CAMBRIDGESHIRE JOINT PRESCRIBING GROUP DDECISION DOCUMENT Recommendation made by CJPG to Commissioners and Prescribers

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1 CAMBRIDGESHIRE JOINT PRESCRIBING GROUP DDECISION DOCUMENT Recommendation made by CJPG to Commissioners and Prescribers Lorcaserin (Lorqess (US name), Arena pharmaceuticals) for obesity Date of last revision Document status Purpose of Document A selective serotonin 2C receptor agonist. 19 July 2012, version 1(1) Prepared by Debbie Morrison, Consultant Pharmacist, PHN and HCD; Reviewed by Katie Smith, Director, East Anglia Medicines Information Service. Considered by CJPG at the July 2012 meeting. To review information currently available on use of the drug, give guidance on potential use and assign a R-A-G classification. Members were asked to consider the clinical efficacy of lorcaserin in a therapeutic area where there is a shortage of treatment options. The drug has a very large potential market and has been approved by the FDA. The weight loss achieved by lorcaserin over placebo is approximately 3kg in a 100kg patient. This was not sustained in patients stopping the drug and only partially maintained in patients remaining on the drug. Recommendations The weight loss is unlikely to impact on levels of obesity in the UK. It is recommended by Cambridgeshire JPG members, and through them to local NHS organisations, that the arrangements for use of lorcaserin are in line with restrictions agreed locally for drugs designated as DOUBLE RED, i.e. that the clinical case for its use is not proven and it will not be funded for prescribing in primary or secondary care. Rationale for Decision Members noted the limited evidence for efficacy for lorcaserin. Members also noted further limitations in the data due to the impact of the lifestyle modification programme, the large number of patients who were not weighed at 52 weeks in the BLOOM trial, the fact that only 45 to 55% of participants entered the second phase of this trial and the use of last observation carried forward (LOCF) data which overemphasised the impact of early weight loss. Members noted that there remained questions over the incidence of valvulopathy with the drug and the use of a 90% confidence interval for an important safety endpoint. Members also noted the need for further investigation of concerns over carcinogenicity. Members acknowledged the need for additional pharmacotherapeutic agents for the adjunctive treatment of obesity but agreed that the evidence base for lorcaserin was too weak and the drug should be designated DOUBLE RED on clinical grounds.

2 Points Considered: The rapid increase in the prevalence of overweight and obesity has resulted in the proportion of adults in England with a healthy BMI ( ) decreasing between 1993 and 2010 from 41.0% to 30.9% among men, and 49.5% to 40.4% among women. In England, currently 26.1% of adults (aged 16 years and over) are obese (HSE 2010).[10] By 2050 the prevalence of obesity is predicted to affect 60% of adult men, 50% of adult women and 25% of children (Foresight 2007).[10] In addition 10.1% of boys and 8.8% of girls in Reception year (aged 4-5 years) and 20.6% of boys and 17.4% of girls in Year 6 (aged years) are also classified as obese according to the British 1990 population monitoring definition of obesity ( 95th centile) (NCMP 2010/11).[10] The fundamental problem underlying obesity is a small, but prolonged, positive energy balance, where energy derived from food exceeds energy expended for everyday living.[6] According to Guidelines (National Heart, Lung, and Blood Institute Guidelines, 1998, the use of medication to help patients adhere to lifestyle change is indicated for individuals with BMI 27 kg/m 2 and at least 1 comorbid condition and for those with BMI 30. With the recent withdrawal of marketing authorisations for rimonabant and sibutramine there are few pharmacological options available for management of obesity. The only agent approved for long-term use in obesity is orlistat. Lorcaserin is not yet licensed or available anywhere in the world. According to BioSpace, a Marketing Authorisation Application has been submitted to the European Medicines Agency for lorcaserin for weight control, including weight loss and maintenance of weight loss, in patients who are obese (BMI >30) or overweight (BMI >27) and have at least one weight-related comorbid condition. The application was submitted