The Race Is On - Pharmaceutical Executive

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The Race Is On


Pharmaceutical Executive


GETTY IMAGES / PHOTOLINK
"I really, really, really want to die and have had enough of being so sick and in so much pain every second of every day and, basically, one serious health crisis after another," wrote Lynn Gilderdale in a 2006 Web post during one of many discussions the 31-year-old British woman had with parents and friends on whether to hasten her own death.

In July 2009, Gilderdale decided to act, injecting herself with what she believed to be a lethal quantity of morphine. An hour later, she was unconscious but still alive, so her mother, Kay, took over the duty of assisting her daughter's suicide. She crushed antidepressants and sedatives and inserted the powder into her daughter's nasogastric tube. When that remedy failed, Kay gave Lynn several more injections of morphine, and later, increasingly desperate, several injections of air. Finally, toward dawn, Lynn's spirit made good her longed-for escape from a body ravaged for 17 years by severe chronic fatigue syndrome (CFS).


Judith Mikovits, Whittemore Peterson Institute
The Gilderdales' personal tragedy became a public story following Kay Gilderdale's arrest for attempted murder. With the British government inching toward legalizing assisted suicide, Lynn's CFS-related loss of almost every physical function, coupled with her mother's steadfast devotion, rendered the Gilderdales the most sympathetic in a series of highly publicized right-to-die cases.

In January, a British jury unanimously found Kay Gilderdale not guilty of attempted murder. Her exoneration marked a triumph for advocates of the legalization of assisted suicide. But lost in that debate was what patients with CFS view as a more urgent story: The disease that took Lynn Gilderdale's life remains as untreatable in 2010 as it was when the first known outbreak occurred in Lake Tahoe in 1984.


Cort Johnson, CFS Patient, Activist, and Blogger
"CFS simply gets no respect. It has been underfunded, understudied, underdiagnosed, and the healthcare system would like nothing better than to sweep it under the rug," says Donnica Moore, a women's health expert and CFS advocate. "But we're not going to allow that."

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
Some 200,000 Americans have been diagnosed with CFS, while anywhere from 1 million to 4 million may suffer from it, according to the CDC. Average life expectancy is about 55, with suicide the third most frequent cause of death. Depression is rampant. "CFS is not a death sentence—it's a life sentence," is a CFS community truism. Meanwhile, skeptics persist in dismissing it as "yuppie flu" and "shirker syndrome."

Yet recent studies show that most CFS patients did not experience clinical depression prior to getting sick. And increasing diagnoses of pediatric and adolescent cases reveal that kids who fall victim to the disease include many high achievers, whose parents can trace the onset of the illness to a routine infection of unusual severity or duration. Still, the CDC's sole treatment recommendation is cognitive-behavioral therapy. The agency's longtime CFS program head was finally axed in February, following years of public criticism by doctors for favoring a research focus on early sexual abuse rather than the search for pathogens.

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."

In XAND Land

Into this bleak landscape last October blazed an unpredictable claim by an obscure researcher from a little-known institute that the cause of CFS may have been discovered: a human retrovirus called xenotropic murine leukemia virus–related virus (XMRV). Biochemist Judith Mikovits at the Whittemore Peterson Institute (WPI) in Reno, NV, along with colleagues at the National Cancer Institute and the Cleveland Clinic, reported in the journal Science that DNA from the mouse-derived retrovirus were found in 67 out of 101 blood samples of CFS patients. Testing of 300 additional samples was said to hit 98 percent. What's more, 3.7 percent of the 218 control samples also contained XMRV.

The media predictably amplified the remarkable, if preliminary, findings into a "cause-of-CFS" story, and WPI was only too happy to oblige. "This is the breakthrough that we have been hoping for. Now we have scientific proof that this infectious agent is a significant factor in CFS," Annette Whittemore, WPI founder and president, proclaimed in the initial press release, which also announced that WPI had renamed CFS as XMRV-associated neuro-immune disorder (XAND).

