Second Lorcaserin Review to Address Risk/Benefit Tradeoffs

As a new Food and Drug Administration advisory committee review on May 10 for the weight-loss drug lorcaserin approaches, the drug’s developers, Arena Pharmaceuticals and Eisai, say they have the benefit of greater clarity on regulatory policy based on encouraging recent developments for two other candidates for the same indication.

Recent decisions by the agency suggest the tide could be turning for obesity drug candidates that are bolstered by additional data and plans for ensuring appropriate use.

The Endocrinologic and Metabolic Drugs Advisory Committee will be considering the resubmission of lorcaserin after a "complete response" letter in October 2010, which noted the detection of tumors in a 2-year rat study, questioned the drug’s marginal efficacy and requested final data from a phase-III trial (BLOOM-DM) in patients with diabetes. The "complete response" followed a negative advisory committee review in September 2010.

Arena expects forthcoming advisory committee documents and discussion at the meeting to focus on the "risk/benefit profile in general" and issues raised in the FDA letter, Craig Audet, Arena’s vice president of global regulatory affairs, said during a March 14 earnings call.

A selective serotonin 2C receptor agonist, lorcaserin (then going under the brand name Lorqess) was one of three weight loss drugs that received "complete response" letters from the agency between October 2010 and January 2011, along with Qnexa (phentermine/topiramate) and Contrave (naltrexone/bupropion).

Despite the availability of an FDA draft guidance on obesity drug development, there has been controversy about appropriate standards and concern about off-label use of new treatments, presenting obstacles for approval. Recent decisions, however, suggest that a more favorable regulatory environment is emerging and the tide could be turning for obesity drug candidates that are bolstered by additional data and plans for ensuring appropriate use.

In late February – swayed by a number of factors including strong efficacy, the need for new obesity therapies, and a solid Risk Evaluation and Mitigation Strategy – the Endocrinologic and Metabolic Drugs Advisory Committee voted 20-2 for approval of Qnexa.

Orexigen also appears to have gotten back on track with Contrave, securing an agreement with the agency on the terms for a preapproval cardiovascular outcomes trial that looks less onerous than had previously been expected.

According to the agreement, the company will study 10,000 patients with an estimated background rate of 1%-1.5% annual risk of major cardiovascular events; an interim analysis could serve as the basis for refiling the application.

The finding of mammary tumors in rats exposed to lorcaserin at doses close to therapeutic doses in humans emerged as a major issue in the FDA’s review. As part of their resubmission of the application, Arena and Eisai re-examined specimens from the rat tumor study and performed new studies to make the case that the findings do not suggest risk for humans. The data from the BLOOM-DM study in patients with type 2 diabetes, released in November 2010, also were submitted.

In the last advisory committee review of the drug, some panelists were concerned about the limited patient populations studied in the two other phase-III trials that supported the application: BLOOM and BLOSSOM. Arena also submitted cell culture experiments to support the selectivity for the serotonin 2C receptor, as lack of selectivity could be associated with a risk for valvulopathy.

During the March 14 call, Arena execs expressed confidence about the upcoming review in May, based on the additional data submitted to the FDA and also the nature of the recent panel discussion on Qnexa.

"We are encouraged that the panel seems to understand that obesity is a serious problem, and they’re looking for ways of addressing this in a significant fashion. So I think that was reflected in the outcome of that panel," CEO Jack Lief commented.

Dr. Christen Anderson, vice president of lorcaserin development for Arena, described the Qnexa committee meeting atmosphere as "supportive."

"We think the discussion indicates an appreciation of the critical need for additional pharmacotherapies for the management of obesity. As in the past, the advisory committee focused on the balance of benefit and risk, an area where we believe lorcaserin will be perceived favorably. We believe lorcaserin’s benefit/risk profile has improved since our original NDA submission," she said.

In BLOOM and BLOSSOM, 47% of patients taking the proposed dose of the drug lost at least 5% of baseline body weight during year one, compared with 23% for placebo, meeting one of the FDA’s efficacy standards, albeit by a small margin. The drug did not meet a second standard based on adjusted mean percentage change in weight from baseline.

A decision is expected in late June.

Emily Hayes is with "The Pink Sheet." This news organization and "The Pink Sheet" are owned by Elsevier.

