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Research
ENews Vol 1 No 12
October 2007
Welcome to the National
Information and Advice Centre for Metabolic Diseases
Research News Sheet - Vol 1 No 12.
The contents of this news sheet
has been gathered from around the globe during our
research to update our information on metabolic
diseases. The contents are general and not specific to
our cause.
Positive KuvanTM Pivotal Phase 3
Trial Results Published in The Lancet
Novato, Calif., August 13,
2007 – BioMarin Pharmaceutical Inc. (Nasdaq and SWX:
BMRN) announced today that final results from the Kuvan™
(sapropterin dihydrochloride) pivotal Phase 3 clinical
trial were published in the August 11, 2007, issue of
The Lancet. The
study suggests that treatment with Kuvan results in
significant reductions in blood Phe levels in some
phenylketonuria (PKU) patients. Kuvan, an
investigational oral small molecule for the treatment of
PKU, is being developed in partnership with Merck Serono,
a division of Merck KGaA, Darmstadt, Germany.
“This marks the first
published Kuvan clinical study, and we expect additional
publications in the coming months to build on the
collection of data related to Kuvan,” said Emil Kakkis,
M.D., Ph.D., Chief Medical Officer of BioMarin. “We
recently received priority review from the FDA and hope
to receive FDA approval by late November. In the
interim, we are pleased to be able to provide Kuvan to
PKU patients prior to commercial availability through
our expanded access program.”
The Phase 3 clinical study
enrolled 89 patients with elevated blood Phe levels aged
eight years and above at 29 sites in the United States,
Europe and Canada. All patients enrolled had
demonstrated a reduction in blood Phe levels following
treatment with Kuvan in a Phase 2 screening study. The
patients were randomly assigned to receive placebo or 10
mg/kg of Kuvan daily for six weeks. Patients were
evaluated every two weeks for changes in blood Phe
levels and adverse events. The primary objective was to
assess the efficacy of Kuvan compared with placebo for
reduction of blood phenylalanine in patients with PKU.
The secondary objective was to assess the safety of
Kuvan compared with placebo. A total of 87 patients
completed six weeks of treatment.
Highlights from the Phase 3
double-blind study are summarized below:
- Patients treated
with Kuvan for six weeks had a mean decrease in
blood Phe level of 236 uM/L (29 percent) compared to
a mean increase of 3 uM/L (3 percent) in the placebo
group (p<0.0001). Prior to treatment, patients in
the Kuvan group and placebo group had mean blood Phe
levels of 843 uM/L and 888 uM/L, respectively.
- After six weeks of
treatment, 54 percent of patients treated with Kuvan
and 23 percent of patients in the placebo group had
a blood phenylalanine concentration below the
recommended 600 uM/L level (p=0.003).
- Blood phenylalanine
concentrations fell by about 200 uM/L after one week
in the Kuvan group, and this reduction persisted for
the remaining five weeks of the study (p<0.0001).
- The type and
incidence of adverse events was similar in the Kuvan
and placebo groups. Kuvan was well tolerated and
investigators reported that no serious adverse event
occurred.
About Kuvan
Kuvan is an investigational
oral small molecule therapeutic for the treatment of
PKU. The active ingredient in Kuvan, sapropterin
dihydrochloride, is the synthetic form of 6R-BH4
(tetrahydrobiopterin), a naturally occurring enzyme
cofactor that works in conjunction with phenylalanine
hydroxylase (PAH) to metabolize Phe. Clinical data
suggest that treatment with Kuvan results in significant
reductions in blood Phe levels in BH4-responsive
patients. It also may enable some patients to minimize
or eliminate highlyrestrictive dietary constraints by
increasing Phe tolerance levels. BioMarin and Merck
Serono estimate that Kuvan could be a potential
treatment option for approximately 30 percent to 50
percent of the estimated 50,000 identified PKU patients
in the developed world. Kuvan has received orphan drug
designation from both the U.S. Food and Drug
Administration (FDA) and the European Medicines Agency
(EMEA). If approved, it will receive seven years of
market exclusivity in the United States and 10 years in
the European Union for this indication. Additionally,
the FDA has granted Kuvan Fast Track designation, which
is designed to facilitate the development of new drugs
that are intended to treat serious or life-threatening
conditions and that demonstrate the potential to address
unmet medical needs.
