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Bioresearch Compliance Report
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Online Update Page, January 25, 2006
Clinical trials
NIH stops trial
of ‘intermittent’ AIDS treatment
NIH Jan. 18 stopped a trial of AIDS drugs, which was intended to discover
whether patients could take breaks from treatment, saying people were much more
likely to become ill or die if they took breaks.
The National Institute of Allergy and Infectious Diseases (NIAID) trial quickly
showed that patients do better when they continuously take the drugs; and a
larger, international trial showed that patients had twice the risk of dying or
developing clinical AIDS if they took breaks from the drug cocktails, called
highly active antiretroviral therapy (HAART).
“Furthermore, there was an increase in major complications such as
cardiovascular, kidney and liver diseases in the participants on the drug
conservation arm,” NIAID said in a statement.
It was hoped that patients would be seen less frequently if they were receiving
less drug because complications have often been associated with HAART, NIAID
explained. The HAART cocktails also cause nausea, diarrhea and other
discomforts, and patients can build up resistance to the drugs, meaning the
virus evolves and the drugs work less effectively over time.
“We were surprised to learn that in the short term, episodic antiretroviral
therapy carries such an increased risk without evidence of sparing patients the
known side effects associated with ART (antiretroviral therapy),” said Wafaa
El-Sadr, M.D., Harlem Hospital Center and Columbia University, New
York, who was working on the trial.
During the study, which began in 2000, known as Strategies for Management of
Anti-Retroviral Therapy, or SMART, patients either continuously took their drug
treatments, or started only when numbers of key immune cells, called CD4
T-cells, dropped below a certain level. When the trial was stopped, it was
running in 33 countries with more than 5,000 patents taking part.
The finding is a blow to AIDS advocates who had hoped that drug-conserving
therapy would reduce side effects — and save money on the expensive
medications, particularly in the world’s poorest countries, where AIDS is
skyrocketing.
“All around, it’s disappointing news,” said Jose Zuniga, president of the International
Assn of Physicians in AIDS Care. He cautioned that the idea of
drug-conserving therapy should not be completely abandoned.
“It might work one day, when there are newer, even more potent anti-HIV
medicines to choose from. It should signal us to invest even more in developing
the next generation of anti-retroviral drugs that may make this a
possibility,” Zuniga said.
“This large international study showed the benefit of the viral suppression
strategy,” added Sandra Lehrman, M.D., of NIH’s AIDS division. The main
message for HIV patients is if you are taking the drug cocktails, “it does not
appear prudent to get off them.”
University of Alberta
announces new drug database
University of Alberta, Edmonton, announced a new, freely available
online resource DrugBank, which contains detailed chemical, pharmaceutical,
medical and molecular biological information on more than 3,000 drug targets and
4,100 approved or experimental drugs products.
Additionally, the DrugBank provides more than 80 data fields for each drug,
including brand names, chemical structures, protein and DNA sequences, links to
relevant Internet sites, prescription information, and detailed patient
information.
Combined with DrugBank’s visualization software, these tools allow scientists
to easily search for new drug targets, to compare drug structures, study drug
mechanisms and discover new drug leads, the university said in an announcement.
“With DrugBank you’re never more than a mouse-click away from finding an
answer—whether you’re a patient, a pharmacist, a doctor, or a scientist,”
said team leader David Wishart, M.D.
“DrugBank is the first database we’re aware of that brings the latest data
from the Human Genome Project together with detailed chemical information about
drugs and drug products.”
Stem cell research
California stem cell
effort mired in legal muddle; Prop. 71 funding on hold
California’s Proposition 71 program was intended to create a $3 billion
West Coast counterpart to NIH, and allow scientists greater access into the new
field of biomedical research centered on human embryonic stem cells. Instead,
the program is wedged in a seemingly endless legal morass, the “San Francisco
Chronicle” reported Jan. 22.
According to the lawsuits, stem cell research opponents and taxpayer advocates
question whether the program was set up with too much independence from elected
decision makers. A trial is scheduled to begin Feb. 27 before Alameda County
Superior Court Judge Bonnie Sabraw in Hayward, but appeals will extend the delay
even if the institute prevails.
Thus, instead of financing the research, officials are reduced to begging for
handouts to avert closing down by June, when existing funds run out. They also
implemented a freeze on most staff hiring. The fundraising effort aims to
generate $50 million — about $30 million has been promised already. But this
is a far cry from the $350 annual spending envisioned by Prop. 71.
Universities have had to put construction plans on extended hold because of
Prop. 71’s slow start, while researchers are beginning to seek other sources
of grants. At the same time, the nation’s main font of medical research
grants, NIH, is implementing cutbacks after its first budget reduction since
1970. Moreover, with the Bush administration’s ban on grants for research on
early-stage human embryos, NIH is not even an option for scientists working with
most human embryonic stem cells.