As a new Food and Drug Administration advisory committee review on May 10 for the weight-loss drug lorcaserin approaches, the drug’s developers, Arena Pharmaceuticals and Eisai, say they have the benefit of greater clarity on regulatory policy based on encouraging recent developments for two other candidates for the same indication.

Recent decisions by the agency suggest the tide could be turning for obesity drug candidates that are bolstered by additional data and plans for ensuring appropriate use.

The Endocrinologic and Metabolic Drugs Advisory Committee will be considering the resubmission of lorcaserin after a "complete response" letter in October 2010, which noted the detection of tumors in a 2-year rat study, questioned the drug’s marginal efficacy and requested final data from a phase-III trial (BLOOM-DM) in patients with diabetes. The "complete response" followed a negative advisory committee review in September 2010.

Arena expects forthcoming advisory committee documents and discussion at the meeting to focus on the "risk/benefit profile in general" and issues raised in the FDA letter, Craig Audet, Arena’s vice president of global regulatory affairs, said during a March 14 earnings call.

A selective serotonin 2C receptor agonist, lorcaserin (then going under the brand name Lorqess) was one of three weight loss drugs that received "complete response" letters from the agency between October 2010 and January 2011, along with Qnexa (phentermine/topiramate) and Contrave (naltrexone/bupropion).

Despite the availability of an FDA draft guidance on obesity drug development, there has been controversy about appropriate standards and concern about off-label use of new treatments, presenting obstacles for approval. Recent decisions, however, suggest that a more favorable regulatory environment is emerging and the tide could be turning for obesity drug candidates that are bolstered by additional data and plans for ensuring appropriate use.

In late February – swayed by a number of factors including strong efficacy, the need for new obesity therapies, and a solid Risk Evaluation and Mitigation Strategy – the Endocrinologic and Metabolic Drugs Advisory Committee voted 20-2 for approval of Qnexa.

Orexigen also appears to have gotten back on track with Contrave, securing an agreement with the agency on the terms for a preapproval cardiovascular outcomes trial that looks less onerous than had previously been expected.

According to the agreement, the company will study 10,000 patients with an estimated background rate of 1%-1.5% annual risk of major cardiovascular events; an interim analysis could serve as the basis for refiling the application.

The finding of mammary tumors in rats exposed to lorcaserin at doses close to therapeutic doses in humans emerged as a major issue in the FDA’s review. As part of their resubmission of the application, Arena and Eisai re-examined specimens from the rat tumor study and performed new studies to make the case that the findings do not suggest risk for humans. The data from the BLOOM-DM study in patients with type 2 diabetes, released in November 2010, also were submitted.

In the last advisory committee review of the drug, some panelists were concerned about the limited patient populations studied in the two other phase-III trials that supported the application: BLOOM and BLOSSOM. Arena also submitted cell culture experiments to support the selectivity for the serotonin 2C receptor, as lack of selectivity could be associated with a risk for valvulopathy.

During the March 14 call, Arena execs expressed confidence about the upcoming review in May, based on the additional data submitted to the FDA and also the nature of the recent panel discussion on Qnexa.

"We are encouraged that the panel seems to understand that obesity is a serious problem, and they’re looking for ways of addressing this in a significant fashion. So I think that was reflected in the outcome of that panel," CEO Jack Lief commented.

Dr. Christen Anderson, vice president of lorcaserin development for Arena, described the Qnexa committee meeting atmosphere as "supportive."

"We think the discussion indicates an appreciation of the critical need for additional pharmacotherapies for the management of obesity. As in the past, the advisory committee focused on the balance of benefit and risk, an area where we believe lorcaserin will be perceived favorably. We believe lorcaserin’s benefit/risk profile has improved since our original NDA submission," she said.

In BLOOM and BLOSSOM, 47% of patients taking the proposed dose of the drug lost at least 5% of baseline body weight during year one, compared with 23% for placebo, meeting one of the FDA’s efficacy standards, albeit by a small margin. The drug did not meet a second standard based on adjusted mean percentage change in weight from baseline.

A decision is expected in late June.

Emily Hayes is with "The Pink Sheet." This news organization and "The Pink Sheet" are owned by Elsevier.

