(dailyRx News) Arena Pharmaceuticals, Inc. has announced positive results from BLOOM (Behavioral modification and Lorcaserin for Overweight and Obesity Management), the first of two pivotal trials evaluating the safety and efficacy of lorcaserin for weight management.

Statistical significance was achieved on all three of the hierarchically ordered coprimary endpoints for patients treated with lorcaserin versus placebo. Treatment with lorcaserin was generally very well tolerated. An assessment of echocardiograms indicates no apparent drug-related effect on the development of FDA-defined valvulopathy (various dysfunctions of the heart valves) over the two-year treatment period.

Lorcaserin is a the first in a new class of selective serotonin 2C receptor agonists. The serotonin 2C receptor is located in areas of the brain involved in the control of appetite and metabolism, such as the hypothalamus. Stimulation of this receptor is strongly associated with feeding behavior and satiety. Lorcaserin is currently being evaluated as a targeted treatment option for the millions of patients who need to better manage their weight.

Primary Endpoint Analysis
The hierarchically ordered endpoints were the proportion of patients achieving 5 percent or greater weight loss after 12 months, the difference in mean weight loss compared to placebo after 12 months and the proportion of patients achieving 10 percent or greater weight loss after 12 months. Compared to placebo, using an intent-to-treat last observation carried forward (ITT-LOCF) analysis, treatment with lorcaserin was associated with highly statistically significant categorical and average weight loss from baseline after 12 months:

• 47.5 percent of lorcaserin patients lost greater than or equal to 5 percent of their body weight from baseline compared to 20.3 percent in the placebo group. This result satisfies the efficacy benchmark in the most recent FDA draft guidance.
• Average weight loss of 5.8 percent of body weight, or 12.7 pounds, was achieved in the lorcaserin group, compared to 2.2 percent of body weight, or 4.7 pounds, in the placebo group. Statistical separation from placebo was observed by week 2, the first post-baseline measurement.
• 22.6 percent of lorcaserin patients lost greater than or equal to 10 percent of their body weight from baseline, compared to 7.7 percent in the placebo group.

Lorcaserin patients who completed 52 weeks of treatment according to the protocol lost an average of 8.2 percent of body weight, or 17.9 pounds, compared to 3.4 percent, or 7.3 pounds, in the placebo group.

"The BLOOM results, demonstrating lorcaserin's medically important weight loss coupled with the tolerability and safety profile displayed in this trial, differentiate lorcaserin from approved drugs or other agents in clinical trials," commented Steven R. Smith, M.D., coprincipal investigator and professor and assistant director for clinical research at the Pennington Biomedical Research Center. "Obesity is a widespread disease; having a well-tolerated and effective therapy that can be used by the majority of patients who need weight reduction could also have beneficial effects on comorbid conditions, such as diabetes, lipid disorders and cardiovascular disease."

Safety and Tolerability Profile
The most frequent adverse events reported with lorcaserin in the first year and their rates for lorcaserin and placebo patients, respectively, were as follows: headache (18 percent versus 11 percent), upper respiratory tract infection (14.8 percent versus 11.9 percent), nasopharyngitis, or inflammation of the nose and pharynx (13.4 percent versus 12 percent), sinusitis (7.2 percent versus 8.2 percent) and nausea (7.5 percent versus 5.4 percent).

The most frequent adverse events reported in the second year and their rates for lorcaserin and placebo patients, respectively, were as follows: upper respiratory tract infection (14.5 percent versus 16.1 percent), nasopharyngitis (16.4 percent versus 12.6 percent), sinusitis (8.6 percent versus 6.9 percent), joint pain (6.6 percent versus 6.2 percent) and influenza (6.6 percent versus 6 percent). In patients crossing over from lorcaserin to placebo after the first year, the rates of these second-year adverse events were 11 percent, 13.8 percent, 10.6 percent, 6 percent and 4.9 percent, respectively.

Adverse events of depression, anxiety and suicidal ideation were infrequent and reported at a similar rate in each treatment group, and no seizures were reported. Serious adverse events occurred with similar frequency in each group throughout the trial without apparent relationship to lorcaserin. One death occurred during the trial, which was a patient in the placebo arm.

"The BLOOM trial, having met all of its primary endpoints and the FDA categorical efficacy benchmark as stated in their guidance, suggests lorcaserin has the potential to become the first in a new class of effective and very well-tolerated weight management therapeutics that selectively target the serotonin 2C receptor," said William R. Shanahan, M.D., Arena's vice president and chief medical officer.

Echocardiogram Assessment
Using an ITT-LOCF analysis, the assessment of echocardiograms performed at baseline and after patients completed six, 12, 18 and 24 months of dosing indicated no apparent drug-related effect on the development of FDA-defined valvulopathy (moderate or greater mitral insufficiency or mild or greater aortic insufficiency).

