BELVIQ XR Extended Release Extended Release (Page 6 of 8)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Mutagenesis

Lorcaserin was not mutagenic in an in vitro bacterial mutation assay (Ames test), was not clastogenic in an in vitro chromosome aberration assay in Chinese hamster ovary cells, and was not genotoxic in an in vivo micronucleus assay in rat bone marrow.

Carcinogenesis

The carcinogenic potential of lorcaserin was assessed in two-year carcinogenicity studies in mice and rats. CD-1 mice received doses of 5, 25 and 50 mg/kg. There were no treatment-related increases in the incidence of any tumor in mice at doses that produced plasma exposure in males and females of 8 and 4-times the daily human clinical dose, respectively.

In the rat carcinogenicity study, male and female Sprague-Dawley rats received 10, 30, and 100 mg/kg lorcaserin hydrochloride. In females, mammary adenocarcinoma increased at 100 mg/kg, which was associated with plasma exposures that were 87-times the daily human clinical dose. The incidence of mammary fibroadenoma was increased in female rats at all doses with no safety margin to the clinical dose. The increases in adenocarcinomas and fibroadenomas may be associated with lorcaserin-induced changes in prolactin homeostasis in rats. The relevance of the increased incidence of mammary adenocarcinomas and fibroadenomas in rats to humans is unknown.

In male rats, treatment-related neoplastic changes were observed in the subcutis (fibroadenoma, Schwannoma), the skin (squamous cell carcinoma), mammary gland (adenocarcinoma and fibroadenoma), and the brain (astrocytoma) at greater than or equal to 30 mg/kg (plasma exposure 17-times human clinical dose). At higher exposure, liver adenoma and thyroid follicular cell adenoma were increased but were considered secondary to liver enzyme induction in rats and are not considered relevant to humans. Human brain exposure (AUC24h,ss ) to lorcaserin at the clinical dose is estimated to be 70-fold lower than brain exposure in rats at the dose at which no increased incidence of astrocytoma was observed. Excluding the liver and thyroid tumors, these neoplastic findings in male rats are of unknown relevance to humans.

Impairment of Fertility

Potential effects on fertility were assessed in Sprague-Dawley rats in which males were dosed with lorcaserin hydrochloride for 4 weeks prior to and through the mating period, and females were dosed for 2 weeks prior to mating and through gestation day 7. Lorcaserin had no effects on fertility in rats at exposures up to 29 times the human clinical dose.

14 CLINICAL STUDIES

The safety and efficacy of lorcaserin for chronic weight management in conjunction with reduced caloric intake and increased physical activity were evaluated in 3 randomized, double-blind, placebo-controlled trials with durations ranging from 52 to 104 weeks. Two trials in adults without type 2 diabetes mellitus (Study 1 and Study 2) and one study in adults with type 2 diabetes mellitus (Study 3) evaluated the effect of immediate-release lorcaserin hydrochloride 10 mg twice daily. The primary efficacy parameter in these studies was weight loss at 1 year, which was assessed by percent of patients achieving greater than or equal to 5% weight loss, percent of patients achieving greater than or equal to 10% weight loss, and mean weight change. All patients received one-on-one instruction for a reduced-calorie diet and exercise counseling that began with the first dose of study medication and continued every four weeks throughout the trial.

Study 1 was a 2-year study that enrolled 3182 patients who were obese (BMI 30-45 kg/m2), or who were overweight (BMI 27-29.9 kg/m2) and had at least one weight-related comorbid condition such as hypertension or dyslipidemia. In Year 2, placebo patients were continued on placebo and lorcaserin patients were re-randomized in a 2:1 ratio to continue lorcaserin or to switch to placebo. The mean age was 44 (range 18-65); 83.5% were women. Sixty-seven percent were Caucasian, 19% were African American and 12% were Hispanic. Mean baseline body weight was 100.0 kg and mean BMI was 36.2 kg/m2.

Study 2 was a 1-year study that enrolled 4008 patients who were obese (BMI 30-45 kg/m2) or were overweight (BMI 27-29.9 kg/m2) with at least one comorbid condition such as hypertension or dyslipidemia. The mean age was 44 (range 18-65); 80% were women. Sixty-seven percent were Caucasian, 20% were African American and 11% were Hispanic. Mean baseline body weight was 100.2 kg and mean BMI was 35.9 kg/m2.

Study 3 was a 1-year study that enrolled 604 adult patients with BMI greater than or equal to 27 kg/m2 and inadequately controlled type 2 diabetes (HbA1c range 7-10%) being treated with metformin and/or a sulfonylurea. Mean age was 53 (range 21-65); 54% were women. Sixty-one percent were Caucasian, 21% African American and 14% were Hispanic. Mean BMI was 36 kg/m2 and mean HbA1C was 8.1%.

