By Ed Ungar
Statistics Canada identifies heart disease, cancer, stroke,
diabetes and chronic respiratory ailments as having the leading
mortality rates. Among diseases, they’re the Gang of
Five—they’ve got a bounty on their heads, and well
they should. Together, they’ve killed tens of millions
of people, more than all wars combined. Odds are that one of
them has a symptom with your name on it.
Medical researchers would dearly love to get them before they
get you. These laboratory superheroes are using every opportunity
and option at their disposal—discovering new genes, figuring
out new ways to restore cell function, investigating marine-life
molecules and employing free-radical scavengers—to handcuff
these public enemies.
They are taking seriously the words of British historian James
Bryce, who described medicine as “the only profession
that labours incessantly to destroy the reason for its own
existence.” Each of the hundreds of new treatments in
development for these diseases is a potential weapon in the
fight for cures. In most cases, the remedies are likely destined
for the pharmacy shelf.
Bearing this in mind, we examine here some of the top pharmaceutical
breakthroughs pharmacists should prepare to see in their dispensaries
over the next decade. The work is slow—painfully slow
sometimes—but hopes are high that these discoveries will
eventually take the Gang of Five out of circulation.
Winnipeg-based Medicure Inc. is developing a cardiac receptor
inhibitor that phase II trials demonstrated has the potential
to reduce heart attacks after bypass surgery by up to 47 percent.
Currently, nearly 15 percent of bypass patients suffer a heart
attack shortly after their operations. Medicure’s work
reaches back to 1996, when Dr. Naranjan S. Dhalla, former director
of the International Academy of Cardiovascular Sciences and
co-founder of Medicure, was screening a number of compounds
for their potential to damage the heart. To his surprise, he
found that the test drug MC-1 actually protected the heart
from injury following a cardiovascular event. Phase III trials
are currently underway involving North Carolina’s Duke
University and 130 hospitals around the world. If results are
encouraging, the drug should be clinically available by 2009.
Another class of drugs, anticoagulants called thrombin receptor
antagonists, is currently in development as an alternative
to warfarin. Unlike warfarin, which is currently used by more
than two million heart-disease patients in North America, TRAs
inhibit thrombin-mediated platelet activation without
the side effects of increased bleeding or ischemic events.
Even with the best treatments on hand, the ultimate goal is
to catch heart disease at its earliest stages. To do that,
researchers at such
institutions as the Ottawa-based Ontario Heart Institute are
investigating the genetic causes of heart disease. A team led
by the Institute’s Dr. Michael Gollob has discovered
a gene, connexin 40, which produces a defective protein causing
atrial fibrillation, the most common human arrhythmia or irregular
heartbeat. With this discovery, researchers can now design
new therapies to treat the condition around a protein target.
Such treatments, which target specific proteins rather than
several proteins assumed to be among the causes of the condition,
will hopefully have fewer side effects and higher success rates.
The Institute is also currently evaluating the DNA of 10,000
men under 55 and women under 65 in the Ottawa Valley region
with early-onset atherosclerosis, or hardening of the arteries.
Once the genes that produce defective proteins are identified,
clinicians can search for ways to counter the proteins. In
addition, says Gollob, genetic testing may help medical professionals
assess how prone a patient is to the condition. In collaboration
with pharmacists, preventive therapies could be developed to
combat the onset of the disease.
Many cancer researchers are optimistic that one day we may
live in a world where nobody has to fear the disease. Certainly,
medical science continues to make advances in fighting this
enemy. The 2007 Canadian Cancer Statistics report from the
Canadian Cancer Society and National Cancer Institute of Canada
reveals that, with the exception of lung cancer in females
and liver cancer in males, mortality rates for all cancers
combined have declined every year since 1994. But according
to the same study, if current trends hold, approximately 40
percent of Canadians will develop cancer in their lifetime,
and one in four Canadians will die from the disease.
Currently, chemotherapy remains one of the top weapons in
the fight against cancer. “It works pretty well,” says
Dr. Aaron Schimmer, a physician and research scientist at Toronto’s
Princess Margaret Hospital and Ontario Cancer Institute.
