治療Alzheimer新藥試用

New Drug Trial Seeks to Stop Alzheimer’s
Before It Starts

By PAM BELLUCK

[試用的藥是Crenezumab is a humanized monoclonal
antibody designed for the
treatment of Alzheimer's disease.^[1] Crenezumab was developed by the
Swiss-based biopharmaceutical company AC
Immune SA, which licensed the drug in 2006 to Genentech,
Inc]

In a clinical trial that
could lead to treatments that prevent Alzheimer’s,
people who are genetically guaranteed to develop the disease — but who do not
yet have any symptoms — will for the first time be given a drug intended to
stop it, federal officials announced Tuesday.

Experts say the study will
be one of the few ever conducted to test prevention treatments for any
genetically predestined disease. For Alzheimer’s, the trial is unprecedented,
“the first to focus on people who are cognitively normal but at very high risk
for Alzheimer’s disease,” said Dr. Francis S. Collins, director of the National
Institutes of Health.

Most participants will come
from the world’s largest family to experience Alzheimer’s, an extended clan
of 5,000 people who live in Medellín, Colombia, and remote mountain villages
outside that city. Family members with a specific genetic mutation begin showing cognitive impairment around age
45, and full dementia
around age 51, debilitated in their prime working years as their
memories fade and the disease quickly assaults their ability to move, eat,
speak and communicate.

Three hundred family members will participate in the initial trial. Those with the mutation
will be years away from symptoms, some as young as 30.

“Because of this study, we
do not feel as alone,” said Gladys Betancur, 39, a family member. Her mother
died of Alzheimer’s, three of her siblings already have symptoms, and she had a
hysterectomy
because of her fears that she has the mutation and would pass it on to her
children. “Sometimes we think that life is ending, but now we feel that people
are trying to help us.”

The $100 million study will last five years, but sophisticated tests may indicate in two years whether
the drug helps delay memory decline or brain changes, said Dr. Eric M.
Reiman, executive director of the Banner
Alzheimer’s Institute in Phoenix and a study leader.

Alzheimer’s experts not
involved in the study said that though only a small percentage of people with
Alzheimer’s have the genetic early-onset form that affects the Colombian
family, the trial was expected to yield information that could apply to
millions of people worldwide who will develop more conventional Alzheimer’s.

“It offers a tremendous
opportunity for us to answer a large number of questions, while at the same
time offering these people some significant clinical help that otherwise they
never would have had,” said Dr. Steven T. DeKosky, an Alzheimer’s researcher
who is vice president and dean of the University of Virginia School of
Medicine. Dr. DeKosky was part of a large group consulted early on, but is not
involved in the study.

Some 5.4 million Americans have Alzheimer’s, and the numbers are
expected to swell as the baby boom generation ages. Dr. Reiman’s team is
planning a similar trial for people in the United States considered at
increased risk for conventional late-onset Alzheimer’s. The study announced
Tuesday will include a small number of Americans with gene mutations guaranteed
to cause early-onset Alzheimer’s.

The drug trial is part of
the federal government’s first national plan to address Alzheimer’s, which was
unveiled Tuesday by Kathleen Sebelius, the secretary for health and human
services. The government took the unusual step of assigning $50 million from
the current year’s N.I.H. budget to research considered too promising to wait,
including the Colombia trial and a study on whether inhaled insulin can ease
mild cognitive impairment, Dr. Collins said. Another $100 million is
proposed for 2013, mostly for research, but also for education, caregiver
support and data collection.

Success for the Colombia
trial is, of course, no sure thing. Many trials fail, and Alzheimer’s research
has so far found no treatment effective for more than several months. But
experts say that trying drugs years before symptoms emerge could have greater
potential because the brain would not yet be ravaged by the disease. The trial
will be financed with $16 million from the National Institutes of Health, $15
million from private donors through the Banner Institute and about $65 million
from Genentech, the drug’s American manufacturer.

The drug, Crenezumab, attacks amyloid plaques in
the brain. If it can forestall memory or cognitive problems, scientists
will know that prevention or delay is possible and appears to lie in targeting
amyloid years before dementia develops. Many, but not all, Alzheimer’s
researchers believe amyloid is an underlying cause of Alzheimer’s.

In 2010, The New York Times
reported on the pervasiveness of dementia in
this large Colombian family and scientists’ hopes of testing prevention
drugs. But persuading pharmaceutical companies to invest took months. There are
scientific and ethical issues involved with giving drugs to people who are
healthy and people who live in a developing country, some of whom have little
education, paltry incomes and longstanding superstitions about the disease they
call La Bobera — the foolishness.

“The first thing I did was
to ask myself the question, Are we taking advantage of these folks?” said
Richard H. Scheller, Genentech’s executive vice president of research and early
development. “The answer was clearly no.”

The risks, he said, are
balanced by the fact that if nothing is done, “they’re going to get this
terrible, terrible disease for sure.”

The few trials of
prevention therapies — involving ginkgo biloba, women’s hormone replacement
treatment and anti-inflammatory drugs — have involved people not guaranteed
to get the disease. These therapies either failed or caused adverse side
effects.

Testing drugs on that kind
of population takes “too many healthy volunteers, too much money, and too many
years,” Dr. Reiman said.

The Colombian population is
ideal because it is large enough to provide solid results, and it is easy to
identify whom the disease will strike and when.

Crenezumab was chosen for
the Colombia trial partly because it appears to have no negative side effects,
unlike other drugs designed to clear amyloid from the brain, said Dr. Francisco
Lopera, a Colombian neurologist who has worked with the family for decades and
is a leader of the study. Other anti-amyloid treatments have caused edema in the
blood vessels, an imbalance of fluid that can have serious consequences.

Crenezumab is currently
being given in two clinical trials to people with mild to moderate symptoms of
dementia in the United States, Canada and Western Europe to see if it can help
reduce cognitive decline or amyloid accumulation, according to Genentech.

In the Colombia study,
expected to start early next year, 100 family members with the mutation will
receive the drug every two weeks in an injection at a hospital. Another 100
carriers will receive a placebo. And because many people do not want to know if
they have the mutation, researchers will include 100 noncarriers in the study;
they will receive a placebo.

Researchers have developed
a sophisticated battery of five memory and cognitive
tests that have been shown in other studies to detect subtle alterations in
recall and thinking ability that usually go unnoticed. Dr. Pierre N. Tariot,
director of the Banner Institute and a leader of the study, said the
measurements would involve recalling words, naming objects, nonverbal
reasoning, remembering time and place, and drawing tests involving copying
complex figures.

Dr. Tariot said researchers
would also assess changes in people’s emotional state, “irritability,
sadness, crying, anxiety, impulsivity — these are cardinal features of the
disease as it emerges.”

The scientists will take
physiological measurements, including PET scans that measure amyloid and how
glucose is metabolized in the brain, M.R.I. scans that
measure whether the brain is shrinking, and cerebral spinal fluid tests that
measure amyloid and tau, a protein in dying brain cells.

If any of these indicators
are improved by the drug, Dr. Reiman said, scientists may then be able to treat
one of these early physiological changes, just as high blood
pressure and cholesterol
are treated to prevent heart disease.

In Medellín, Marcela
Agudelo, 17, has Alzheimer’s on both sides of her family because her parents
are distant cousins. Marcela watched her maternal grandmother die, and her
father, 55, once a vibrant livestock trader, has deteriorated so much that he
can no longer walk, talk or laugh.

With the research, “we have
more hope for a cure,” Marcela said, “or at least a better life.”

Dabrali Jimenez contributed reporting.