Lorqess’ Slight Efficacy, Potential Safety Issues to be Addressed at Advisory Panel

A demonstration of only slight efficacy compared with placebo – coupled with safety questions – signals tough going for the obesity drug lorcaserin at a Food and Drug Administration advisory committee meeting Sept. 16.

Lorcaserin (developed by Arena Pharmaceuticals under the brand name Lorqess) met only one of the two efficacy criteria set out in the FDA’s draft guidance on weight management drugs, and did so “by a slim margin,” Eric Colman, deputy director of the Division of Metabolism and Endocrinology Products, noted in a memo to the advisory panel.

The question before the Endocrinologic and Metabolic Drugs Advisory Committee meeting will be whether that narrow demonstration of benefit is sufficient in light of FDA concerns about the adequacy of data for assessing the drug’s potential to cause valvular heart disease, neuropsychiatric and cognitive-related adverse events, and malignancies.

One way to positively affect the benefit/risk equation is a Risk Evaluation and Mitigation Strategy. Arena has pledged to implement comprehensive education and communication programs to encourage safe use of lorcaserin in appropriate patients, but has not put forth a formal REMS.

Given the advisory panel’s concerns about the unknowns surrounding long-term use of obesity drugs to maintain weight loss in a large population – aired at the committee’s review of Vivus’s Qnexa – a REMS appears to be a logical pathway to approval.

The FDA already is considering instituting REMS for several obesity drugs. Vivus proposed a REMS including education for physicians and a voluntary pregnancy registry for Qnexa (phentermine/topiramate combination). Abbot’s Meridia has a REMS, but proposed upgrades are being considered at the panel’s Sept. 15 review of that drug, ranging from a communication plan to restricted distribution, which would be an element to ensure safe use.

The 14-member Lorqess panel includes eight of the participants from the Qnexa review. Of those repeat committee members, four voted yes and four voted no on whether Qnexa was ready for approval.

Lorcaserin Meets One of Two Obesity Drug Efficacy Criteria

Lorcaserin’s efficacy shortcomings stem from its ability to meet only one of two efficacy standards outlined in FDA draft guidance on developing weight management products.

The drug was evaluated in two phase III trials that involved more than 7,000 patients. The 1-year BLOSSOM trial evaluated the drug at 10 mg twice daily and 10 mg once a day against placebo, while the two-year BLOOM trial looked at 10 mg twice daily lorcaserin versus placebo. At the end of the first year of BLOOM, patients receiving the drug were rerandomized 2:1 to lorcaserin or placebo, while those on placebo continued receiving placebo.

About 23% of placebo patients lost at least 5% of baseline body weight during year 1 of the trials, compared with 47% of patients receiving lorcaserin 10 mg b.i.d. and 40% of those receiving lorcaserin 10 mg once a day. The guidance calls for at least 35% of patients receiving the drug to achieve that goal, and for the proportion of drug-treated patients achieving the goal to be about double the proportion in the placebo group – meaning at least 46% in this trial. The difference between the two groups should also be statistically significant.

Lorcaserin failed to achieve the other efficacy measure for obesity drugs: at least a 5% difference in mean weight loss between the active-product and placebo-treated groups.

Numerous Patient Withdrawals Prompt Look at Placebo-Adjusted Effect

The FDA’s statistical reviewer was concerned about the efficacy findings because between 40% and 55% of participants withdrew prior to week 52 during the phase III studies. To address this issue, the statistician examined the placebo-adjusted odds of being classified as a 5% responder and used a logistic regression model to estimate the placebo-adjusted effect of the active drug, allowing for factors and covariates of the study design.

The placebo-adjusted effect of lorcaserin on average weight loss was fairly consistent across different analyses and analysis populations. “This consistency, even with a substantial proportion of withdrawals, may reflect the modest efficacy of lorcaserin, and may not extend in general to other weight loss products,” according to the statistical review.

However, the statistician noted that the placebo-adjusted weight loss was relatively low and should be evaluated for clinical significance.

