The FDA's complete response letter on chronic fatigue drug Ampligen looked like a potentially fatal blow to Hemispherx Biopharma Inc., essentially sending the company back to the drawing board on a program that had already spanned more than a decade.
But William Carter, chairman, president and CEO of Philadelphia-based Hemispherx, isn't throwing in the towel just yet.
Ampligen is a Toll-like receptor 3 modulator that has been studied in at least a dozen indications, including cancer, HIV, West Nile virus, severe acute respiratory syndrome and influenza. The most advanced application is chronic fatigue syndrome (CFS), for which no drug has yet gained FDA approval.
Ampligen met its endpoints in controlled Phase IIb and Phase III CFS studies. The Phase III trial randomized 234 patients to receive Ampligen or placebo, and Ampligen patients showed a 17.7 percent improvement in mean treadmill exercise duration compared to a 4.3 percent improvement in the placebo group. (See BioWorld Today, May 4, 2004.)
Yet the clinical and regulatory process has been anything but smooth for Hemispherx. The Phase III trial took about six years to complete, and the new drug application filing took another three years, followed by two years of review punctuated by numerous requests from the FDA for more information. (See BioWorld Today, Oct. 12, 2007.)
After all of that, the outcome was a complete response letter. The FDA said the Phase IIb and Phase III trials "did not provide credible evidence of efficacy" for Ampligen and asked for an additional clinical study evaluating six months of treatment with multiple dose regimens. And the study will have to be even bigger than Hemispherx's last, with at least 300 patients on the dose regimens intended for marketing.
The FDA also wants the new trial to incorporate a QT-interval study and pharmacokinetic evaluations. In addition, the agency asked for complete rodent carcinogenicity studies in two species, additional nonclinical studies, data relating to product quality and resolution of outstanding manufacturing issues.
Shares of Hemispherx (AMEX:HEB) fell 49 cents, or 41 percent, to close at 71 cents on Wednesday.
Carter said the FDA's request for a third controlled trial was not entirely unexpected, although he had hoped that such a trial could be completed on a post-marketing basis. He noted that the agency required three trials to support the approval of Pfizer Inc.'s Lyrica (pregabalin) in fibromyalgia, an indication that has some patient overlap with CFS.
"The agency is following the model they applied to fibromyalgia," Carter said.
The next step for Hemispherx is to meet with the FDA and obtain a special protocol assessment (SPA) for the confirmatory trial the agency requested. Carter noted that although the previous Phase III Ampligen trial design was reviewed by the FDA's Antiviral Advisory Committee, the SPA process didn't exist at that time, and the drug was subsequently bounced through four FDA review divisions.
Ampligen is now in the hands of the cardiorenal division, which Carter said is "definitely" the right place for it. With the NDA on file, Carter predicted review of the supplemental data should move forward far more efficiently than last time around.
Carter also believes the confirmatory trial will proceed quickly. He declined to provide specific timelines, but he noted that Hemispherx has already engaged CROs to facilitate enrollment.
Perhaps most importantly, Carter said Hemispherx has the money to complete such a trial as the FDA requested. The company reported $61 million in cash and equivalents as of Sept. 30, and it burns about $8 million per year. Those well-padded coffers are the result of two offerings completed earlier this year, on the heels of a stock bump fueled by interest in Ampligen's potential as a flu vaccine adjuvant on the heels of the H1N1 swine flu scare. (See BioWorld Today, May 12, 2009.)
A little additional revenue comes from emergency treatment use of Ampligen for CFS, and a little more may come from sales of Alferon N, a marketed drug for venereal warts that Hemispherx acquired in 2003 from Interferon Sciences Inc. A previous cash crunch had forced Hemispherx to stop production of the drug, but the company expects to begin booking modest revenues again in 2010.
Hemispherx is hoping to see additional cash inflows from partnerships for Ampligen. The company has been looking to partner the drug for more than a year, but Carter said "very substantial negotiations" are under way.
Ampligen also is being studied as a vaccine adjuvant, and trials are planned for cancer as well as seasonal flu and swine flu. Hemispherx's pipeline also includes a low-dose oral version of Alferon, and Oragen, an early stage derivative of Ampligen.