Still No Winner in Acute HAE; FDA Wants New Cinryze Trial

Another runner has stumbled on a regulatory hurdle on the race to get the first acute hereditary angioedema (HAE) drug to market.

In a complete response letter to ViroPharma Inc., the FDA asked for a new trial of Cinryze (C1-esterase inhibitor) in treating acute HAE attacks, citing a lack of robustness in data - but no safety concerns - from the placebo-controlled Phase III trial. Cinryze already has approval as a prophylaxis therapy, but ViroPharma had been hoping to secure the C1 inhibitor market in HAE for itself under the seven-year orphan drug exclusivity rule.

It looked like the drug might have a chance late last year when competing C1 inhibitor Berinert, from King of Prussia, Pa.-based CSL Behring, got a complete response letter of its own, leaving the space potentially clear for a Cinryze sweep. But the latest setback might, instead, prove a boon to CSL, which has since resubmitted its biologics license application for Berinert, though that company said no review date has yet been set.

That raises the question of whether Exton, Pa.-based ViroPharma will opt for the expense of another Phase III trial.

Analyst Joel Sendek, of Lazard Capital Markets, wrote in a research note that the firm most likely will initiate a new trial, though Liisa Bayko, an analyst with JMP Securities, said management had indicated Thursday morning that the company remained "undecided as to whether or not it will pursue an additional study."

Bayko, however, remained optimistic, predicting "little impact" of the complete response letter to Cinryze revenue projections.

Cinryze sales totaled $6.7 million in the first quarter. Lazard's Sendek is projecting full-year 2009 revenue to reach $61 million based on the prophylaxis label alone.

But, as the first product to hit the market for any use in HAE, Cinryze easily could be picked up for acute treatment use even if the company is unable to promote that indication. ViroPharma also recently got an expansion on the prophylaxis label to include a more convenient self-administration, which could increase the probability of off-label use.

An approval of Cinryze in acute treatment of HAE "would have been strategic in nature, as it would have effectively blocked CSL from entering the market," Bayko wrote in a research note, but the fact that patients and physicians already are familiar with the product gives it "a significant leg up from the competition, should there be any."

Investors seemed to agree, as shares of ViroPharma (NASDAQ:VPHM) were dinged a mere 9 percent in trading Thursday, losing 64 cents to close at $6.29.

But another potential competitor got a boost on the news. Shares of Cambridge, Mass.-based Dyax Corp. (NASDAQ:DYAX) gained 19 cents, or 11.6 percent, to close Thursday at $1.83.

Dyax received a complete response letter in late March for Kalbitor (ecallantide), a plasma kallikrein inhibitor that works via a different mechanism than a C1 inhibitor and, therefore, would not be kept off the market by a C1 inhibitor approval.

Dyax is working to resolve issues raised in the agency's letter, including a request for a risk evaluation and mitigation strategy and additional information relating to the chemistry, manufacturing and controls section of the BLA. No new trials were required. (See BioWorld Today, March 30, 2009.)

Also coming down the regulatory pipeline is Pharming Group NV's Rhucin, another C1 inhibitor. The firm, based in Leiden, the Netherlands, said in April that it was in pre-BLA meetings with the FDA. (See BioWorld Today, April 17, 2009.)

And Basingstoke, UK-based Shire plc has said it plans to conduct another pivotal study of icatibant, a bradykinin B2 receptor antagonist, in acute HAE attacks later this year in a second attempt to get the product on the market in the U.S.

The FDA rejected a new drug application for icatibant last year, though the drug subsequently was launched in Europe as Firazyr. (See BioWorld Today, April 25, 2008.)

The BLA for Cinryze initially was filed in mid-2007 seeking approval in both prophylactic and acute treatment indications. The FDA issued an approvable letter in early 2008, though no new trials were required at that time according to Lev Pharmaceuticals Inc., which had developed the product prior to the firm's acquisition last year by ViroPharma. (See BioWorld Today, Feb. 1, 2008.)

Most of ViroPharma's revenue comes from sales of Vancocin (vancomycin), the only approved product for treating Clostridium difficile-associated pseudomembranous colitis.

Despite having lost patent protection several years ago, Vancocin has been spared generic competition largely due to the FDA's cumbersome clinical trial requirements for generic vancomycin. But the agency has scheduled an advisory panel Aug. 4 to discuss bioequivalence recommendations for generic vancomycin products.

Vancocin also could face completion from a macrocyclic antibiotic in late-stage development at Optimer Pharmaceuticals Inc., of San Diego, which reported striking Phase III data in C. difficile-based infections last year showing that the drug surpassed the primary endpoint of noninferiority to Vancocin. Later data, however, showed no difference between the two drugs in treating the most virulent strain of C. difficile, which analysts had been hoping ultimately would give fidaxomicin a marketing edge over ViroPharma's drug.

Assuming no generic versions are approved this year, ViroPharma anticipates Vancocin sales of between $250 million to $270 million.

Source : www.bioworld.com

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