Potential Safety Issues Remain

The phase III safety program was designed with a noninferiority margin of 1.5 to assess the development of valvular heart disease in participants. The FDA considered this margin arbitrary but reasonable to initially evaluate the incidence in lorcaserin patients. The trial data rule out a 55% or larger increase in the relative risk for FDA-defined valvular heart disease with lorcaserin, according to the briefing documents.

The trials also found that while 2.7% of patients on lorcaserin 10 mg twice daily, compared with 1.4% in the placebo group, reported adverse events mapped in a broad categorization of depression, there was no imbalance in treatment groups when depression-related AEs were confined to a narrower category.

Memory impairment, disturbance in attention, amnesia, and other cognitive AEs were reported infrequently overall, but three times more often in the lorcaserin 10-mg-twice-daily group than in subjects treated with placebo.

There were no imbalances in reports of cancer between lorcaserin and placebo patients in the phase III trials, but a number of malignant tumor types developed in rats treated with lorcaserin for as long as two years. The excess risk of malignant breast tumors is related to lorcaserin-mediated increases in serum prolactin, the company says, but FDA reviewers say there are not enough data to support this hypothesis.

Lorcaserin targets activation of the serotonin 5HT2c receptor to promote pre- and postmeal satiety. Arena’s proposed indication is for weight management, including weight loss and maintenance of weight loss in obese patients (body mass index of at least 30 kg/m²) or overweight patients (BMI of 25-29.9 kg/m²) who have one or more weight-related comorbid medical conditions.

A demonstration of only slight efficacy compared with placebo – coupled with safety questions – signals tough going for the obesity drug lorcaserin at a Food and Drug Administration advisory committee meeting Sept. 16.

Lorcaserin (developed by Arena Pharmaceuticals under the brand name Lorqess) met only one of the two efficacy criteria set out in the FDA’s draft guidance on weight management drugs, and did so “by a slim margin,” Eric Colman, deputy director of the Division of Metabolism and Endocrinology Products, noted in a memo to the advisory panel.

The question before the Endocrinologic and Metabolic Drugs Advisory Committee meeting will be whether that narrow demonstration of benefit is sufficient in light of FDA concerns about the adequacy of data for assessing the drug’s potential to cause valvular heart disease, neuropsychiatric and cognitive-related adverse events, and malignancies.

One way to positively affect the benefit/risk equation is a Risk Evaluation and Mitigation Strategy. Arena has pledged to implement comprehensive education and communication programs to encourage safe use of lorcaserin in appropriate patients, but has not put forth a formal REMS.

Given the advisory panel’s concerns about the unknowns surrounding long-term use of obesity drugs to maintain weight loss in a large population – aired at the committee’s review of Vivus’s Qnexa – a REMS appears to be a logical pathway to approval.

The FDA already is considering instituting REMS for several obesity drugs. Vivus proposed a REMS including education for physicians and a voluntary pregnancy registry for Qnexa (phentermine/topiramate combination). Abbot’s Meridia has a REMS, but proposed upgrades are being considered at the panel’s Sept. 15 review of that drug, ranging from a communication plan to restricted distribution, which would be an element to ensure safe use.

The 14-member Lorqess panel includes eight of the participants from the Qnexa review. Of those repeat committee members, four voted yes and four voted no on whether Qnexa was ready for approval.

Lorcaserin Meets One of Two Obesity Drug Efficacy Criteria

Lorcaserin’s efficacy shortcomings stem from its ability to meet only one of two efficacy standards outlined in FDA draft guidance on developing weight management products.

The drug was evaluated in two phase III trials that involved more than 7,000 patients. The 1-year BLOSSOM trial evaluated the drug at 10 mg twice daily and 10 mg once a day against placebo, while the two-year BLOOM trial looked at 10 mg twice daily lorcaserin versus placebo. At the end of the first year of BLOOM, patients receiving the drug were rerandomized 2:1 to lorcaserin or placebo, while those on placebo continued receiving placebo.

