BioWorld Today Contributing Writer

Arena Pharmaceuticals Inc. has vowed to press forward for approval of its weight loss drug lorcaserin despite the FDA's issuance of a complete response letter (CRL) in October.

In a conference call with investors Wednesday morning, officials at the San Diego company said they have completed an end-of-review meeting with the FDA and plan to resubmit a new drug application (NDA) for lorcaserin by the end of 2011.

The company's stock (NASDAQ:ARNA) which has been volatile in recent days, fell 24 cents, closing at $1.80. On Monday, the stock closed up 73 cents at $2.38. Tuesday, the stock closed down 34 cents at $2.04. Volume has been heavy all week.

Lorcaserin, the lead candidate in Arena's pipeline, is designed for weight loss in individuals who are obese (BMI > 30) or overweight (BMI > 27) and have at least one weight-related comorbidity. The 5-HT2C serotonin receptor stimulator is one of three players in the race to treat obesity. Mountain View, Calif.-based Vivus Inc.'s Qnexa (phentermine/topiramate CR) also received a CRL in October, while San Diego-based Orexigen Therapeutics Inc.'s Contrave (bupropion SR/naltrexone SR) received a thumbs-up from the FDA's Endocrinologic and Metabolic Drugs Advisory Committee earlier this month. (See BioWorld Today, Nov. 1, 2010, and Dec. 8, 2010.)

In July, Arena also inked a multi-million-dollar marketing deal with Eisai Inc., of Woodcliff Lake, N.J., the U.S. pharmaceutical subsidiary of Tokyo-based Eisai Co. Ltd. The milestone-loaded arrangement included a $50 million up-front payment. (See BioWorld Today, July 2, 2010.)

Arena acknowledged in its conference call that a number of nonclinical issues still must be resolved with the FDA. However, "the discussions during the meeting, along with FDA's written communication prior to the meeting, have provided us with further guidance and reinforced our position that we have a path forward to seek approval of lorcaserin," Jack Lief, Arena's president and CEO, told investors.

In fact, the company is already moving to respond to the FDA's recommendations, according to Lief. "We gave guidance that we're going to do everything before the end of next year, but that doesn't mean we're going to wait until December to refile," he told BioWorld Today.

Analysts seemed unmoved by the company's optimistic outlook, peppering officials with questions during the conference call about details of the FDA's concerns and the company's ability to satisfy those questions.

In a research update released after the call, JP Morgan analyst Cory Kasimov remained "skeptical and would continue to avoid ARNA shares." Company officials focused their comments on preclinical issues, including lorcaserin's potential preclinical association with breast and brain cancer, he pointed out. "But what about lorcaserin's clinical shortcomings – most notably its 'marginal' efficiency?" he asked. "We do not believe the drug can overcome this stigma as a monotherapy, which makes any subsequent benefit/risk debate problematic."

Elemer Piros, analyst at Rodman & Renshaw, LLC, agreed, maintaining a negative outlook on lorcaserin.

"Today's update suggests that the drug's potential approval timeline has been shifted to 2012, but more importantly we see significant risk in the planned studies," he wrote in a research note. "Specifically, we believe that brain and mammary tumor risk is a great concern to the agency, and while the planned animal and human studies may help to address some of these concerns, it is not clear if they would be adequate to satisfy the FDA's threshold for safety for a drug that is likely to be used chronically in a relatively healthy population."

Arena's immediate activities in satisfying FDA concerns relate to three nonclinical issues outlined in the CRL. (See BioWorld Today, Oct. 26, 2010.)

In regard to the first issue, diagnostic uncertainty in the classification of mammary masses in female rats, "some of the preliminary tissue diagnoses for mammary tumors differed from the final diagnoses in the study report," noted Christy Anderson, vice president of lorcaserin development. "In particular, some mammary tumor types were recharacterized from benign to malignant, and vice versa."

The company has convened a group of five independent pathologists to review the relevant tissues from the rat carcinogenicity study and to readjudicate the diagnoses of female rat mammary tumors in a blinded fashion, as requested by the agency, which has reviewed and approved the protocol, Anderson said.

The second nonclinical issue was an unresolved exposure-response relationship for lorcaserin-emergent mammary adenocarcinoma. The FDA has asked Arena to demonstrate the mechanism by which lorcaserin causes mammary tumors in rats and to demonstrate that this mechanism is "reasonably irrelevant" to human risk, Anderson said. The company maintains that lorcaserin-mediated increases in serum prolactin explain the risk for malignant breast tumors – a finding that would be "reasonably irrelevant to human risk," Anderson said, adding that the FDA has previously accepted this mechanism for other drugs. Arena has initiated nonclinical studies to provide evidence that demonstrates clear, persistent increases in prolactin in intact female rats at doses of lorcaserin associated with mammary tumors in rats.

"The FDA hasn't asked us to demonstrate tumors in rats," Anderson added. "They've only asked us to show a convincing increase in prolactin in response to lorcaserin."

The third nonclinical issue was an unidentified mode of action and unclear safety margin for lorcaserin-emergent brain astrocytoma – cancer that occurred in male rats who received the highest dose of lorcaserin. In the absence of information about the mechanism in which these tumors form, the FDA has asked Arena to clarify the safety margin in rats, relative to humans. The company has initiated several nonclinical experiments and plans to initiate a small clinical study to enroll approximately 10 volunteers who will be dosed with lorcaserin for about one week, followed by parallel cerebrospinal fluid and blood collection.

"Although lorcaserin cannot be readily measured in the human brain, the concentration in cerebrospinal fluid, which can be measured, will provide an additional estimate of brain levels," Anderson said.

In short, the FDA has accepted Arena's explanation of the controversial rat data, Lief maintained. "We just have to show them the data," he told BioWorld Today.

Arena also is seeking clarity from the FDA on a labeling issue. The FDA stated in its CRL that, based on the materials submitted in the NDA, it would recommend placement of lorcaserin in schedule four of the Controlled Substances Act. However, the agency is willing to "review and consider" preclinical studies and data in the company's complete response that might provide new information about the potential for abuse and a final scheduling recommendation. Arena is preparing to initiate these studies, Lief said.

"We are encouraged by the end-of-review meeting," Lief said. "I wouldn't pop champagne corks when we refile, but we understand what the FDA wants, and we have a clear path to get there."