Lorcaserin Re-Review Expected To Address Risk/Benefit Trade-offs, Rat Tumors

Arena Pharmaceuticals gets new May 10 advisory committee review for its obesity therapy lorcaserin; execs say the recent positive review for competing Qnexa bodes well, and that this time around the risk/benefit profile for lorcaserin is much stronger.

As partners Arena Pharmaceuticals Inc. and Eisai Inc. prepare for a new FDA advisory committee review on May 10 for the weight loss drug lorcaserin, they have the benefit of greater clarity on regulatory policy based on encouraging recent developments for two competing candidates.

Recent decisions 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 the candidate after a “complete response” letter in October 2010, which noted the detection of tumors in a two-year rat study, questioned the drug’s marginal efficacy and requested final data from a Phase III trial called BLOOM-DM in patients with diabetes (Also see "Arena Ready For FDA To Reconsider Weight-Loss Drug Lorcaserin" - Pink Sheet, 4 Jan, 2012.). The “complete response” followed a negative advisory committee review in September 2010.

The drug now has a user fee date of June 27.

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, said Craig Audet, vice president of global regulatory affairs, 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 Vivus Inc.’s Qnexa (phentermine/topiramate) and Orexigen Therapeutics Inc.’s 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Despite the availability of an FDA draft guidance on obesity drug development, there has been controversy about appropriate standards and concern about off-label use of new treatments, presenting obstacles for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. But recent decisions suggest 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 (Also see "Qnexa REMS Should Deter Off-Label Use Of Components, But Not Place Undue Burden" - Pink Sheet, 27 Feb, 2012.).

Orexigen also appears to have gotten back on track with Contrave, securing an agreement with the agency on the terms for a pre-approval cardiovascular outcomes trial that looks less onerous than what had previously been expected (Also see "Orexigen Agreement On Contrave CV Trial Hints At FDA’s Thinking On Obesity" - Pink Sheet, 26 Sep, 2011.).

Per the agreement, the company will study 10,000 patients with an estimated background rate of 1% to 1.5% annual risk of major cardiovascular events; an interim analysis could serve as the basis for re-filing the application. The company also has assurance that FDA will not change the plan pursuant to the outcome of a March 28-29 advisory committee meeting on cardiovascular risk assessment for obesity drugs (Also see "Advisory Committee Set To Review Cardiovascular Risk Assessment For Obesity Drugs" - Pink Sheet, 7 Feb, 2012.).

The mammary tumor findings emerged as a major issue in the review of lorcaserin (Also see "Arena Must Deal With Rat Neoplasms To Move Forward With Lorqess" - Pink Sheet, 20 Sep, 2010.). 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, were also 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 by 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.

Arena: Risk/Benefit Profile Has Improved

During the March 14 call, Arena execs expressed confidence about the upcoming review in May, based on the additional data submitted to 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.

Christy Anderson, vice president of lorcaserin development, 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.”

In BLOOM and BLOSSOM, 47% of patients taking the proposed dose for the drug lost at least 5% of baseline body weight during year one, compared to 23% for placebo, meeting one of 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.

During the upcoming committee review, the company plans to demonstrate that lorcaserin improves patient health, which is the goal of weight loss, Anderson said. The exec pointed out that the BLOOM and BLOSSOM studied patients with significant weight-related comorbid medical conditions: 10% had dyslipidemia, 25% had impaired fasting glucose and 30% had hypertension. In addition to significant weight loss versus placebo, those taking lorcaserin achieved favorable changes over placebo in a variety of parameters associated with cardiovascular and metabolic risk, Anderson pointed out.

In the BLOOM-DM study, the drug also met one but not both efficacy standards, as 37.5% of patients on the test drug lost 5% of body weight after 52 weeks of treatment, versus 16.1% achieving that goal in the placebo group.

Anderson noted that the BLOOM-DM study evaluated the drug in a difficult-to-treat population of obese and overweight patients with type 2 diabetes. In addition to weight loss, those taking lorcaserin had a .9% decline in hemoglobin A1c levels. Furthermore, more than 50% achieved the American Diabetes Association targets for blood sugar and many were able to reduce their diabetes medications.

“We believe that the weight loss, efficacy, safety profile and additional benefit for glycemic control shown in BLOOM-DM improved the overall benefit/risk profile from that presented in the original NDA submission,” Anderson said.

Analysts expect that the May advisory committee review will focus mainly on the rat tumor findings and also the efficacy data for lorcaserin. Based on the total data package, they are not expecting valvulopathy to emerge as a major issue during the review, or for there to be much impact from the March meeting on cardiovascular guidelines for obesity drugs.

During the company’s March 14 call, analysts expressed concern that the company does not appear to be prepared for a REMS, considering that this was an important factor in the positive Qnexa review.

“FDA has not yet told us we are subject to a REMS,” Anderson responded. “In the absence of that communication, what we’re preparing for is a more general risk management program, and that’s what we’re under discussion with Eisai about right now. The risk management plan is a bit broader than the REMS concept that was discussed at the [Qnexa] advisory committee last month, so it will contain components to ensure that the distribution and access is appropriate” Anderson said.

The company said that is looking at a number of options to ensure that the supply of the drug is safe, appropriate and delivered to the intended patient population.