About 23% of placebo patients lost at least 5% of baseline body weight during year 1 of the trials, compared with 47% of patients receiving lorcaserin 10 mg b.i.d. and 40% of those receiving lorcaserin 10 mg once a day. The guidance calls for at least 35% of patients receiving the drug to achieve that goal, and for the proportion of drug-treated patients achieving the goal to be about double the proportion in the placebo group – meaning at least 46% in this trial. The difference between the two groups should also be statistically significant.

Lorcaserin failed to achieve the other efficacy measure for obesity drugs: at least a 5% difference in mean weight loss between the active-product and placebo-treated groups.

Numerous Patient Withdrawals Prompt Look at Placebo-Adjusted Effect

The FDA’s statistical reviewer was concerned about the efficacy findings because between 40% and 55% of participants withdrew prior to week 52 during the phase III studies. To address this issue, the statistician examined the placebo-adjusted odds of being classified as a 5% responder and used a logistic regression model to estimate the placebo-adjusted effect of the active drug, allowing for factors and covariates of the study design.

The placebo-adjusted effect of lorcaserin on average weight loss was fairly consistent across different analyses and analysis populations. “This consistency, even with a substantial proportion of withdrawals, may reflect the modest efficacy of lorcaserin, and may not extend in general to other weight loss products,” according to the statistical review.

However, the statistician noted that the placebo-adjusted weight loss was relatively low and should be evaluated for clinical significance.

Potential Safety Issues Remain

The phase III safety program was designed with a noninferiority margin of 1.5 to assess the development of valvular heart disease in participants. The FDA considered this margin arbitrary but reasonable to initially evaluate the incidence in lorcaserin patients. The trial data rule out a 55% or larger increase in the relative risk for FDA-defined valvular heart disease with lorcaserin, according to the briefing documents.

The trials also found that while 2.7% of patients on lorcaserin 10 mg twice daily, compared with 1.4% in the placebo group, reported adverse events mapped in a broad categorization of depression, there was no imbalance in treatment groups when depression-related AEs were confined to a narrower category.

Memory impairment, disturbance in attention, amnesia, and other cognitive AEs were reported infrequently overall, but three times more often in the lorcaserin 10-mg-twice-daily group than in subjects treated with placebo.

There were no imbalances in reports of cancer between lorcaserin and placebo patients in the phase III trials, but a number of malignant tumor types developed in rats treated with lorcaserin for as long as two years. The excess risk of malignant breast tumors is related to lorcaserin-mediated increases in serum prolactin, the company says, but FDA reviewers say there are not enough data to support this hypothesis.

Lorcaserin targets activation of the serotonin 5HT2c receptor to promote pre- and postmeal satiety. Arena’s proposed indication is for weight management, including weight loss and maintenance of weight loss in obese patients (body mass index of at least 30 kg/m²) or overweight patients (BMI of 25-29.9 kg/m²) who have one or more weight-related comorbid medical conditions.

A demonstration of only slight efficacy compared with placebo – coupled with safety questions – signals tough going for the obesity drug lorcaserin at a Food and Drug Administration advisory committee meeting Sept. 16.

Lorcaserin (developed by Arena Pharmaceuticals under the brand name Lorqess) met only one of the two efficacy criteria set out in the FDA’s draft guidance on weight management drugs, and did so “by a slim margin,” Eric Colman, deputy director of the Division of Metabolism and Endocrinology Products, noted in a memo to the advisory panel.

The question before the Endocrinologic and Metabolic Drugs Advisory Committee meeting will be whether that narrow demonstration of benefit is sufficient in light of FDA concerns about the adequacy of data for assessing the drug’s potential to cause valvular heart disease, neuropsychiatric and cognitive-related adverse events, and malignancies.

One way to positively affect the benefit/risk equation is a Risk Evaluation and Mitigation Strategy. Arena has pledged to implement comprehensive education and communication programs to encourage safe use of lorcaserin in appropriate patients, but has not put forth a formal REMS.

Given the advisory panel’s concerns about the unknowns surrounding long-term use of obesity drugs to maintain weight loss in a large population – aired at the committee’s review of Vivus’s Qnexa – a REMS appears to be a logical pathway to approval.

