Wednesday, March 24, 2010

The Race is On - Pharmaceutical Executive

The CFIDS Assoc. posted a summary of the following article to their
Facebook page today- "A long article about CFS, XMRV and drug
companies' new interest in CFS appears this month in Pharmaceutical
Executive, a magazine that serves the pharmaceutical and biotech
industry. Writer Walter Armstrong interviewed many people for the
article that provides historical context as well as a look to the
horizon for treatments."


'The Race Is On'
Mar 1, 2010
By: Walter Armstrong
Pharmaceutical Executive

"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).

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.

"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.

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

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

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

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

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
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

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

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

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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