As a new Food and Drug Administration advisory committee review on May 10 for the weight-loss drug lorcaserin approaches, the drug’s developers, Arena Pharmaceuticals and Eisai, say they have the benefit of greater clarity on regulatory policy based on encouraging recent developments for two other candidates for the same indication.

Recent decisions by the agency suggest the tide could be turning for obesity drug candidates that are bolstered by additional data and plans for ensuring appropriate use.

The Endocrinologic and Metabolic Drugs Advisory Committee will be considering the resubmission of lorcaserin after a "complete response" letter in October 2010, which noted the detection of tumors in a 2-year rat study, questioned the drug’s marginal efficacy and requested final data from a phase-III trial (BLOOM-DM) in patients with diabetes. The "complete response" followed a negative advisory committee review in September 2010.

Arena expects forthcoming advisory committee documents and discussion at the meeting to focus on the "risk/benefit profile in general" and issues raised in the FDA letter, Craig Audet, Arena’s vice president of global regulatory affairs, said during a March 14 earnings call.

A selective serotonin 2C receptor agonist, lorcaserin (then going under the brand name Lorqess) was one of three weight loss drugs that received "complete response" letters from the agency between October 2010 and January 2011, along with Qnexa (phentermine/topiramate) and Contrave (naltrexone/bupropion).

Despite the availability of an FDA draft guidance on obesity drug development, there has been controversy about appropriate standards and concern about off-label use of new treatments, presenting obstacles for approval. Recent decisions, however, suggest that a more favorable regulatory environment is emerging and the tide could be turning for obesity drug candidates that are bolstered by additional data and plans for ensuring appropriate use.

In late February – swayed by a number of factors including strong efficacy, the need for new obesity therapies, and a solid Risk Evaluation and Mitigation Strategy – the Endocrinologic and Metabolic Drugs Advisory Committee voted 20-2 for approval of Qnexa.

Orexigen also appears to have gotten back on track with Contrave, securing an agreement with the agency on the terms for a preapproval cardiovascular outcomes trial that looks less onerous than had previously been expected.

According to the agreement, the company will study 10,000 patients with an estimated background rate of 1%-1.5% annual risk of major cardiovascular events; an interim analysis could serve as the basis for refiling the application.

The finding of mammary tumors in rats exposed to lorcaserin at doses close to therapeutic doses in humans emerged as a major issue in the FDA’s review. As part of their resubmission of the application, Arena and Eisai re-examined specimens from the rat tumor study and performed new studies to make the case that the findings do not suggest risk for humans. The data from the BLOOM-DM study in patients with type 2 diabetes, released in November 2010, also were submitted.

In the last advisory committee review of the drug, some panelists were concerned about the limited patient populations studied in the two other phase-III trials that supported the application: BLOOM and BLOSSOM. Arena also submitted cell culture experiments to support the selectivity for the serotonin 2C receptor, as lack of selectivity could be associated with a risk for valvulopathy.

During the March 14 call, Arena execs expressed confidence about the upcoming review in May, based on the additional data submitted to the FDA and also the nature of the recent panel discussion on Qnexa.

"We are encouraged that the panel seems to understand that obesity is a serious problem, and they’re looking for ways of addressing this in a significant fashion. So I think that was reflected in the outcome of that panel," CEO Jack Lief commented.

Dr. Christen Anderson, vice president of lorcaserin development for Arena, described the Qnexa committee meeting atmosphere as "supportive."

"We think the discussion indicates an appreciation of the critical need for additional pharmacotherapies for the management of obesity. As in the past, the advisory committee focused on the balance of benefit and risk, an area where we believe lorcaserin will be perceived favorably. We believe lorcaserin’s benefit/risk profile has improved since our original NDA submission," she said.

In BLOOM and BLOSSOM, 47% of patients taking the proposed dose of the drug lost at least 5% of baseline body weight during year one, compared with 23% for placebo, meeting one of the FDA’s efficacy standards, albeit by a small margin. The drug did not meet a second standard based on adjusted mean percentage change in weight from baseline.

A decision is expected in late June.

Emily Hayes is with "The Pink Sheet." This news organization and "The Pink Sheet" are owned by Elsevier.