A substantial percentage of randomized subjects withdrew from each study prior to week 52: 50% in Study 1, 45% in Study 2 and 36% in Study 3.

One-Year Weight Management in Patients without Diabetes Mellitus

Weight loss at 1 year in Studies 1 and 2 is presented in Table 6. The pooled data are reflective of the individual study results.

Statistically significantly greater weight loss was achieved with lorcaserin compared to placebo at week 52. The Year 1 placebo-adjusted weight loss achieved in patients treated with lorcaserin was 3.3 kg by ITT/LOCF analysis. The time course of weight loss with lorcaserin and placebo through week 52 is depicted in Figure 1.

Patients who did not lose at least 5% of baseline body weight by week 12 were unlikely to achieve at least 5% weight loss at week 52.

Table 6. Weight Loss at 1 Year in Studies 1 and 2 Combined
Lorcaserin * N=3098 Placebo N=3038
Weight (kg)
Baseline mean (SD)100.4 (15.7)100.2 (15.9)
Change from baseline (adjusted mean1) (SE)-5.8 (0.1)-2.5 (0.1)
Difference from placebo (adjusted mean1) (95% CI)-3.3** (-3.6, -2.9)
Percent change from baseline (adjusted mean1) (SE)-5.8 (0.1)-2.5 (0.1)
Difference from placebo (adjusted mean1) (95% CI)-3.3** ( -3.6, -3.0)
% of Patients losing greater than or equal to 5% body weight 47.122.6
Difference from placebo (95% CI)24.5** (22.2, 26.8)
% of Patients losing greater than or equal to 10% body weight 22.48.7
Difference from placebo (95% CI)13.8** (12.0, 15.5)

SD=Standard Deviation; SE=Standard Error; CI=Confidence Interval

Intent to Treat Population using last observation carried forward method; All patients who received study medication and had a post-baseline body weight. Forty-four percent (44%) of patients in lorcaserin and 51% in placebo dropped out before the 52-week endpoint.

1 Least squares means adjusted for baseline value, treatment, study and treatment by study interaction.

** p<0.001 compared to placebo. Type 1 error was controlled across the three endpoints.

* Immediate-release lorcaserin hydrochloride 10 mg twice daily

Figure 1.	Longitudinal Weight Change (kg) in Completer Population: Studies 1 and 2
(click image for full-size original)

Figure 1. Longitudinal Weight Change (kg) in Completer Population: Studies 1 and 2

Two-Year Weight Management in Patients without Diabetes Mellitus

The safety and efficacy of lorcaserin for weight management during 2 years of treatment were evaluated in Study 1. Of the 3182 patients who were randomized in Year 1, 1553 (48.8%) were randomized in Year 2. Patients in all three Year 2 patient groups (lorcaserin Year 1/ lorcaserin Year 2, lorcaserin Year 1/placebo Year 2, and placebo Year 1/placebo Year 2) regained weight in Year 2 but remained below their Year 1 mean baseline weight (Figure 2).

Figure 2.	Body Weight Changes during Study 1 in the Completers Population
(click image for full-size original)

Figure 2. Body Weight Changes during Study 1 in the Completers Population

Effect of L orcaserin on Cardiometabolic Parameters and Anthropometry

Changes in lipids, fasting glucose, fasting insulin, waist circumference, heart rate, and blood pressure with lorcaserin are shown in Table 7.

In a substudy of 154 patients conducted as part of Study 2, DEXA analysis showed a 9.9% reduction in fat mass from a baseline of 44.5 kg in patients treated with lorcaserin compared to a 4.6% reduction from a baseline of 45.0 kg in patients treated with placebo. The placebo-adjusted reduction in fat mass achieved on lorcaserin was -5.3%. Reductions in lean body mass were 1.9% and 0.3% from baseline values of 48.0 kg and 51.0 kg, respectively, for lorcaserin- and placebo-treated patients.