But not everyone is worried. “The prevailing opinion is we will prevail,
it’s just a matter of when,” said Susan Bryant, dean of the UC Irvine
School of Biological Sciences, who serves as a member of the Stem Cell
Institute’s governing board. UC Irvine has drawn up detailed plans for a $60
million stem cell research facility big enough to house about 20 laboratories.
Those plans have been shelved until Prop. 71 grants can be sought. Instead, UC
Irvine is making do with rented space for a half-dozen labs in a university
research park.
“Expectations for this research are fine as long as people understand it could
be a long time,” Bryant said. “It will never happen if we never get started.
... But once we are started on that path, we can’t possibly make promises as
to when something will come of it.”
However, the problems surrounding Prop. 71 have caused stem cell advocates in
other states to move more cautiously to set up their own programs. In Missouri,
for example, a ballot proposal aimed at the fall election does not even call for
public money for research grants; it simply seeks to allow stem cell research in
the state. And, legislative leaders in New Jersey have delayed
stem-cell-friendly bills citing fears that Prop. 71 may be the wrong approach.
Although California state officials say they are optimistic about their chances
in court, it is expected that the program will take at least 15 more months to
struggle through appeals and start issuing the first major grants.
Additionally, California officials said they are planning a conference in May on
the safety of human-egg extraction, and they want to sponsor 16 California
researchers who have been invited to Britain to discuss collaborative efforts.
The California Stem Cell Institute also wants to convene a meeting of stem cell
scientists from around the state in September.
Cloned stem cells
safe for therapeutic purposes, study finds
Stem cells taken from cloned embryos are likely to be safe when used for
therapeutic purposes, according to a new study conducted at the Whitehead
Institute for Biomedical Research, Cambridge, MA, and published in Jan. 16
issue of “Proceedings of the National Academy of Sciences.”
Tobias Brambrink, Ph.D., lead author of the study, said although the research
was done in mice, there is hope the findings will translate to humans.
Researchers are calling the technique “therapeutic cloning,” or somatic cell
nuclear transfer. Scientists first created a clone by removing the nucleus from
a donor cell (perhaps a skin cell), Brambrink explained, and then putting it
into an egg that was missing its nucleus.
The engineered egg then became an early stage embryo that produced stem cells.
The researchers said they then took the stem cells with an aim to growing them
into specific, customized cells for cell-replacement therapy.
The hope is that these cells may one day provide treatments or cures for
diseases such as diabetes, liver failure, spinal injury, stroke, Alzheimer’s
disease and heart disease. “Stem cells hold great promise for human
therapy,” Brambrink said. “In an optimal world, we would make stem cells
genetically matched to a patient.”
The therapeutic cloning Brambrink’s team used is the same technique that South
Korean scientist Hwang Woo-suk claimed to have used to clone human embryonic
stem cell lines, but his research turned out to have been faked. [See BioResearch Compliance
Report, Jan. 11]
‘Cocktail’ helps
adult stem cells thrive in lab, scientists say
Scientists from the Center for Gene Therapy at Tulane University
Health Sciences Center, New Orleans, have discovered a “cocktail” of
growth factors that expands the number of stem cells they can grow in the
laboratory at least 10 times beyond what anyone has been able to do before.
The technique, if replicated in humans, could greatly enhance the effectiveness
of bone marrow transplants, and may even help refine gene therapy, according to
their findings, which appear in the Jan. 22 online issue of “Nature
Medicine.”
Chengcheng Zhang, Ph.D., lead author of the paper, said the researchers were
able to show that these stem cells had specific genes that were activated and
encoded for growth factor proteins. One such growth factor, IGF-2, had already
been discovered. IGF-2 contributed to an eight-fold growth in stem cells.
Chengcheng’s research team added two more growth factors to the roster:
Angiopoietin-like 2 and -3. When these were combined with IGF-2 and added to
hematopoietic stem cells, the growth was 30-fold.
Senior study author Harvey Lodish, M.D., a member of the Whitehead Institute,
said: “It’s a numbers game. One of the major issues for hematopoietic [stem
cells that go on to form blood cells] and bone marrow transplantation has been
the inability to get sufficient numbers of cells because they just don’t want
to grow in the laboratory,”
Lodish said his lab is in the process of testing the findings in human cells.
“There are some immediate experiments to see if we can use the same cocktails
of growth factors to expand cord blood cells or human stem cells,” Lodish
said.
The work has several potential applications, the researchers explained. One is
to increase the efficiency of existing bone marrow transplants. “This would
increase the chance of getting a good transplant,” Lodish said. Another
relates to gene therapy. Currently, a healthy version of a gene is introduced
into a group of the patient’s stem cells via a virus. The stem cells, now with
the correct version of the gene, are re-administered to the patient. With this
method, however, scientists cannot control where the virus ends up and, in
several cases, the virus activated cancer-causing genes. For this reason, the
researchers said, FDA is not currently approving any gene therapy clinical
trials.