WPI did not discover the XMRV virus, however. That distinction goes to scientists at the Cleveland Clinic and the University of California San Francisco, who in 2005 detected this fourth human retrovirus in the cancerous prostate tissue of 40 percent of men with a particular defective gene. WPI's Mikovits made the opportune leap from prostate cancer to CFS when she learned of the high incidence of lymphoma among the original Lake Tahoe cohort. XMRV seemed a possible culprit because it decimates natural killer blood cells, the immune defense against cells infected by HTLV-I. In addition, some CFS patients carry the same genetic mutation as men with prostate cancer who tested positive for XMRV. The working hypothesis at WPI is that XMRV indirectly causes CFS by inflicting so potent an assault on the immune system that it reactivates other viral infections and a chronic inflammatory response. "XMRV is the sort of agent that could create that effect on the immune system," Daniel Peterson, WPI's medical director and the co-discoverer of the original Lake Tahoe outbreak, told The New York Times in a piece headlined "A Big Splash by an Upstart Medical Center."

WPI was founded in 2006 by Whittemore and her husband, Harvey, a prominent Nevada couple whose daughter, Andrea, 31, has lived with a severe case of CFS for 20 years. Frustrated by Andrea's marginalization by doctors and by the lack of leadership, funding, and research at CDC, Annette Whittemore invested $5 million to launch her own research institute at the University of Nevada Medical School in Reno.

A flurry of activity followed on the heels of the discovery. Other researchers raced to confirm the WPI study. Patients flocked to the Internet for more information: Was XMRV fatal? How was it transmitted? Could they get tested for it? The answer to the last question was yes. A diagnostic test for the virus was already being marketed at $650 a shot by VIP Dx, which just happens to be owned by Annette and Harvey Whittemore. "Leaving aside the issue of who's right and who's wrong, the original paper did not establish the virus [causes CFS] and didn't establish it as a viable marker," Tufts University retrovirologist John Coffin, who wrote the editorial accompanying the original Science study, told the journal. Nevertheless, VIP Dx reported a six-to-eight-week backlog for results.

In general, patients' emotions bordered on the euphoric. Cort Johnson, whose Phoenix Rising Web site is one of the most trusted sources of information in the CFS community, says, "Patients are starved for good news. A discovery like this excites researchers, brings in funding, and gives patients hope—something they haven't had for many years." Meanwhile, the nation's handful of CFS specialists tried to temper patients' expectations with YouTube educational lectures on XMRV and its potential treatment implications.

For public health officials, the most alarming data point was XMRV's 3.7 percent prevalence rate in the control group. Extrapolating a worst-case scenario led to the prospect that as many as 10 million Americans could be carrying an infectious retrovirus already linked to two serious diseases. In January, a federal task force was convened to safeguard the nation's blood supply, an operation that could take a year or more, according to member Suzanne Vernon. Then again, a little public panic has its upside. "As we saw in the early years of HIV, fear among the general population at least gets the money flowing," says Moore.

A Pharma Screening

XMRV is exactly the kind of bug that hooks Big Pharma. "Two of the world's biggest drug companies contacted us the day our Science paper appeared," says Judith Mikovits. "By showing that XMRV is an infectious agent, we think we've convinced them to become interested in this target." Although Mikovits refused to disclose the identity of the two companies—"for fear that patients might seek out the treatments before studies"—she said that both were already screening HIV antiretroviral compounds in WPI cell lines for a hit.

Given the similarities among human retroviruses, an HIV drugmaker may already possess an effective anti-XMRV agent—if not a drug already on the market, then one of the thousands of marginally variant molecules made in the painstaking process of discovery—and currently gathering dust. Two classes of HIV drugs are in the running.

Both HIV and XMRV replicate by virtue of reverse transcriptase, the enzyme that links their viral RNA to the host cell's DNA. Reverse-transcriptase blockers were the first victory Big Pharma scored against HIV. Ironically, in the February Virology, Mayo Clinic researchers reported that after testing 10 HIV drugs against XMRV in vitro, the virus was susceptible only to AZT, a nucleoside reverse-transcriptase inhibitor (NRTI) notorious for its toxicity. "No CFS patient wants to go near AZT," says Mikovits.