Contact:
Investors Media
Eugenia Shen
Susan
Berg
BioMarin
Pharmaceutical Inc.
BioMarin Pharmaceutical Inc.
(415) 506-6570
(415)
506-6594
Effect of miglustat on bone
disease in adult Type 1 Gaucher Disease (GD1): results
of a pooled analysis
Reduction of bone pain in more than 80% of the GD1
patients after 2 years miglustat therapy – Improvement
in Bone Mineral Density – No new bone crisis or
fractures
LONDON
– 17 September 2007 – Actelion UK Ltd announces the
publication of "Effect of miglustat on bone disease in
adult type 1 Gaucher disease: a pooled analysis of three
multinational open label studies" (Pastores et Al) in
Clinical Therapeutics, vol 29, number 8, 2007.
This
pooled analysis investigates the efficacy of miglustat
(Zavesca®) in controlling bone manifestations, such as
bone pain, osteopenia and osteoporosis, bone crisis and
fractures, in Gaucher Disease type 1 (GD1) patients. The
data in this analysis are drawn from the miglustat
pivotal studies OGT 918 – 001, 004, 005.
Bone
manifestations are considered among the most painful and
debilitating components of Gaucher Disease type 1 highly
impacting on patients’ quality of life(1)(2). It has
been estimated that bone pain occurs in more than half
of GD1 patients and that 26% will develop bone crisis
(1)(2); in addition GD1 has been shown to affect bone
metabolism leading to an increase in bone resorption,
which causes a decrease in bone mineral density (BMD),
osteopenia and osteoporosis in the majority of the GD1
patients(2).
The
analysis involved 72 patients, including 41 (57%) who
had received previous ERT and 20 (28%) who had undergone
splenectomy. Patients’ mean (SD) age was 41.2 (13.1)
years. The most frequent bone related manifestations at
study entry were osteoporosis (43/63 [68%] patients) and
bone pain (41/65 [63%] patients).
This
paper, led by Dr. Gregory Pastores, associate professor
of neurology and pediatrics at the New York University
School of Medicine, has shown that at two years 83%
(54/65) of the patients reported no bone pain. The
reductions in bone pain were comparable among all
subgroups, including high-risk patients (i.e.
splenectomized). Moreover, there were no new cases
of “bone crisis”, osteonecrosis or fracture; BMD
Z-scores were improved from baseline at both the lumbar
spine and femoral neck at each time point (months 6, 12,
and 24) (P < 0.001). As early as 6 months after the
initiation of miglustat monotherapy, significant
increases from baseline in the BMD Z-score were observed
at both the lumbar spine (mean, 0.15; P = 0.022) and
femoral neck (0.23; P < 0.001); the increases remained
significant at 12 months (0.19 [P = 0.012] and 0.21 [P =
0.017], respectively) and 24 months (0.21 [P = 0.015]
and 0.18 [P = 0.039]). Significant increases in BMD
Z-scores were observed at the femoral neck in
splenectomized patients (P < 0.001) and at both sites in
osteoporotic patients (lumbar spine: P < 0.001; femoral
neck: P = 0.006).
Lead
investigator Dr Gregory Pastores commented: “Bone
disease in patients with Gaucher Disease type1 can be a
source of severe debilitation and remains a major
management issue. The beneficial effect of
miglustat on bone manifestations and especially on bone
pain in these patients might be explained by its wide
tissue distribution even in deep organs such as bone and
by a direct effect on bone cells.”
Zavesca® is currently not approved for the treatment of
bone manifestations in Gaucher disease type 1.
Santé
Communications: 020 7379 7377
Helen
Clark (hclark@sante.co.uk)
Celia
Hall (chall@sante.co.uk)
Brain
Defect Helps Drive Fragile X Syndrome
THURSDAY, Sept. 20 (HealthDay News) -- A newly
discovered brain defect might be a target for the
treatment of the inherited mental disorder known as
fragile X syndrome, researchers report.