Lorcaserin met the primary safety endpoint of no significant difference in rates of valvulopathy at 12 months. Rates of valvulopathy at six, 12, 18 and 24 months for lorcaserin versus placebo were 2.1 percent versus 1.9 percent, 2.7 percent versus 2.3 percent, 2.9 percent versus 3.1 percent and 2.6 percent versus 2.7 percent. At 18 and 24 months, rates of valvulopathy for lorcaserin patients crossing over to placebo were 3.6 percent and 1.9 percent, respectively.

The FDA has requested that Arena rule out a 1.5-fold or greater risk of valvulopathy with 80 percent power. Assuming similar results in BLOSSOM (Behavioral modification and Lorcaserin Second Study for Obesity Management), the integrated data set from the two trials will be more than sufficiently large to meet this requirement.

"The echocardiographic safety data is very reassuring," commented Neil J. Weissman, M.D., coprincipal investigator and president of MedStar Research Institute. "In this double-blind, prospective study, there was no evidence of a difference in the development of valve disease in the large number of patients on lorcaserin versus control for up to two years of continuous use. No prospective valvulopathy trial has ever studied this many patients for this period of time, particularly under such well-controlled circumstances."

Secondary Endpoint Analysis
Treatment with lorcaserin was also associated with statistically significant improvements (ITT-LOCF) in a range of secondary endpoints compared to treatment with placebo:

• Total cholesterol
• Low-density lipoprotein (LDL, or "bad") cholesterol
• Triglycerides
• Blood pressure

Changes in high-density lipoprotein (HDL, or "good") cholesterol were similar in the two groups. Analysis of the above and additional endpoints, including glucose, insulin and waist circumference, is ongoing and will be announced at a later date.

During the second year of the trial, patients continuing on lorcaserin were better able to maintain more of the week 52 weight loss than first-year lorcaserin patients rerandomized to placebo in the second year.

BLOOM Trial Design
BLOOM, the first of three lorcaserin phase 3 trials, is a double-blind, randomized, placebo-controlled trial involving 3,182 patients in approximately 100 sites in the U.S. The trial evaluated 10 mg of lorcaserin twice daily versus placebo over a two-year treatment period in obese patients, who had body mass index (BMI) between 30 to 45, with or without comorbid conditions, along with overweight patients, who had BMI between 27 and less than 30, with at least one comorbid condition. The trial did not include any dose titration or run-in period.
Patients were randomized in a 1:1 ratio to lorcaserin or placebo at baseline. At week 52, 856 patients taking lorcaserin were rerandomized in a 2:1 ratio to continue lorcaserin or to switch to placebo, and 697 patients on placebo were continued on placebo. Patients received echocardiograms at screening and at six, 12, 18 and 24 months after initiating dosing in the trial; patients with FDA-defined valvulopathy were excluded from enrolling in the trial.

The phase 3 program consists of three trials, BLOOM, BLOSSOM and BLOOM-DM (Behavioral modification and Lorcaserin for Overweight and Obesity Management in Diabetes Mellitus), and is planned to enroll a total of approximately 7,800 patients. BLOOM and BLOSSOM comprise the phase 3 pivotal registration program. BLOSSOM has enrolled 4,008 patients and is evaluating 10 mg of lorcaserin once or twice daily versus placebo over a one-year treatment period in obese patients with or without comorbid conditions and overweight patients with at least one comorbid condition at about 100 sites in the U.S. Results are expected around the end of September 2009.

BLOOM-DM is currently enrolling and is evaluating 10 mg of lorcaserin once or twice daily versus placebo over a one-year treatment period in obese and overweight patients with type 2 diabetes at 60 sites in the U.S. Approximately 600 patients are expected to be enrolled in BLOOM-DM, which is planned as a supplement to the lorcaserin NDA.

A standardized program of moderate diet and exercise guidance is included in the phase 3 program. The program's hierarchically ordered coprimary efficacy endpoints are the proportion of patients achieving 5 percent or greater weight loss after 12 months, the difference in mean weight loss compared to placebo after 12 months, and the proportion of patients achieving 10 percent or greater weight loss after 12 months.

Arena is also studying several key secondary endpoints, including changes in serum lipids and HbA1c levels and, in the BLOOM-DM trial, other indicators of glycemic control. In BLOSSOM and BLOOM-DM, all patients will receive echocardiograms at baseline, at six months and at the end of the study to assess heart valve function over time. In contrast to the BLOOM trial, however, there are no echocardiographic exclusion criteria for entry into these trials, and there is no monitoring by an independent monitoring board.

Contact:
David Walsey
858-453-7200 ext. 1682