Several groups are looking to improve the effectiveness of
chemotherapy through the use of nanotechnology. At the University
of Utah, for instance, researchers are investigating the delivery
of chemotherapy to tumours with nano bubbles, which are popped
open with ultrasound when they reach their target.
Sometimes even the most aggressive chemotherapy doesn’t
work, and some cancer cells survive and multiply. In many cases,
this occurs because of the presence of the Bcl-2 protein, which
protects cancer cells from elimination by chemo drugs. Montreal-based
Gemin X Biotechnologies Inc. is working on an agent, obatoclax
(GX15-070), to target a number of the protein’s family
members and homologs. The treatment is currently in Phase II
clinical trials. Meanwhile, pharmaceutical manufacturer Abbott
is targeting Bcl-2 specifically with an oral medication (ABT-737)
in clinical trials.
Schimmer notes that because the Gemin X agent targets a protein
family, there is a greater chance it may also harm healthy
cells and cause greater toxicity. It is important to note,
however, that the drug was successful in Phase I safety trials.
Schimmer adds that Abbott’s approach, although more specific,
may miss a cancer-causing target, such as Bcl-2 related Mcl-1,
that Gemin X’s treatment might pick up.
Further promising anti-cancer weapons may lie in the world’s
oceans. Raymond Anderson, professor of chemical/geochemical
oceanography at the University of British Columbia, says that
although 50 to 60 percent of all cancer drugs originate from
natural sources, marine life remains largely unexplored. “Man
would never think of these molecules with his own imagination,” he
says, “but nature has created them over millions of years
by evolution.” Anderson and his colleagues at UBC have
been inspired by a molecule in the sea sponge (AQX-MN100) that
works against the enzyme SHIP, which aids uncontrolled cell
growth in blood-borne cancers. The molecule also shows promise
as a potent drug against many forms of inflammation, including
arthritis. It’s likely that the entire supply of the
sea sponge phosphatase needed for drug production could be
synthesized from just a pound of raw material, so the sea sponge
population will not be threatened.
As more drugs are developed against increasingly specific
causes of cancer, Schimmer predicts that physicians will be
increasingly reliant on pharmacists. “Physicians are
going to need pharmacists to help come up with the right combinations
while watching out for drug interactions,” he says.
Stroke is currently the third-leading cause of death in Canada.
Right now, when paramedics help stroke victims, there is little
else they can do except get them to a hospital. The drug tPA
(Tissue Plasminogen Activator) can be effective against stroke,
if it’s administered early enough. But tPA is also volatile,
in that it affects glutamate receptor functioning. If administered
incorrectly, it can shut down the entire nervous system.
“Stroke has been a minefield of drug disasters in the
last 20 years,” says Dr. Michael Hill, who, among other
appointments, holds the Heart and Stroke Foundation of Alberta
Professorship in Stroke Research at the University of Calgary.
Despite the challenges, some very promising developments are
on the horizon—two of which are under investigation in
Canada. Dr. Hill is currently involved in phase III trials
of a high-dose human albumin approach. High-dose human albumin
seems to be a free radical scavenger that also helps blood
flow better through the capillaries of the microcirculation
system. It also seems to promote neuron metabolism, helping
brain cells survive where oxygen is lacking.
A second approach under investigation at Toronto’s NoNO
Inc., a spinoff company of the Canadian Stroke Network, involves
attaching a small peptide to yet another peptide that has the
ability to get into the brain. The attached peptide works to
block a protein (PSD95) involved in the activation of an enzyme
called nitric oxide synthase, which produces toxic free radicals
that destroy nerve cells. The drug is administered by injection.
The chemical letters for nitric oxide are NO—hence the
curiously styled company name.
Phase I human trials suggested the approach is safe, because
healthy human subjects could tolerate doses that, in experimental
animals, reduced the size of strokes. As a result, this drug
might be safe for paramedics to administer at the time of a
perceived stroke. If effective, the drug would reduce further
loss of brain function, without producing side effects—a
problem that plagued previous stroke drugs. And if doctors
later find the patient did not suffer a stroke, “the
only thing you would lose is a vial of medicine,” says
Michael Tymianski, senior scientist with the Division of Fundamental
Neurobiology at the Toronto University Health Network. NoNO’s
product is based upon his research.
