Manufacturer: Arena Pharmaceuticals FDA Approval Date: 06/27/2012 Belviq® - lorcaserin Manufacturer: Arena Pharmaceuticals FDA Approval Date: 06/27/2012

Belviq® - lorcaserin Clinical Application Indications: Chronic weight management in: Adults with BMI ≥ 30kg/m2 or BMI ≥ 27kg/m2 and at least one weight related condition (HTN, HLD, T2DM) Place in therapy: As adjunct to diet and exercise for chronic weight management

Belviq® - lorcaserin Clinical Application Contraindications: Pregnancy Warnings: Serotonin syndrome Valvular heart disease Psychiatric disorders or cognitive impairment

Belviq® - lorcaserin Clinical Application Precautions: Hypoglycemia in diabetics Priapism Heart rate decreases Pulmonary hypertension

Belviq® - lorcaserin Clinical Application Pregnancy: Category X Lactation: Not recommended. Belviq® may increase prolactin.

Belviq® - lorcaserin Drug Facts Pharmacology: The exact mechanisms is not known. Belviq® is believed to decrease food consumption and promote satiety by selectively activating 5-HT2C receptors on anorexigenic proopiomelanocortin neurons located in the hypothalamus.

Belviq® - lorcaserin Drug Facts Pharmacokinetics: A Bioavailability: Not been determined Cmax: 1.5-2 hours D Loracersin distributes to the CSF and CNS in humans. Moderately bound (~70%) to human plasma proteins. M Extensively hepatic, producing two major inactive metabolites as well as minor metabolites. E Urine (92%, as metabolites), feces (2%, as metabolites). Half-life of ~ 11hrs, SS reached within 3 days after BID dosing, and accumulation is estimated to be approximately 70%.

Belviq® - lorcaserin Drug Interactions Drug Interactions – Object Drugs:  serotonergic effect of other serotonergic agents or agents that impair serotonin metabolism  effect of CYP2D6 substrates Inhibits CYP2D6 metabolism

Belviq® - lorcaserin Drug Interactions Drug Interactions – Precipitant Drugs: None given in the package insert.

Belviq® - lorcaserin Adverse Effects Common Adverse Effects: Lorcaserin Placebo Headache 16.8% 10.1% Dizziness 8.5% 3.8% Nausea 8.3% 5.3% Fatigue 7.2% 3.6% Diarrhea 6.5% 5.6% Constipation 5.8% 3.9%

Belviq® - lorcaserin Monitoring Parameters Efficacy Monitoring: Loss of at least 5% of baseline body weight by week 12 Toxicity Monitoring: S/sx of serotonin syndrome S/sx of valvulopathy Serotonin syndrome s/sx = Mental status changes, tachycardia, labile blood pressure, hyperthermia, N/V/D Valvulopathy s/sx = Dyspnea, dependent edema, CHF, new heart murmur

Belviq® - lorcaserin Prescription Information Dosing: 10mg po twice daily Cost: AWP $240 (60ct) Net Invoice Cost $202 Cardinal Health (12/21/14)

Belviq® - lorcaserin Literature Review Purpose: To evaluate the safety and efficacy of lorcaserin for weight loss and maintenance of weight loss when administered with a lifestyle modification plan Design: Randomized, placebo- controlled, double-blind clinical trial Smith SR, et al., NEJM. 2010 Jul 15;363(3):245-56.

Belviq® - lorcaserin Literature Review Inclusion Exclusion Inclusion Exclusion 18 to 65 years old Moderate or more severe mitral regurgitation or mild or more severe aortic regurgitation BMI of 30 to 45 or BMI of 27 to 45 with at least 1 coexisting condition (HTN,HLD, CVD, impaired glucose tolerance, sleep apnea) Depression or other major psychiatric disease within 2 years before randomization that necessitated treatment with prescription medication Diabetes SBP > 140mmHg or DBP > 90 Pregnancy or lactation Smith SR, et al., NEJM. 2010 Jul 15;363(3):245-56.

Belviq® - lorcaserin Literature Review Baseline Characteristics: Characteristic Lorcaserin (n=1595) Placebo (n=1587) White 1081 (67.9) 1046 (66.0) Female 1321 (82.9) 1331 (84.0) Age 43.8 ± 0.3 44.4 ± 0.3 Weight in kg 100.4 ± 0.4 99.7 ± 0.4 BMI 36.2 ± 0.1 Waist Circum. (cm) 109.6 ± 0.3 109.2 ± 0.3 100.4 kg ~ 220 pounds 109.6 cm ~ 43 inches Smith SR, et al., NEJM. 2010 Jul 15;363(3):245-56.

