West Coast Editor

The filing of a new drug application by Hemispherx Biopharma Inc. for Ampligen could lead to the first approved toll-like receptor-based therapy and the first drug cleared by the FDA for chronic fatigue syndrome (CFS) - a condition once derided as "the Yuppie flu," but confirmed by the Centers for Disease Control as a true ailment that may afflict 1 million people in the U.S.

Hemispherx has included in the massive regulatory package data "going back over a period of about 12 years," said William Carter, chairman and CEO of the Philadelphia-based firm, who said results from trials involve more than 1,200 subjects given about 90,000 dose administrations.

No one knows what causes CFS, or how many causes might be involved, but "in some instances, it clearly is connected to an acute viral progression, which becomes sub-acute and then progresses," Carter said.

"The genetic fingerprints of these patients [drew] great interest at CDC for about two years," he added. "They have done a large number of gene chip analysis studies looking at host defense genes. Surprisingly, there's a very strong pattern."

In CFS patients, CDC researchers found "roughly two dozen genes, which are consistently dysfunctional," and the genes have to do with mitochondrial processes such as high-energy ATP transfer. That's where TLR3 - known to engage a set of genes involved in energy metabolism - comes in. Ampligen binds to TLR3.

Carter acknowledged critics of the CDC work. The British claimed that the genes studied by the CDC may not be the most disturbed genes, and there may be other "more severely deranged," he said, although all investigators have consistently found some abnormalities in gene modulation," particularly in energy metabolism.

"This is a far cry from six or eight years ago," when doctors claimed the derangement in CFS might not lie within genes, but within the psychology of the patients, who "simply need[ed] to get a grip" on their depression, Carter said.

Hemispherx tailored the NDA data to answer the FDA's questions about safety, while addressing efficacy. "We basically embedded those questions, which came to us in the early part of 2007, into our ongoing open-label, compassionate-use trials," Carter said. The agency's queries focused on any potential evidence of cytokine disturbance or autoimmune disease.

"It's generally better to have compounds [such as Ampligen] that are fully degradable into natural building blocks of RNA," Carter said. Adding something foreign as a backbone to boost stability could invite problems.

What's more, Ampligen - co-discovered by Carter and developed at Johns Hopkins University, and then licensed to Hemispherx - "doesn't need to be around very long, so we built a half-life of about 30 minutes into the drug design," which likely means benefit as well, he said.

CFS often gets mentioned in the same breath as fibromyalgia, the pain indication for which New York-based Pfizer Inc.'s Lyrica (pregabalin) won FDA approval earlier this year.

"There is about a 10 or 15 percent overlap, [patients] who have fibromyalgia syndrome who could also meet the CFS diagnostic criteria," Carter said. Although the CDC has not offered an opinion on fibromyalgia, the American Rheumatism Association (ARA) offers a diagnostic profile used by Pfizer in getting Lyrica cleared.

"Pain is the sine qua non of fibromyalgia," he said. "It can be seen in CFS, but is not by any means the overarching symptom." To meet the CDC's diagnostic guidelines in CFS, "basically, you've got to be substantially disabled most of the time. So far as I know, looking at the [ARA] criteria, there are no exclusionary diseases [to consider] when diagnosing fibromyalgia, but there are for CFS."

The differences mean, among other things, that Pfizer's Lyrica may have provided a path for approval of Phase III-positive milnacipran, the compound for fibromyalgia pain from Cypress Bioscience Inc., of San Diego, and New York-based Forest Laboratories Inc., not to mention Indianapolis-based Eli Lilly and Co.'s Cymbalta (duloxetine, already cleared for painful diabetic neuropathy and depression).

No such second and third comers exist, though, for Ampligen against CFS. Hemispherx also is "looking at two interrelated areas very actively," Carter told BioWorld Today. The double-stranded RNA drug might work as an immune modulator in vaccines, such as avian influenza and seasonal flu.

"That's a big target for us," he said. "Ultimately, it moves into other diseases such as HIV, which, of course, needs vaccines," though the field of research has had "a very negative history so far."

Cancer vaccines might also benefit from Ampligen. As many as 95 such drugs are undergoing study, Carter noted. "Generally what they need is immunological boosting at the level of the dendrite or some other cell that's relevant," he said.