Medicine's "Problem Child"

From almost any angle, CFS presents a vexing picture. No cause—not even a single biomarker—has been identified. Symptoms are as diverse as they are unpredictable, including debilitating fatigue, post-exertion malaise, and an enduring flu-like state ranging from aches and pains to severe headaches, cognitive disturbances, paralysis, and myriad complications. "CFS defies the established structure of medical disease," says Kimberly McCleary, who has headed the CFIDS Association of America for 20 years. "Many doctors still don't 'believe' in it. They treat a single symptom without seeing the whole. Or, worse, they dismiss it as a psychological problem." In turn, a fierce mistrust of not only the medical profession but the federal research establishment is endemic in the CFS community. Conspiracy theories abound.

Suzanne Vernon, CFIDS Association of America

The tenacity of its "disputed diagnosis" status has earned CFS the dubious distinction as the only orphan disease with literally millions of "silent sufferers." Pharma's longstanding disinterest in CFS is predictable, given the disease's unforgiving uncertainties. "I don't blame the drug industry—CFS is medicine's 'problem child,'" says virologist Suzanne Vernon, the CFIDS Association's scientific director. "If so many doctors do not recognize CFS, how can a drugmaker sell a treatment?"

CFS presents a kind of Gordian Knot to any pharma wishing to brave clinical trials: the lack of a biomarker confounds diagnosis; the lack of quantitative measurements of fatigue—the telltale symptom—confounds evaluation of a drug's efficacy; the presence of such diverse symptoms confounds validation of data.

"The drug industry works best on a 'bug and drug' model, and CFS has been slow to deliver a target," says McCleary. Early on, hopes were high that basic science would uncover a single virus behind CFS's devastating immune-system collapse—as took place in HIV. Academic research into the human retrovirus HTLV-II yielded especially promising preliminary results in 1991, raising patients' hopes, but replication studies foundered and funding was cut.

Until now, pharma's contribution to CFS treatment has been largely limited to the off-label use of a panoply of drugs, such as stimulants, sedatives, antidepressants, and anti-migraine medications to treat symptoms. However, with the success of Lyrica and Cymbalta for fibromyalgia (another "disputed diagnosis") drugmakers may find themselves inching into the CFS market.

Pharma may in fact stand to gain considerably by investing in CFS R&D. Expert consensus is that CFS is actually a suite of diseases, with some overlapping symptoms but many differences—and multiple causes. Advanced research is identifying biological trends, including chronic low-grade immune activation, latent activation of infections, and specific abnormalities in cognition, metabolism, and blood pressure. Deeper forays into CFS pathogenesis could yield finds that apply to many other conditions.

"CFS is a huge opportunity for pharma," says Moore. "The market is big, the bar is low, and they don't need a home run. Even incremental improvements to quality of life would be fantastic."

Unfortunately, the first CFS drug to face FDA review bombed in December: Hemispherx's sloppy NDA for Ampligen, an antiviral and immune booster in experimental use since the late '80s, contained 15-year-old data that "did not provide credible evidence of efficacy." The drug, which requires twice-weekly IVs and costs thousands of dollars a month, appears to work well in about 15 percent of patients. "This is the right drug in the wrong hands," says McCleary. "They cut too many corners."