The Race Is On in XAND Land

[Guest guest]

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 , 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 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 . " 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

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, " , 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, ,

31, has lived with a severe case of CFS for 20 years.

Frustrated by '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 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

, 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 .

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, GlaxoKline'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 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 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 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.' "