped analysis of the participants from the BLOOM, BLOSSOM and BLOSSOM DM trials, which indicated that weight loss was not as strongly correlated with improvements in diabetes parameters, such as circulating HbA1c and fasting glucose compared with other parameters such as the reduction in blood pressure and circulating triglycerides [10]. Based on this evidence, the risk of hypoglycemia does not seem to be directly attributable to lorcaserin treatment in overweight and obese diabetic subjects. However, evidence in mice has revealed a neuronal circuit activated by lorcaserin which improved glucose clearance without requiring weight loss [11]. This pathway was dependent on melanocortin 4 receptors in the arcuate nucleus and indicates that activation of hypothalamic 5-HT2c receptors can have acute hypoglycemic effects in addition to improvements in insulin sensitivity associated with weight loss.

The CAMELIA-TIMI 61 study was also subjected to similar scrutiny and it was suggested that the increased risk of hypoglycemic events might offset the benefits of reduced microvascular pathologies that were measured in pre-diabetic subjects [12]. On the other hand, the CAMELLIA-DM study analyzed the cohort and showed that there was a decrease in the development of diabetes associated with long-term use of lorcaserin [13].

Earlier in 2020, the FDA communicated that their analysis of the data from the CAMELLIA-TIMI 61 study found that 462 patients (7.7%) treated with lorcaserin had cancer diagnosed, compared with 423 patients (7.1%) in the placebo group. Among the range of cancer types that were reported, pancreatic, colorectal, and lung cancer occurred more frequently in the lorcaserin group [5]. As a result, the FDA requested that Eisai voluntarily withdraw the drug from distribution in the USA, which they complied with while releasing a statement that the company’s interpretation of the data differed from the FDA.

4. Expert opinion

In the CAMELLIA-TIMI 61 trial, lorcaserin’s safety and efficacy was tested in a cohort at high risk of developing cardiovascular problems and was found to induce weight loss without the valvulopathy and other circulatory side effects that had plagued previous drugs that targeted the satiety pathway activated by serotonin. Having successfully navigated this historic obstacle and criticisms of side effects including possible hypoglycemia, it seems quite ironic that the increase in cancer detected by the FDA’s initial analysis should now have led to the requested voluntary withdrawal of the drug. Thus, the FDA’s action aligns the USA with other regulatory bodies in Canada and Europe where applications for approval have been withdrawn (the latter also raising concern about a potential increase in cancer with long-term use) [14,15]. While the analysis by the FDA is ongoing, it seems unlikely that lorcaserin will be re-introduced without further trials, this time focusing on the putative carcinogenic risk. This risk was noted in animal studies as an increase in mammary tumors induced at high, non-therapeutic doses that cause prolactin hypersecretion, which was not elevated in human trials [6]. The animal data may be re-analyzed to check for the incidence of the cancers reported in the human trials. A recent review of the human cancer cases showed that while the increase in the number of cancers in the lorcaserin treatment group, was numerically small,the incidence remained consistently elevated compared to the placebo group when treatment continued beyond 180 days duration [5]. While it remains to be seen if lorcaserin will ever return to the market, it seems likely that any proposal in that regard would have to address the FDA’s stated concern over the relative risk (of cancer) outweighing the benefit of a reduction in obesity. Caution may entail that lorcaserin be used at a lower dose (10 mg/d) in high responders, ie. individuals who lose >5% body weight in 12 weeks. Consistent with evaluation of the risk:benefit ratio for any drug, it is important to identify parameters that may predict which individuals are likely to be high responders in terms of achieving a substantial weight loss benefit. A recent study [16] showed that lorcaserin reduced activation of brain areas associated with emotional responses to images of foods, which was correlated with a greater effect on weight loss. While this was a short study (4 weeks of lorcaserin), it indicates that baseline predictors of weight loss benefit in response to lorcaserin treatment could include psychological assessment of emotional responses to desirable foods.

An alternative strategy to improve efficacy is based on evidence that lorcaserin can be used in combination with other drugs such as phentermine. This strategy combined the normal dose of lorcaserin (10 mg bd) with phentermine (15–30 mg), resulting in greater weight loss than lorcaserin alone [17], which may allow the dose of lorcaserin to be reduced without reducing weight loss efficacy. These strategies assume that the risk of developing cancer during chronic treatment is proportional to the dose of lorcaserin, which may not be valid. The viability of this proposition can be tested by analyzing the incidence of cancer is greater in the high responders (>5 and 10% weight loss), which would indicate if the weight loss efficacy also increases the risk of cancer when lorcaserin treatment is longer than 180 days.

Alternatively, pharmaceutical companies may attempt to develop other selective 5-HT2c agonists with a strategy to specifically avoid the risk of cancer. This is the opposite situation to that of a previous weight loss drug, Rimonabant (a cannabinoid receptor-1 antagonist), which was withdrawn due to its property of crossing the blood-brain barrier and causing serious psychological adverse effects in some subjects [18] – what is needed is a 5-HT2c agonist drug that partitions preferentially in brain tissue, thereby reducing the risk of cancer in peripheral tissues. Other 5-HT2c agonist drugs are in development, such as vabicaserin, which was shown to be a full agonist at 5-HT2c receptors and an antagonist at 5-HT2a and 2b receptors [19].It was shown to induce weight loss in animal trials and in a clinical study, improved symptoms of schizophrenia without causing the usual weight gain induced by olanzapine. The short duration of these trials (6 weeks) indicates the feasibility of short term efficacy as a psychiatric treatment, but the risk: benefit ratio for chronic use as a weight loss drug would again require evaluation by regulatory bodies.

In addition to the development of new and more specific 5-HT2c receptor agonists, there is also the strategy of allosteric modulation of receptor activation. The 5-HT2c receptor has been shown to have extracellular allosteric sites that can positively modulate activation in response to agonist binding. Several drugs and natural molecules have been shown to confer positive allosteric modulation, as reviewed recently [20]. One compound (N-[(1-benzyl1H-indol-3-yl)methyl]pyridin-3-amine) was shown to achieve higher concentrations in brain tissue compared to plasma in rats and reduce body weight and food intake [21].Thus, an exciting path forward is to explore the use of positive allosteric modulators, either independently or in combination with lower doses of selective 5-HT2c agonists.

In summary, it remains to be seen if approval will be returned for the use of lorcaserin under restricted conditions. The possibilities include as a short term adjunct therapy to diet and exercise, in a lower dose in combination with other weight loss drugs, or in people who demonstrate a high response. Thus, while the use of lorcaserin for weight loss and other indications such as drug addiction [22] has been set back, the 5-HT2c receptor remains an attractive target for the development of pharmaceuticals with different modalities to activate the neuronal mechanisms subserving weight loss and other behaviors. The flowering in the use of lorcaserin is starting to wither, but the fruit of this first-in-class drug may yet emerge.

Declaration of Interest

ML Mathai has received a Victoria University Research Fellowship as well as in-house support from Victoria University through a grant scheme. He has also received industry sponsorship from Gencorp-Pacific. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This manuscript was not funded.