The discovery in rats
provides an understanding of how the gene mutation
responsible for the condition changes the way brain
cells communicate, according to the report in this
week's issue of the Proceedings of the National
Academy of Sciences.
"Fragile X syndrome is
the most common form of inherited mental retardation,"
explained co-author Gary J. Bassell, a professor of cell
biology at Emory University in Atlanta. "It has strong
links to autism and epilepsy."
Fragile X syndrome
occurs in approximately one in 4,000 males and one in
8,000 females, Bassell noted.
Working with rat brain
cells, the team found that synapses between brain cells
in the part of the brain called the hippocampus are
defective in animals with fragile X, Bassell said.
"We discovered what the
specific underlying defect is," he said. "It is actually
a defect in the mGluR5 receptor, which is on the surface
of neurons. The defect is that there is excessive
signaling."
Children with fragile X
have difficulty in processing information, because these
receptors allow too much signaling and change the
function of other receptors, Bassell theorized.
When his team treated
the receptor with an mGluR5 antagonist called MPEP, they
were able to reverse the effects of the mutation. "When
you quiet down this receptor, it corrects the defects
that occur in other receptors as well," he noted.
Bassell stressed that
MPEP is not a suitable drug for humans. However, the
discovery should help researchers find other drugs that
do the same thing safely.
Any drug that targets
the receptor will not be a cure for fragile X, Bassell
cautioned. "These children have a permanent defect in
their DNA," he said. "The goal here is to improve the
quality of life for these children. We are going to
decrease the severity of episodes to help them focus
better on learning tasks and help with the behavior
problems and improve their cognitive function," he said.
One expert hailed the
finding.
"This is a very
important paper," said Dr. Randi Hagerman, a professor
of pediatrics and medical director of the M.I.N.D.
Institute at the University of California, Davis. "It
proves that mGluR5 antagonists will be helpful in kids
with fragile X syndrome," she added. "We are looking
forward to a new age of treatment in fragile X
syndrome."
Hagerman noted that
trials with mGluR5 antagonists on adults with fragile X
syndrome will be starting this fall. "If things go well
with adults, then we will move to pediatric trials," she
said.
"This is a very hopeful
message," Hagerman said. "This means that there will be
very specific treatments that will have an impact in the
very near future."
Another expert agreed
that the discovery should lead to new treatments for
children with fragile X.
"This is a very
exciting paper, which is a powerful confirmation of the
mGluR theory of fragile X," said Dr. Michael Tranfaglia,
medical director of the FRAXA Research Foundation.
"Since FRAXA Research Foundation is currently working
with several pharmaceutical companies to bring mGluR5
antagonists into clinical trials for fragile X, we are
delighted to see this elegant proof of the therapeutic
potential of this class of drugs."
SOURCES: Gary J.
Bassell, Ph.D., professor, cell biology, Emory
University, Atlanta; Randi Hagerman, M.D., professor,
pediatrics, and medical director, M.I.N.D. Institute,
University of California, Davis; Michael Tranfaglia,
M.D., medical director, FRAXA Research Foundation,
Newburyport, Mass; Sept. 17-21, 2007, Proceedings of
the National Academy of Sciences
http://www.medicinenet.com/script/main/art.asp?articlekey=84019
New
Drug Aids Muscle Function in Myasthenia Gravis
FRIDAY, Aug. 17
(HealthDay News) -- A new drug -- oral EN101antisense --
reduced the severity of muscle weakness in patients with
myasthenia gravis, researchers report.
Myasthenia gravis (MG),
which affects about 20 in 100,000 people, causes fatigue
and reduced strength in voluntary muscles. Other
symptoms may include double vision, drooping eyelids,
difficulty swallowing, or slurred speech.
The small open-label
study included 16 MG patients who took daily doses of
oral EN101antisense for four days and were monitored for
a month. On average, the patients experienced a 46
percent reduction in symptom severity. Side effects
included dryness of the eyes and mouth.
The study, published in
the Aug. 14 issue of Neurology, was supported by
the biotechnology company Ester Neuroscience Ltd.