in the EU for approval for weight control on 5/3/2012. An FDA panel supported approval of lorcaserin for weight loss on 11/05/2012. PharmaTimes reported that the United States Food and Drug Administration s (FDA) Endocrinologic and Metabolic Drugs Advisory Committee voted 18 to 4, with one abstention, that available data demonstrate that the potential benefits of lorcaserin (Lorqess ) outweigh the potential risks when used long-term for weight loss. The drug was initially rejected by the FDA in 2010 because of data showing only a modest weight loss and concerns about ADRs and tumours observed in animal studies. In 2012, the FDA reiterated its concerns but noted that new data from the company seemed to rule out an excess risk of valvular heart disease, although some of the panellists did not agree. Lorcaserin is believed to act as an agonist of the selective serotonin 2C receptor, which is expressed in the brain, including the hypothalamus, which is believed to be involved in the control of appetite and metabolism. Lorcaserin administered in conjunction with a lifestyle modification program was associated with dose-dependent weight loss that was significantly greater than with placebo (least squares mean weight loss for the BD dose of lorcaserin was 5.8% weight loss compared to 2.8% with placebo).[1] In the BLOOM trial, at 1 year, 55.4% of patients (883 of 1595) receiving

3 Numbers Needed to Treat (NNT) Numbers Needed to harm (NNH) Other Submissions lorcaserin and 45.1% of patients (716 of 1587) receiving placebo remained in the trial; 1553 patients continued into year 2.[2] Lorcaserin is highly selective for a subtype of 5-HT receptors important in appetite regulation, with low affinity for other 5-HT-receptor subtypes whose activation is thought to underlie serious cardiovascular adverse effects; such effects have been seen with non-selective serotonergic agents for weight loss (e.g., fenfluramine).[4] In two of the three Phase III trials to date, lorcaserin use was not found to increase the risk of cardiac valvulopathy; however, in the other Phase IIl trial, which focused on patients with diabetes, lorcaserin use was associated with an increased rate of new valvulopathy.[4] A study in rats indicated that lorcaserin, and likely other selective 5-HT 2C receptor agonists, similarly affect both food- and nicotine-motivated behaviors, and nicotine-induced impulsivity. Collectively, these findings highlight a therapeutic potential for 5-HT 2C agonists such as lorcaserin beyond obesity into addictive behaviors, such as nicotine dependence. In a carcinogenicity evaluation involving laboratory rats, lorcaserin was linked to the development of various malignancies, a finding with uncertain implications for its potential future use in humans. For a 5% reduction in body weight for lorcaserin 10mg BD over placebo, NNT = 4.5 [1] For a 10% reduction in body weight for lorcaserin 10mg BD over placebo, NNT = 7.8 [1] Not calculable NICE CG 43: Guidance on the prevention, identification, assessment and management of overweight and obesity in adults and children indicates that where pharmacological therapy is indicated the following approach should be taken: Offer a 6 12-month trial of orlistat, with regular review of effectiveness, adverse effects and adherence. [In a 4-year double-blind, randomized, placebo-controlled trial with orlistat in 3304 overweight patients, 21% of whom had impaired glucose tolerance, 23% achieved a weight loss during the first year of >11% below baseline in the orlistat-treated group compared with 6% below baseline in the placebo-treated group. Over the remaining 3 years of the trial, there was a small regain in weight, such that by the end of 4 years, the orlistat-treated patients were 6.9% below baseline in comparison with 4.1% for those receiving placebo. [6]]. [The NELM reported on 28/6/2012 that the FDA has approved lorcaserin hydrochloride, as an addition to a reduced-calorie diet and exercise, for chronic weight management. The drug is approved for use in adults with a body mass index (BMI) of 30 (obese), or adults with a BMI of 27 (overweight) and who have at least one weight-related condition such as hypertension, type 2 diabetes, or dyslipidaemia. The drug should be discontinued in patients who fail to lose 5% of their body weight after 12 weeks of treatment, as these patients are unlikely to achieve clinically meaningful weight loss with continued treatment.