This category includes such killer diseases as emphysema,
bronchitis and chronic obstructive pulmonary disease (COPD).
While positive downward trends have been recorded in the incidence
of cancer and heart disease, the reverse is true with this
category. COPD is currently listed as the fourth-leading cause
of death in Canada. The Canadian Lung Association predicts
COPD will soon move up to number three, with recent research
suggesting that as many as three million Canadians are currently
unaware they have the disease.
The Association estimates 80 to 90 percent of COPD cases can
be linked to smoking. Presently, avoiding tobacco as early
as possible is the best treatment. Dr. Paul Hernandez, Chair
of the Canadian Thoracic Society COPD Guideline Dissemination
and Information Committee and Associate Professor of Medicine
at Dalhousie University, notes that “right now, other
than smoking cessation, we have no treatment that can change
the natural history of the disease.”
Despite that ominous assessment, Hernandez believes new weapons
in the battle against respiratory ailments may be a breakthrough
away. For instance, researchers are investigating medications
already used against other inflammatory conditions, such as
irritable bowel syndrome and rheumatoid arthritis. Drugs that
act as Tumour Necrosis Factor (TNF) inhibitors, such as infliximab,
are also being studied for their potential use. There are a
number of other inflammatory targets under investigation, such
as drugs that block transforming growth factor-beta (TGF-b).
In 1921, physician Frederick Banting discovered the process
for successfully isolating insulin in Toronto. Within a year,
diabetes patients who had faced imminent death could look forward
to the promise of long, productive lives. Banting and his team
of researchers won the Nobel Prize for Medicine in 1923, the
first Canadians to win the award.
But more than 85 years after that key discovery, diabetes
remains one of the healthcare industry’s leading enemies.
With more than 250 million diabetics around the world, most
in countries with advanced economies, it is little wonder that
more than 300 diabetes drugs are in development—a close
second to the number of cancer drugs under study.
Dr. Amir Hanna, professor of medicine at the University of
Toronto and director, diabetes clinics at Toronto’s St.
Michael’s Hospital, says new advances in diabetes medication
hold the potential to help patients control blood sugar more
effectively than they can with current treatments.
Exenatide (marketed as Byetta by Amylin Pharmaceuticals and
Eli Lilly) was approved for use in the U.S. in April 2005.
It is the first of a new class of drugs called incretin mimetics,
which lower blood-glucose levels by increasing insulin secretion.
The drug resulted from scientists’ discovery that exendin-4,
a chemical present in the saliva of the Gila monster, works
to help the lizard digest its prey. Exenatide, like insulin,
is delivered by subcutaneous injections—at present, twice
daily. A new formulation before the FDA holds the promise of
requiring just one injection a week, with fewer side effects.
The inhibitor is currently awaiting Health Canada approval.
The next class of diabetes drugs to arrive in Canadian pharmacies
will most likely be DPP-4 (dipeptidyl peptidase-4) inhibitors.
Gastrointestinal hormones called incretins increase the release
of insulin after eating, helping control blood sugar and food
intake. The problem facing researchers is that DPP-4 blocks
the effectiveness of incretins; the inhibitors work to stop
the enzyme.
The inhibitor sitagliptin was granted FDA approval in October
2006, and is marketed as Januvia by Merck & Co. While not
so exotic in origin as exenatide, an advantage of sitagliptin
is that it can be taken orally. A second oral DPP-4 inhibitor,
vildagliptin, is being considered for approval by Health Canada.
Another intriguing approach under study involves restoring
the ability of a diabetic’s insulin-producing beta cells
to work more efficiently, effectively transforming insulin
cells to normal functioning. A patient would take a drug once
a day for one to three months, and then not need to take it
for at least the next six. Transition Therapeutics of Toronto
is entering phase II trails of its drug, TT-223. If the phase
is successful, the company predicts phase III would be completed
by 2011.
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