"This is the first time
we've been able to show that antisense is effective and
safe when taken orally for a neurological disease,"
study author Dr. Zohar Argov, of the Hadassah Hebrew
University Medical Center in Jerusalem, said in a
prepared statement.
Further research is
planned to study the effects of the drug over a longer
period of time.
Antisense is a
synthetic, short segment DNA that blocks production of
specific proteins. Oral EN101antisense inhibits
production of an enzyme called acetylcholine esterase,
which plays an important role in the function of the
neuromuscular junction, where nerves connect with
muscles.
-- Robert Preidt
SOURCE: American
Academy of Neurology, news release, Aug. 13, 2007
http://www.medicinenet.com/script/main/art.asp?articlekey=83350
FDA Approves New Drug to Treat
Rare Disease, Acromegaly
The U.S. Food and Drug
Administration today approved Somatuline Depot
(lanreotide acetate injection) for the treatment of
acromegaly, a rare and potentially life threatening
disease in adults caused by abnormal secretion of growth
hormone (GH), commonly from a benign tumor located in
the pituitary gland located in the brain.
"This type of therapy
provides an alternative for patients who have not
responded to other therapies," said Steven Galson, M.D.,
M.P.H., director, Center for Drug Evaluation and
Research. "The new approval reflects FDA's goals for
making effective and safe treatments available to
patients with rare diseases under the Orphan Drugs
program."
FDA has approved
Somatuline Depot for the long-term treatment of patients
with acromegaly who have had inadequate response to or
can not be treated with surgery and/or radiation
therapy. This new treatment lowers the levels of certain
hormones in the body, including GH and insulin-like
growth factor. Excessive GH secretion, working through
insulin-like growth factor, can cause enlargement of the
hands, feet, facial bones, and enlargement of internal
organs such as the heart and liver. If untreated,
patients with acromegaly often have a shortened life
span because of heart and respiratory diseases, diabetes
mellitus, and colon cancer.
The safety and
effectiveness of Somatuline Depot (administered through
injection) was determined in two pivotal clinical trials
involving a total of 400 patients. Common side effects
include diarrhoea, gallstones, skin reactions such as
itching, slow heart rate, and change in blood sugar
levels. Patients with diabetes who receive treatment
with Somatuline Depot may need to have their diabetes
medication adjusted.
FDA designated
Somatuline Depot orphan status because the drug treats a
rare disease and meets other criteria. Orphan products
are developed to treat rare diseases or conditions that
affect fewer than 200,000 people in the United States.
The Orphan Drug Act provides a seven-year period of
exclusive marketing to the first manufacturer who
obtains marketing approval for a designated orphan
product. Acromegaly affects approximately 15,000 people
in the United States and Canada and is most commonly
found in middle-aged adults. Patients with acromegaly
have reduction in life expectancy of 5 to 10 years.
The drug will be
marketed by Tercica, Inc. in Brisbane, CA.
Media
Inquiries:
Christopher Kelly, 301-827-6242
Consumer Inquiries:
888-INFO-FDA
Natural
Chemical Found in Broccoli Helps Combat Skin Blistering
Disease
Johns Hopkins
scientists have found yet another reason why you should
listen to your mother when she tells you to eat your
vegetables. Sulforaphane, a chemical present at high
levels in a precursor form in broccoli and related
veggies (cauliflower, Brussels sprouts, etc.), helps
prevent the severe blistering and skin breakage brought
on by the rare and potentially fatal genetic disease
epidermolysis bullosa simplex (EBS).
The researchers treated
newborn mice with a severe form of EBS-so bad they all
died within three days-with a topical solution
containing sulforaphane and found marked improvement;
after four days more than 85 percent of the treated mice
were alive and blister-free. These findings appear
online this week in Proceedings of the National Academy
of Sciences.
The basis of EBS, notes
study author Pierre Coulombe, Ph.D., professor of
biological chemistry, lies in two specific genes that
make proteins known as keratins. Normally, the keratins
join together and form highly resilient fibers in the
lower portion of skin, helping make it durable. If
either keratin is defective, they don’t mesh and the
lower skin tissue becomes unusually fragile and gets
damaged from the mildest mechanical stress - leading to
blistering pain, a higher risk of infection, and in the
most severe cases, death.
