The second time proved to be a charm for Arena Pharmaceuticals Inc.'s lorcaserin as it sought a vote of confidence from the FDA's Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) in its benefit-risk profile as a weight-loss drug.

Not only did it get the vote, the San Diego-based company scored an expanded licensing agreement with its partner, Eisai Inc.

EMDAC's 18-4 vote, with one abstention, was greeted with applause Thursday, as getting any weight-loss drug past the committee has proven to be quite a challenge. But the audience enthusiasm was not matched by the committee.

This was "one of the hardest votes," said panelist Lamont Weide, chief of diabetes and endocrinology at the University of Missouri. Although he voted against approval in 2010, he gave lorcaserin a thumbs up this time. While he remained concerned about the modest 3 percent efficacy improvement over placebo, he voted yes because a significant population had more than 10 percent weight loss.

When lorcaserin (Lorqess) came before EMDAC nearly two years ago, it was voted down 9-5. The FDA followed the vote a month later with a complete response letter (CRL). (See BioWorld Today, Sept. 20, 2010, and Oct. 26, 2010.)

Weide's vote, like that of several others on the committee, came with conditions.

He urged the FDA to require a risk evaluation and mitigation strategy and ongoing echocardiography monitoring for valvulopathy signals. He also said patients should be removed from the drug if they don't respond in three months.

Coming down on the other side of the vote, Sanjay Kaul, director of the Fellowship Training Program in Cardiovascular Diseases at Cedars-Sinai Heart Institute, said he had difficulty seeing the drug's benefit as clinically meaningful and expressed concern about its long-term use.

A few on the panel were more positive. "It's time to approve this drug," said Peter Gross, chairman of the Hackensack University Medical Center.

Robert Smith, professor of medicine at the Alpert Medical School of Brown University, agreed, saying he felt comfortable with the benefit. While he would like to see higher weight loss, he added "that might not be the right place to set the bar."

Many of the concerns raised at EMDAC's first meeting on lorcaserin came up again Thursday. While the FDA seemed more comfortable about potential safety signals, including tumors and valvulopathy, many of the committee members needed some convincing, especially given what they described as the "modest" benefits of the drug. (See BioWorld Today, May 9, 2012.)

EMDAC's concerns reflected its vote a few months ago when it recommended the inclusion of two-stage cardiovascular outcomes trials (CVOTs) for all obesity drugs. However, Kaul acknowledged Thursday that it wouldn't be fair to sponsors with obesity drugs this far advanced to "change the goal post in the middle of the game." (See BioWorld Today, March 30, 2012.)

FDA staff responded that the agency has yet to develop a policy based on EMDAC's recommendation for CVOTs. However, when a similar policy was set in place for diabetes drugs, the agency required sponsors with applications already in house to address CV risks before approval – in much the same way that Arena responded to the FDA's CRL.

Besides lorcaserin, two other drugs – Qnexa (phentermine/topiramate, Vivus Inc.) and Contrave (naltrexone HCl/bupropion HCl, Orexigen Therapeutics Inc.) – were past Phase III when EMDAC recommended CVOTs for all obesity drugs. Although the committee, in 2010, recommended approval of Contrave with a postmarket CVOT, the FDA required the biotech to conduct a 10,000-patient CVOT prior to approval. Qnexa got EMDAC’s endorsement on its second try last month without a pre-approval CVOT. (See BioWorld Today, Dec. 16, 2011 , and Feb. 23, 2012.)

However, the FDA has yet to approve Qnexa, extending its PDUFA date to July 17.

Blockbuster Potential

Given the obesity epidemic facing the nation, any weight-loss drug approved by the FDA could have blockbuster potential – if the REMS isn't too restrictive. That's something EMDAC panelist Ed Hendricks, a clinician and medical director for the Center for Weight Management, cautioned against.

While a REMS is needed for lorcaserin, he said, it should focus on education. He worried that the proposed REMS for Qnexa is so onerous that it could make the drug inaccessible for patients who could benefit from it.

Within an hour of EMDAC's vote Thursday, Arena and Eisai, of Woodcliff Lake, N.J., reported they had expanded their marketing and supply agreement. In addition to the U.S., Eisai now has exclusive rights to market lorcaserin in most of North and South America, including Canada, Mexico and Brazil.

In exchange, Arena will be eligible to receive increased payments based on Eisai's net sales of the obesity drug and it will receive an undisclosed up-front payment, along with regulatory and development milestone payments.

Even without the expanded agreement, Piper Jaffray analyst Edward Tenthoff expected shares of San Diego-based Arena (NASDAQ:ARNA) to open significantly higher Friday than Wednesday's $3.66 closing price.

Regardless of whether the FDA pushes lorcaserin's June 27 PDUFA date back 90 days as it did with Qnexa, Tenthoff said he anticipates Eisai will launch the drug this year. The drug could conservatively generate $249 million in 2013 U.S. sales, he said, growing to $1.9 billion in 2018.