Though not a huge surprise, the complete response letter (CRL) from the FDA for Lemtrada (alemtuzumab) sent a rumble through the multiple sclerosis (MS) therapy space, and shook investors in Genzyme Corp., which has been told by the agency that approval of the CD52-targeting antibody requires more trials.

The Cambridge, Mass.-based firm was acquired in 2011 by Sanofi SA, of Paris, in a deal that became acrimonious at times. In the end, the transaction was valued at $20.1 billion, one of the largest in biotech history. (See BioWorld Today, Feb. 17, 2011.)

Also included in the agreement were $74 cash per share, plus a half-dozen contingent value rights (CVRs), which could pay investors as much as $14 per share. This is where the bad, if not altogether unexpected, news about Lemtrada comes in. Sanofi said the CRL means the company probably will not achieve the CVR milestone of Lemtrada’s FDA approval by the end of March, and other, sales-based goals likely won’t be met, either, without marketing clearance in the U.S. Genzyme could not be reached for comment.

Wells Fargo analyst Brian Abrahams pointed out in a research report that the FDA’s advisory panel meeting in November raised worries about the safety of Lemtrada and the design of trials, “which had substantially lowered its likelihood of approval.” Still, he noted, the panel “gave mixed final votes and seemed more comfortable that the agent’s safety profile was sufficiently characterized for the drug to be appropriate for certain patients.” (See BioWorld Today, Nov. 14, 2013.)

The Peripheral and Central Nervous System Drugs Advisory Committee did not vote on the matter of whether to recommend approval of Lemtrada, but balloted 17-0, with one abstention, that the drug’s safety profile shouldn’t preclude its reaching the market.

Panelists also discussed, though, the array of serious adverse events brought about by alemtuzumab when used at a higher dose as Campath for leukemia. Those included autoimmune disorders and thyroid cancer – a sevenfold increase – as well as melanoma. Leerink Swann analyst Seamus Fernandez was warily upbeat after the panel meeting, citing the panel’s focus “on specific checks in place on an annual basis to ensure compliance and effectiveness, referencing the Tysabri [natalizumab, Biogen Idec Inc.] risk evaluation and mitigation strategy as a benchmark comparator.”

Last summer, Sanofi withdrew Campath, reduced the dose and rebranded it as a prospective treatment for MS. Later in the year, Genzyme unveiled disability data from its Care MS II Phase III head-to-head trial of Lemtrada, confirming superiority over Rebif (interferon beta-1a) in patients with relapsing-remitting MS who had relapsed on prior therapy. Sixty-five percent of patients on alemtuzumab were relapse-free at two years, compared with 47 percent on Rebif, which is marketed by the Merck Serono arm of Darmstadt, Germany-based Merck KGaA. (See BioWorld International April 25, 2012, and Aug. 23, 2012.)

The supplemental biologics license application for Lemtrada to treat relapsing/remitting MS was accepted about a year ago, and Genzyme submitted for European marketing authorization, too. Action by the FDA had been expected in the second quarter of this year. Approval in Europe came in mid-September.

CAMPATH BIOSIMILAR PERIL

Other ripples follow the latest news. Lemtrada is partnered with Leverkusen, Germany-based Bayer AG through a potential $2.9 million deal that gave Genzyme control of the Phase III alemtuzumab program in MS, and required contingent revenue-based payments to Bayer, capped at $1.25 billion or 10 years. (See BioWorld Today, April 1, 2009.)

Sanofi said it will appeal the FDA’s decision, which Wells Fargo’s Abrahams called an “incremental positive” for Biogen Idec Inc., of Cambridge, Mass. The firm has Tecfidera (dimethyl fumarate) in the top market spot for MS, recently surpassing Gilenya (fingolimod, Novartis AG) for the pole position. (See BioWorld Today, Oct. 29, 2013.)

Now, the big questions are whether Sanofi could win the appeal and, if not, whether the pharma firm will commit to several years’ worth of more trials, considering that, by then, infused Lemtrada would be far behind in the MS race. Genzyme/Sanofi also markets the oral dihydroorotate dehydrogenase inhibitor Aubagio (teriflunomide), approved last year. (See BioWorld Today, Sept. 14, 2012.)

Whichever way the appeal goes, investors may be worrying about another potential fly in the ointment, in the form of biosimilars to Campath, which faces patent expiration in 2015. BioWorld’s report, The Biosimilars Game: A Scorecard for Opportunities, Threats and Critical Strategies, noted that a biosimilar for Campath “could thwart Sanofi’s efforts to free up the bases for Lemtrada. Since biosimilars are specifically prescribed rather than substituted at the pharmacy like a generic, a Campath biosimilar would have a clear path if the reference biologic is off the market. And some physicians, upset with Sanofi’s game plan, may prescribe the biosimilar, which could be even cheaper than Campath, off-label for MS.”

So far, though, Tecfidera has proven the standout. Its victory over Gilenya, both also oral therapies, has put the spotlight on MS treatments given by mouth, and the space is hot all around. More than 800 trials are under way or have recently ended for drugs targeting MS, according to Cortellis Clinical Trials Intelligence, and more than 100 of these are Phase III programs. Although most involve attempts at label expansions for marketed products, several star new molecular entities in late-stage development by companies such as Active Biotech AB/Teva Pharmaceutical Industries Ltd., Nuron Biotech and Receptos Inc. (See BioWorld Insight, Nov. 4, 2013.)