"Humans have around 54
distinct keratins, many of which are similar in
structure and function," says Coulombe. "We figured we
might be able to exploit this similarity and dial up a
replacement by triggering the activation of a suitable
signaling pathway in skin." He predicted that
sulforaphane might stimulate the formation of a
surrogate skin-strengthening keratin to stand in for the
defective one.
The desire to learn
more about sulforaphane led Coulombe and his co-workers
to Paul Talalay, M.D., professor of pharmacology who had
previously identified sulforaphane as a
cancer-preventive agent. "It turns out that treatment
with low doses of sulforaphane triggers the expression
of selected keratin genes in skin," says Coulombe. "So
we began what evolved into a highly rewarding
collaboration and found it does indeed work in a mouse
model for EBS."
"This is the first
suggestion that we may be able to treat this terrible
disease," adds Talalay, a co-author of this study. "And
we didn’t need to invent a new drug; sulforaphane is
naturally found in our diet."
The team will next test
whether sulforaphane can stimulate the proper keratin
protein in the appropriate subset of human skin cells -
a vital matter for any future medical hopes. Beyond that
are issues of how effective a topical application would
be on human skin, which is considerably thicker than
mouse skin, as well as examining the long term effects
of sulforaphane treatment.
"If we can clear these
important hurdles, then sulforaphane can potentially be
a tremendous therapeutic, with the added benefit of
having anticancer properties," Coulombe says. "And when
you consider that the only current option for EBS is
wrapping gauze around trauma-prone areas to minimize
breakage, and otherwise avoiding infection and making
sure blisters heal properly, then even a mild success
would be a significant benefit for these patients."
The research was funded
by the National Institutes of Health, the March of Dimes
Birth Defect Research Foundation, the American Institute
for Cancer Research, and the Lewis B. and Dorothy
Cullman Foundation.
Authors on the paper
are Michelle L. Kerns, Daryle DePianto, Albena T.
Dinkova-Kostova, Talalay and Coulombe, all of Hopkins.
Johns Hopkins Medicine
Media Relations and Public
Affairs
Media Contacts: Audrey
Huang; 410-614-5105;
audrey@jhmi.edu
Nick
Zagorski; 443-287-2251;
nzagors1@jhmi.edu
Drug Combo Helps Fight Marfan Syndrome
TUESDAY, Oct. 2
(HealthDay News) -- Treatment with the heart drug
perindopril, along with a beta blocker, may help reduce
certain cardiac complications of the hereditary disorder
Marfan syndrome, research shows.
Marfan syndrome, which
principally affects connective tissues, is often
characterized by excessive bone elongation and joint
flexibility, and eye and cardiovascular system
abnormalities. Progressive dilation and rupture of a
major blood vessel, the aorta, are the most serious
complications and the most common cause of premature
death in people with the disorder, according to
background information in the study.
Beta blockers are the
current standard treatment for Marfan syndrome, but may
not be as effective in treating aortic wall degeneration
as other therapies. Previous research has found that ACE
inhibitors such as perindopril help reduce arterial
stiffness.
Reporting in the Oct. 3
issue of the Journal of the American Medical
Association, Australian researchers at the Baker
Heart Research Institute examined the effectiveness of
perindopril in adult Marfan syndrome patients receiving
standard beta-blocker therapy. Ten patients received 8
milligrams/day of perindopril while seven others
received a placebo for 24 weeks.
"The major novel
finding of our study was that perindopril therapy for 24
weeks reduced aortic diameters relative to placebo in
both systole (the contraction of the chambers of the
heart) and diastole (the expanding of the chambers of
the heart) in patients with Marfan syndrome taking
standard beta-blocker therapy," the study authors wrote.
"In systole,
perindopril reduced the progression of aortic dilatation
observed in the placebo group. However, in diastole,
perindoperil actually reduced aortic diameters below
baseline levels," they noted.
The researchers
recommended a larger, longer-term clinical trial.
-- Robert Preidt
SOURCE: Journal of
the American Medical Association, news release, Oct.
2, 2007 |