4 Treatment Alternatives Weight loss programmes, orlistat, metformin (off-licence not approved in NHSC&P) and topiramate (off-licence not approved in NHSC&P) and surgery (the BNF no longer recommends use of phentermine and diethylpropion). Not yet licensed Place in current therapy Future Alternatives None known JPG Decision/Date July 2012 Review Date On licensing and/or consideration by NICE Indication(s) Contraindications Cautions Source of Review Guidance on Use Clinical Efficacy Likely to be for weight control, including weight loss and maintenance of weight loss, in patients who are obese (BMI >30) or overweight (BMI >27) and have at least one weight-related co-morbid condition. Not defined The most frequent adverse events (AEs) were transient headache, nausea, and dizziness. Echocardiograms showed no apparent drug-related effects on heart valves or pulmonary artery pressure (PAP). [3] [1] Fidler MC, Sanchez M et al. A one-year randomized trial of lorcaserin for weight loss in obese and overweight adults: the BLOSSOM trial. Journal of Clinical Endocrinology & Metabolism 2011; 96 (10): [2] Smith SR, Weissman NJ, Anderson CM, Sanchez M, Chuang E, Stubbe S, Bays H, Shanahan WR, Behavioral Modification and Lorcaserin for Overweight and Obesity Management (BLOOM) Study Group. Multicenter, placebo-controlled trial of lorcaserin for weight management. New England Journal of Medicine 2010; 363 (3): [3] Steven R. Smith, Warren A. Prosser et al. Lorcaserin (APD356), a Selective 5- HT2C Agonist, Reduces Body Weight in Obese Men and Women. Obesity 2008, 17: [4] Hurren KM, Berlie HD. Lorcaserin: An investigational serotonin 2C agonist for weight loss. American Journal Health-Syst Pharm. 2011; 68: [5] Martin CK, Redman LM, Zhang J, et al. Lorcaserin, a 5-HT(2C) receptor agonist, reduces body weight by decreasing energy intake without influencing energy expenditure. Journal of Clinical Endocrinology & Metabolism 2011; 9 (3): [6] Bray G.A., Ryan D.H. Medical therapy for the patient with obesity. Circulation 2012; 125 (13): [7] Floyd JS, Heckbert SR. Correspondence: New England Journal of Medicine. 2010; 363: [9] Finer N, James WPT et al. One-year treatment of obesity: a randomized, doubleblind, placebo-controlled, multicentre study of orlistat, a gastrointestinal lipase inhibitor. International Journal of Obesity 2000, 24 (3): [10] Solutions for Public Health Website accessed 21/06/2012 ; Source: OECD: Likely dosage is lorcaserin 10mg BD. [1] The objective of the BLOSSOM study was to evaluate the effects of lorcaserin on body weight, cardiovascular risk factors, and safety in obese and overweight patients. This randomized, placebo-controlled, double-blind, parallel arm trial took place at 97 U.S. research centers. Patients included 4008 adults, aged 18-65yr, with a body mass index between 30 and 45 kg/m 2 or between 27 and 29.9 kg/m 2 with an obesityrelated comorbid condition.

5 Patients were randomly assigned in a 2:1:2 ratio to receive lorcaserin 10 mg twice daily (BD), lorcaserin 10 mg once daily (OD), or placebo. All patients received diet and exercise counseling. The ordered primary endpoints were proportion of patients achieving at least 5% reduction in body weight, mean change in body weight, and proportion of patients achieving at least 10% reduction in body weight at 1 yr. Serial echocardiograms monitored heart valve function. Significantly more patients treated with lorcaserin 10 mg BD and OD lost at least 5% of baseline body weight (47.2 and 40.2%, respectively) as compared with placebo (25.0%, P < vs. lorcaserin BD). Least squares mean (95% confidence interval) weight loss with lorcaserin BD and OD was 5.8% ( %) and 4.7% ( %), respectively, compared with 2.8% ( %) with placebo (P < vs. lorcaserin BD; least squares mean difference, 3.0%). Weight loss of at least 10% was achieved by 22.6 and 17.4% of patients receiving lorcaserin 10 mg BD and OD, respectively, and 9.7% of patients in the placebo group (P < vs. lorcaserin BD). Headache, nausea, and dizziness were the most common lorcaserin-related adverse events. U.S. Food and Drug Administration-defined echocardiographic valvulopathy occurred in 2.0% of patients on placebo and 2.0% on lorcaserin 10 mg BD. [2] In the BLOOM double-blind