Other RTs (or experimental versions) that may show promise include Bristol-Myers Squibb ddI and d4T, GlaxoSmithKline's Ziagen, and Gilead's Emtriva and Viread. Merck's first-in-class integrase inhibitor, Isentress, may work "because of its broad-spectrum activity," according to Coffin. In the best case, an already-approved antiretroviral will reveal XMRV-busting prowess, allowing the drugmaker to bypass safety and other early tests and advance straight into humans. "If one of the drugmakers currently screening candidates gets lucky, we could start a clinical trial in a month," says Mikovits.

Veteran advocates like Kimberly McCleary do a double-take at the news that two global pharmas are on the trail of CFS. "Now what we need is a race between them to see which can be first to market," she says.

WPI and Full Disclosure

When XMRV was first discovered in 2005, pharma held back because it was reported that the virus appeared to be inactive in prostate cancer cells. But Abbott Diagnostics jumped at the challenge of developing assays to detect XMRV. Last month, Abbott HIV Global Surveillance Program's John Hackett reported early progress on several fronts. But the main takeaway was that detecting XMRV in human blood samples is proving far more difficult than the WPI study had led anyone to expect. Using their new assay that can detect three different antibody proteins, the Abbott team found XMRV in only three of 2,851 random human samples. That's good news for the general population—a .01 percent extrapolated prevalence rate—but bad news for CFS patients.

Nor is Abbott alone in judging XMRV hard to find. Since January, three confirmation studies—two British, one Dutch—have reported results, and none found the retrovirus in either their CFS blood samples or their controls. As doubt is increasingly cast on WPI's theory that XMRV causes CFS, arguments have raged across the Atlantic. Accusations of sloppiness, bias, and even fraud have been hurled, mostly by Judith Mikovits and WPI's defenders. Old suspicions of patients have reappeared.

When asked for a more considered opinion, others choose their words carefully. "Validation and confirmation are not coming as fast as one might like, that's for sure," says John Coffin. "If you can't establish a disease association, then there is less interest in developing a drug, obviously." Coffin also notes that uncertainty remains about whether or not the virus is replicating. "If it does so, like HIV, then an antiretroviral would be very effective. But if not, as it appears in prostate cancer, a drug would not make any difference."

Writing on the CFIDS Association of America's Web site, Suzanne Vernon made a valiant effort to keep hope in the causal hypothesis flickering by emphasizing that none of the three studies is a "proper and robust replication study." And she concluded by throwing down the gauntlet: "Until methods are standardized and the scientific community is provided information about the specific characteristics of the CFS subjects who tested positive in the Science paper, be prepared to read more negative studies. Hopefully the Science investigators will make this information available before interest in XMRV being associated with CFS fades."

Given the great diversity in CFS symptoms, disclosure of the medical histories and clinical conditions of the high number of WPI's XMRV-infected CFS patients is critical. "Of course, this would generate more questions, but a cleaner association is needed," Vernon says. "I don't know why WPI won't provide this."

So far, Mikovits has refused to budge. "No additional medical histories or anything about the patient population would shed any light on XMRV," she says.

Sleuthing on her own, Vernon was able to uncover some suggestive information about the 32 CFS patient samples about which WPI originally reported assay results. Only 12 tested positive on more than one assay (WPI ran four assays); of those 12, four had been diagnosed with cancer. Another 13 of the total 67 XMRV-positive CFS samples also had cancer.

Whether XMRV is a cause or a passenger or merely a geographical coincidence of a particular CFS outbreak remains to be learned. But one thing is clear: With its big discovery, the upstart medical center has made more than a big splash. WPI has placed CFS—and itself—at the center of the perfect storm. "I knew how serious a retrovirus is," Annette Whittemore told the Times. "I was very concerned, knowing the implications. My second thought was, 'Of course, it was going to be something serious like that. Look at my daughter and how ill she is.'"

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