Judith Mikovits,
Whittemore Peterson Institute
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>>>> 31 December 2010 <<<<
Editorship : j.van.roijen@chello.nl
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http://pharmaceuticalvalidation.blogspot.com/2010/12/race-is-on.html
Pharmaceutical Validation
validation refers to establishing documented evidence that a
process or system, when operated within established
parameters, can perform effectively and reproducibly to
produce a medicinal product meeting its pre-determined
specifications and quality attributes
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By Walter Armstrong
"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 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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