clinical trial, 3182 obese or overweight adults (mean body-mass index [the weight in kilograms divided by the square of the height in meters] of 36.2) were randomly assigned to receive lorcaserin at a dose of 10 mg, or placebo, twice daily for 52 weeks. All patients also underwent diet and exercise counseling. At week 52, patients in the placebo group continued to receive placebo but patients in the lorcaserin group were randomly reassigned to receive either placebo or lorcaserin. Primary outcomes were weight loss at 1 year and maintenance of weight loss at 2 years. Serial echocardiography was used to identify patients in whom valvulopathy (as defined by the Food and Drug Administration) developed. At 1 year, 55.4% of patients (883 of 1595) receiving lorcaserin and 45.1% of patients (716 of 1587) receiving placebo remained in the trial; 1553 patients continued into year 2. At 1 year, 47.5% of patients in the lorcaserin group and 20.3% in the placebo group had lost 5% or more of their body weight (P<0.001), corresponding to an average loss of 5.8+/-0.2 kg with lorcaserin and 2.2+/-0.1 kg with placebo during year 1 (P<0.001). Among the patients who received lorcaserin during year 1 and who had lost 5% or more of their baseline weight at 1 year, the loss was maintained in more patients who continued to receive lorcaserin during year 2 (67.9%) than in patients who

6 received placebo during year 2 (50.3%, P<0.001). Among 2472 patients evaluated at 1 year and 1127 evaluated at 2 years, the rate of cardiac valvulopathy was not increased with the use of lorcaserin. Among the most frequent adverse events reported with lorcaserin were headache, dizziness, and nausea. The rates of serious adverse events in the two groups were similar. CONCLUSIONS: In conjunction with behavioral modification, lorcaserin was associated with significant weight loss and improved maintenance of weight loss, as compared with placebo. (Funded by Arena Pharmaceuticals). [A response to the above paper in the NEJM commented that: In the trial reported on by Smith et ai., only 64% of patients in the lorcaserin group and 56% of patients in the placebo group were weighed at 52 weeks. Potentially confounding factors may be unbalanced across treatment groups, rendering any estimate of a treatment effect uninterpretable. Because most weight loss in clinical trials occurs early and is not sustained, last observation - carried-forward and repeated-measures analyses will result in an overestimation of the true effect. Failure to perform echocardiographic evaluations in all patients at 52 weeks may have resulted in bias, since the rate of valvulopathy may have been higher among patients lost to follow-up. A lack of evidence of harm is not evidence of safety. Also, the use of a 90% confidence interval for an important safety end point is nonconventional; a standard, 95% confidence interval should be reported. The authors responded that secondary sensitivity analyses mirror and therefore support the prespecified primary analyses. [7]]. [3] Smith and Prosser et al evaluated the safety and efficacy of lorcaserin for weight reduction in obese patients during a 12-week period. Lorcaserin (APD356) is a potent, selective 5-HT2C agonist with ~15-fold and 100-fold selectivity vs. 5-HT2A and 5-HT2B receptors, respectively. The randomized, double-blind, placebocontrolled, parallel-arm study enrolled 469 men and women between ages 18 and 65 and with BMI kg/m 2. Patients received placebo, lorcaserin 10 mg OD lorcaserin 15 mg OD, or lorcaserin 10 mg BD for 12 weeks, and were counselled to maintain their usual diet and activity. The primary end point was change in weight from baseline to day 85 by completer analysis. Safety analyses included echocardiograms at Screening and day 85/study exit. Lorcaserin was associated with progressive weight loss of 1.8 kg, 2.6 kg, and 3.6 kg at 10 mg OD, 15 mg OD, and 10 mg BD, respectively, compared to placebo weight loss of 0.3 kg (P < for each group). Similar results were seen by intent-to-treat last observation-carried forward (ITTLOCF) analysis. The proportions of completers achieving 5% of initial body weight were 12.8, 19.5, 31.2, and 2.3% in the 10 mg OD, 15 mg OD, 10 mg BD, and placebo groups,