Belviq® - lorcaserin Literature Review Treatment Arms: Lorcaserin or placebo twice daily (1:1) x52 weeks Lorcaserin or placebo x52 weeks Placebo → Placebo Lorcaserin → lorcaserin or placebo (2:1) Efficacy: Weight loss Smith SR, et al., NEJM. 2010 Jul 15;363(3):245-56.

Belviq® - lorcaserin Literature Review Statistical Analysis: Echocardiographic safety end point was primary determinant of sample size 1879 patients (940 in each group) required for 80% power at the 5% level of significance 3182 patients recruited Modified ITT population (screening Echo and at least one post-baseline Echo) analyzed Echocardiographic safety end point = proportion of patients in whom FDA-defined valvulopathy had developed by week 52 Proportion of patients in placebo group in whom FDA-defined valvulopathy would develop was estimated at approximately 5% per year A noninferiority margin of −0.025 (equivalent to a relative risk of valvulopathy with lorcaserin of 1.5) was also used in the estimation of sample size Smith SR, et al., NEJM. 2010 Jul 15;363(3):245-56.

Belviq® - lorcaserin Literature Review Primary Endpoint: Weight loss at 1 year Maintenance of weight loss at 2 years Secondary Endpoint: Waist circumference, BP, cholesterol, fasting insulin and glucose, CRP, fibrinogen, impact of weight on QOL Echocardiography Smith SR, et al., NEJM. 2010 Jul 15;363(3):245-56.

Belviq® - lorcaserin Literature Review Results: ITT Population End Point Lorcaserin (n=1538) Placebo (n=1499) P-value Loss of ≥5% of body weight Patients (%) 47.5 20.3 <0.001 Weight change (kg) -5.82 ± 0.2 -2.2 ± 0.1 Loss of ≥10% of body weight (%) 22.6 7.7 Waist circumference (cm) -6.8 ± 0.2 -3.9 ± 0.2 BMI -2.09 ± 0.06 -0.78 ± 0.05 5.82kg = 12.8 pounds 2.2 kg = 4.84 pounds Waist circumference 6.8 cm = 2.7 inches Smith SR, et al., NEJM. 2010 Jul 15;363(3):245-56.

Belviq® - lorcaserin Literature Review Selected Adverse Events: n, (%) Event Lorcaserin (n=1593) Placebo (n=1584) Headache 287 (18.0) 175 (11.0) Dizziness 130 (8.2) 60 (3.8) Nausea 119 (7.5) 85 (5.4) Diarrhea 109 (6.8) Fatigue 95 (6.0) 48 (3.0) Dry mouth 83 (5.2) 37 (2.3) Vomiting 59 (3.7) 42 (2.7) Insomnia 41 (2.6) 58 (3.7) Smith SR, et al., NEJM. 2010 Jul 15;363(3):245-56.

Belviq® - lorcaserin Literature Review Discussion: At year 1, 47.5% of lorcaserin group vs 20.3% of placebo had lost 5% or more of body weight Loss was maintained in more patients who continued to receive lorcaserin in year 2 (67.9%) vs placebo (50.3%) Rate of valvulopathy was NOT increased with use of lorcaserin Smith SR, et al., NEJM. 2010 Jul 15;363(3):245-56.

Belviq® - lorcaserin Literature Review Pros Cons New agent for weight management as adjunct to reduced-calorie diet and exercise. Patients may have regained their weight after trial withdrawal (ITT population with LOCF) Over 50% of lorcaserin patients achieved goal 5% of body weight amounted to approximately 12 pounds Weight loss of 5% to 10% can have beneficial effects Assumed valvulopathy would develop in 5% of placebo within 1 year (only 2.3% found) – underpowered Increased valvulopathy and psychiatric issues not observed Rate of discontinuation was nearly 50% Applicability (white, females, healthy) Trial also had neither a placebo run-in period nor a dose adjustment period Smith SR, et al., NEJM. 2010 Jul 15;363(3):245-56.

Belviq® - lorcaserin Summary Belviq®, lorcaserin, is indicated for weight management in adults (BMI≥30 or BMI≥27 + 1 RF) as an adjunct to diet and exercise Potentially increases effects of other serotonergic agents and may increase substrates metabolized by CYP2D6 Dosed 10mg po BID ADE include headache, dizziness, & fatigue Long-term data is lacking Belviq® was required to submit additional data as the agent was reported to be associated with tumor risk in rodents (mammary adenocarcinomas)

Belviq® - lorcaserin References www.belviq.com. Accessed 09/14/14. Belviq® Package Insert. Arena Pharmaceuticals. June 2012. Smith SR, et al., Multicenter, placebo-controlled trial of lorcaserin for weight management. N Engl J Med. 2010 Jul 15;363(3):245-56.