The FDA already is considering instituting REMS for several obesity drugs. Vivus proposed a REMS including education for physicians and a voluntary pregnancy registry for Qnexa (phentermine/topiramate combination). Abbot’s Meridia has a REMS, but proposed upgrades are being considered at the panel’s Sept. 15 review of that drug, ranging from a communication plan to restricted distribution, which would be an element to ensure safe use.

The 14-member Lorqess panel includes eight of the participants from the Qnexa review. Of those repeat committee members, four voted yes and four voted no on whether Qnexa was ready for approval.

Lorcaserin Meets One of Two Obesity Drug Efficacy Criteria

Lorcaserin’s efficacy shortcomings stem from its ability to meet only one of two efficacy standards outlined in FDA draft guidance on developing weight management products.

The drug was evaluated in two phase III trials that involved more than 7,000 patients. The 1-year BLOSSOM trial evaluated the drug at 10 mg twice daily and 10 mg once a day against placebo, while the two-year BLOOM trial looked at 10 mg twice daily lorcaserin versus placebo. At the end of the first year of BLOOM, patients receiving the drug were rerandomized 2:1 to lorcaserin or placebo, while those on placebo continued receiving placebo.

About 23% of placebo patients lost at least 5% of baseline body weight during year 1 of the trials, compared with 47% of patients receiving lorcaserin 10 mg b.i.d. and 40% of those receiving lorcaserin 10 mg once a day. The guidance calls for at least 35% of patients receiving the drug to achieve that goal, and for the proportion of drug-treated patients achieving the goal to be about double the proportion in the placebo group – meaning at least 46% in this trial. The difference between the two groups should also be statistically significant.

Lorcaserin failed to achieve the other efficacy measure for obesity drugs: at least a 5% difference in mean weight loss between the active-product and placebo-treated groups.

Numerous Patient Withdrawals Prompt Look at Placebo-Adjusted Effect

The FDA’s statistical reviewer was concerned about the efficacy findings because between 40% and 55% of participants withdrew prior to week 52 during the phase III studies. To address this issue, the statistician examined the placebo-adjusted odds of being classified as a 5% responder and used a logistic regression model to estimate the placebo-adjusted effect of the active drug, allowing for factors and covariates of the study design.

The placebo-adjusted effect of lorcaserin on average weight loss was fairly consistent across different analyses and analysis populations. “This consistency, even with a substantial proportion of withdrawals, may reflect the modest efficacy of lorcaserin, and may not extend in general to other weight loss products,” according to the statistical review.

However, the statistician noted that the placebo-adjusted weight loss was relatively low and should be evaluated for clinical significance.

Potential Safety Issues Remain

The phase III safety program was designed with a noninferiority margin of 1.5 to assess the development of valvular heart disease in participants. The FDA considered this margin arbitrary but reasonable to initially evaluate the incidence in lorcaserin patients. The trial data rule out a 55% or larger increase in the relative risk for FDA-defined valvular heart disease with lorcaserin, according to the briefing documents.

The trials also found that while 2.7% of patients on lorcaserin 10 mg twice daily, compared with 1.4% in the placebo group, reported adverse events mapped in a broad categorization of depression, there was no imbalance in treatment groups when depression-related AEs were confined to a narrower category.

Memory impairment, disturbance in attention, amnesia, and other cognitive AEs were reported infrequently overall, but three times more often in the lorcaserin 10-mg-twice-daily group than in subjects treated with placebo.

There were no imbalances in reports of cancer between lorcaserin and placebo patients in the phase III trials, but a number of malignant tumor types developed in rats treated with lorcaserin for as long as two years. The excess risk of malignant breast tumors is related to lorcaserin-mediated increases in serum prolactin, the company says, but FDA reviewers say there are not enough data to support this hypothesis.

Lorcaserin targets activation of the serotonin 5HT2c receptor to promote pre- and postmeal satiety. Arena’s proposed indication is for weight management, including weight loss and maintenance of weight loss in obese patients (body mass index of at least 30 kg/m²) or overweight patients (BMI of 25-29.9 kg/m²) who have one or more weight-related comorbid medical conditions.