7 respectively. [5] The study by Martin and Redman et al tested the effect of lorcaserin on energy intake (EI) and and energy expenditure (EE). Lorcaserin, a selective 5- hydroxytryptamine (5-HT)(2C) receptor agonist, reduces body weight. It is unclear whether weight loss is due to reduced EI or also to enhanced EE. In a double-blind, randomized, placebo-controlled trial, 57 (39 women) overweight and obese (body mass index, kg/m 2 ) adults were randomized to placebo (n = 28) or 10 mg twice daily lorcaserin (n = 29) for 56 days. Weight maintenance was imposed during days 1-7. Beginning on day 8, participants followed a diet and exercise plan targeting a 600 kcal/day deficit. At baseline and after 7 and 56 days of treatment, body weight, body composition (dual x-ray absorptiometry), blood pressure, heart rate, EI at lunch and dinner, subjective appetite ratings, and 24-h EE and 24-h-respiratory quotient (RQ), were measured by indirect calorimetry in a respiratory chamber. After 7 days of weight maintenance, EI was significantly (P < 0.01) reduced with lorcaserin but not placebo (mean +/- sem for lorcaserin, /- 86 kcal; placebo, /- 89 kcal). After 56 days, lorcaserin resulted in significantly larger reductions in body weight (lorcaserin, /- 0.4 kg; placebo, /- 0.5 kg; P < 0.01), EI (lorcaserin, /- 87 kcal; placebo, /- 91 kcal; P <.05), and appetite ratings than in placebo. Changes in 24-h EE and 24-h RQ did not differ between groups, even after 24-h EE was adjusted for body weight and composition. Compared with placebo, lorcaserin had no effect on systolic or diastolic blood pressure or heart rate after 56 days. Impact for Cambridgeshire and Peterborough PCTs Costs CONCLUSIONS: Lorcaserin reduces body weight through reduced EI, not altered EE or RQ. If lorcaserin is made available for adult obesity patients there are likely to be 26.1% of 671,000 adult obese patients in NHSC&P who may potentially be eligible for the drug, i.e. 175,000 patients. There may be additional patients who would fit the proposed licensing for overweight patients with BMI >27 and 1 or more co-morbidities. The costs of lorcaserin are not currently known. The NNT for a 5% weight loss at 12 weeks for orlistat is 7 and the NNT for a 10% weight loss is 9. There is therefore a cost for one patient to benefit from a 5% reduction in weight associated with use of orlistat of 2,886 and a cost of 3,710 for a one patient to benefit from a reduction in weight of 10%. [based on a BNF63 price for orlistat of per annum] Therefore the cost of lorcaserin should not exceed per annum to be considered at least as cost-effective as orlistat in acheiving a weight loss of 5% body weight and should not exceed per annum to be considered as cost-effective as orlistat in achieving a weight loss of 10% body weight.

8 Clinician Comments Comments to: The cost-effectiveness of orlistat has been considered by NHSC previously and deemed to not be cost-effective at the current price. Lead Obesity Consultant (CUHFT) comments: Even though lorcaserin s effects appear modest, I would be keen to have access to prescribe this drug if it is licenced. Obesity medical therapy is currently limited and this drug may be a useful adjunct for the specialist level 3 service to have access to. Certainly I could see it having a role being prescribed to patients who were orlistat intolerant patients and in whom any weight loss would be medically indicated. In addition I can see the drug having an important role in our intensive weight management programme for helping with weight maintenance. Patients in this programme lose on average of their weight and the use of such compounds has been well documented as an aid to weight maintenance (Nick Finer has published on this approach 20years ago). I think that this drug does have a potentially important role in the level 3 service, albeit as a second line agent. As such, I would envisage it being required for only a small percentage of patients in our clinic population. Obviously this though is all dependent on the drug obtaining a licence. Debbie Morrison, Consultant Pharmacist, CJPG, Cambridgeshire and Peterborough Public Health Network, Hunts Area Office, California Road, Huntingdon, Cambridgeshire, PE29 1BN. debbie.morrison@cambsphn.nhs.uk