Table 7. Mean Changes in Cardiometabolic Parameters and Waist Circumference in Year 1 of Studies 1 and 2
Lorcaserin± N=3096 Placebo N=3039 Lorcaserin minus Placebo (LSMean)
Baseline mg/dL % change from Baseline (LSMean 1 ) Baseline mg/dL % change from Baseline (LSMean)
Total Cholesterol194.4 -0.9194.8 0.4-1.2*
LDL Cholesterol114.3 1.6 114.12.9-1.3*
HDL Cholesterol53.2 1.8 53.50.61.2*
Triglycerides135.4 -5.3137.0-0.5-4.8*
Baseline change from Baseline (LSMean) Baseline change from Baseline (LSMean) Lorcaserin minus Placebo (LSMean)
Systolic blood pressure (mmHg)121.4 -1.8121.5-1.0-0.7*
Diastolic blood pressure (mmHg)77.4 -1.6 77.7-1.0-0.6*
Heart Rate (bpm)69.5-1.269.5-0.4-0.8
Fasting glucose (mg/dL)92.1 -0.292.40.6-0.8
Fasting insulin2 (µIU/mL)15.9-3.315.8-1.3-2.1*
Waist Circumference (cm)109.3-6.5109.6-4.0-2.5
  • 1 Least squares means adjusted for baseline value, treatment, study and treatment by study interaction
  • 2 Measured in Study 1 only (n=1538)* Statistically significant versus placebo based on the pre-specified gatekeeping method for controlling Type I error in key secondary endpoints.
±Immediate-release lorcaserin hydrochloride 10 mg twice daily

One-Year Weight Management in Patients with Type 2 Diabetes Mellitus

Weight loss among patients with type 2 diabetes mellitus who were treated with lorcaserin was statistically significantly greater than that among patients treated with placebo (Table 8).

Table 8. Weight Loss at 1 Year in Study 3 (Type 2 Diabetes Mellitus)
Lorcaserin * N=251 Placebo N=248
Weight loss (kg)
Baseline mean (SD)103.5 (17.2)102.3 (18.0)
Change from baseline (adjusted mean1) (SE)-4.7 (0.4)-1.6 (0.4)
Difference from placebo (adjusted mean1) (95% CI)-3.1** (-4.0, -2.2)
Percent change from baseline (adjusted mean1) (SE)-4.5 (0.4)-1.5 (0.4)
Difference from placebo (adjusted mean1) (95% CI)-3.1** (-3.9, -2.2)
% of Patients losing greater than or equal to 5% body weight 37.516.1
Difference from placebo (95% CI)21.3** (13.8, 28.9)
% of Patients losing greater than or equal to 10% body weight 16.34.4
Difference from placebo (95% CI)11.9** (6.7, 17.1)

SD=Standard Deviation; SE=Standard Error; CI=Confidence Interval

Intent to Treat Population using last observation carried forward method; All patients who received study medication and had a post-baseline body weight. Thirty-four percent (34%) of patients in lorcaserin and 38% in placebo dropped out before the 52-week endpoint.

1 Least squares means adjusted for baseline value, baseline HbA1c stratum and prior antihyperglycemic medication stratum.

*Immediate-release lorcaserin hydrochloride 10 mg twice daily

**p<0.001 compared to placebo. Type 1 error was controlled across the three endpoints.

Effect of L orcaserin on Cardiometabolic Parameters and Anthropometry in Patients with Type 2 Diabetes Mellitus

Patients in Study 3 were taking either metformin and/or a sulfonylurea at study start, and had inadequate glycemic control (HbA1c range 7-10%). Changes in HbA1c and fasting glucose with lorcaserin use are shown in Table 9.

Table 9. Mean Changes in Cardiometabolic Parameters and Waist Circumference in Patients with Type 2 Diabetes Mellitus
Lorcaserin± N=256 Placebo N=252 Lorcaserin minus Placebo ( LSMean )
Baseline Change from Baseline (LSMean 1 ) Baseline Change from Baseline (LSMean)
HbA1C (%)8.1-0.98.0-0.4-0.5*
Fasting glucose (mg/dL)163.3-27.4160.0-11.9-15.5*
Systolic blood pressure (mmHg)126.6-0.8126.5-0.90.1
Diastolic blood pressure (mmHg)77.9-1.178.7-0.7-0.4
Heart Rate (bpm)72.3-2.072.7-0.4-1.6
Waist Circumference (cm)115.8-5.5113.5-3.3-2.2
Baseline % Change from Baseline (LSMean) Baseline % Change from Baseline (LSMean) Lorcaserin minus Placebo (LSMean)
Total Cholesterol (mg/dL)173.5-0.7172.0-0.1-0.5
LDL Cholesterol (mg/dL)95.04.294.65.0-0.8
HDL Cholesterol (mg/dL)45.35.245.71.63.6
Triglycerides (mg/dL)172.1-10.7163.5-4.8-5.9

Intent to Treat Population using last observation carried forward method; All patients who received study medication and had a post-baseline measurement.

* Statistically significant versus placebo based on the pre-specified gatekeeping method for controlling Type I error in key secondary endpoints.

1 Least squares means adjusted for baseline value, baseline HbA1c stratum and prior antihyperglycemic medication stratum.

±Immediate-release lorcaserin hydrochloride 10 mg twice daily

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