But the new discovery might enable scientists to multiply the patient’s stem
cells in the lab, and run tests to see if the virus ends up in the right place.
The bad cells could then be thrown away, and the good ones re-administered to
the patient.
“Right now, the techniques for gene therapy are kind of brute force. You put
the gene in and hope it goes into the right place. There’s no selection,”
Lodish said. “What we would like to do is put the gene into stem cells, grow
them and watch them to be as sure as one can be that we’ve got the right gene
into the right cells and nothing untoward has happened.”
The new findings also hold implications for basic science. “We want to
understand how stem cells make this decision to differentiate or stay stem
cells,” Lodish added. “What signals do they get? These are big questions,
difficult questions, and we need to answer them. These are hard questions, but
slowly we’ll get the ability to answer them.”
Tulane’s gene therapy center is the only NIH-sponsored organization to
distribute adult stem cells to other academic researchers around the world.
Gene
research/genomics
UM researchers
identify ataxia gene
Researchers at the University of Minnesota Medical School have discovered
the gene responsible for a type of ataxia, an incurable degenerative brain
disease affecting movement and coordination.
This is the first neurodegenerative disease shown to be caused by mutations in
the protein â-III spectrin, which plays an important role in maintaining the
health of nerve cells.
Ataxia is a hereditary disease that causes loss of coordination resulting in
difficulty with everyday tasks, such as, walking, speech and writing. About 1 in
17,000 people have a genetic form of ataxia. Spinocerebellar ataxia type 5
(SCA5) is a dominant gene disorder; if a parent has the disease, each of their
children has a 50% chance of inheriting the mutation and developing ataxia
sometime during their lifetime.
Understanding the effects of this abnormal protein, which provides internal
structure to cells, will clarify how nerve cells die and may provide insight
into other diseases, including amyotrophic lateral sclerosis (Lou Gehrig’s
disease) and Duchenne muscular dystrophy, the researchers explained.
The scientific discovery has historical implications as well — the gene was
identified in an 11-generation family descended from the grandparents of
President Abraham Lincoln, with the President having a 25% risk of inheriting
the mutation.
The research will be published in the February print issue of “Nature
Genetics.”
Sickle cell
corrected with gene copy
Scientists at the University of California, San Francisco, said they have
found a way to use embryonic stem cells to correct the mutation that causes
sickle cell disease in mice. The study, which is published in the “Proceedings
of the National Academy of Sciences,” suggests the technique could allow
people born with this genetic defect to live with few or no complications from
their illness.
With sickle cell disease, a genetic mutation causes red blood cells that carry
oxygen through the body to become hard and pointed, which makes it difficult for
the blood to circulate. This causes anemia, lung damage and pain in the arms,
legs, chest and abdomen.
In the study, Y.W. Kan and colleagues said they used embryonic stem cells
carrying the sickle cell mutation and they replaced the mutated copy of the gene
with a healthy copy.
The researchers said they eventually hope to be able to genetically alter human
embryonic stem cells from a patient’s own DNA and transplant them into the
patient.
Research
and development
Weill Cornell/Columbia
collaboration gives insight into how drugs influence key cellular receptors
A family of proteins called G protein-coupled receptors (GPCRs) lies on the
surface membranes of cells and is the target for about half of all currently
used drugs, but until now, experts have not clearly understood how these
receptors are switched on or off by pharmaceuticals.
Researchers at Weill Medical College of Cornell University and Columbia
University College of Physicians and Surgeons, however, have streamlined the
method and published their findings in a recent issue of “Proceedings of the
National Academy of Sciences.”
Experts had long assumed that receptors function as monomers in the membrane,
but, over the past several years, increasing experimental and theoretical
evidence began to highlight the functional importance of receptors organizing in
pairs — dimerizing — as they bind and react to other molecules.
The Weill/Columbia research team examined how dimerization occurs at the cell
surface. In the process, the investigators also shed new light on a higher
organization phenomenon, called oligomerization, that organizes the dimers and
may also play a key role in drug-receptor interface.
“Work on the light receptor rhodopsin has suggested that these receptors are
not only arranged in pairs but also that these pairs are arranged in rows
something we call ‘oligomerization,’“ explained senior researcher Jonathan
Javitch, M.D., associate professor of psychiatry and pharmacology at Columbia
University Medical Center.
The researchers designed and used a complex computer model to predict which
parts of GPCRs might link up with which part of a particular pharmaceutical
molecule to turn on or off the receptor.
The group then spent nearly two years perfecting a method that mimicked the
activity of either GPCR agonist or antagonist drugs on the GPCRs and their
dimers, using an approach called cysteine cross-linking.
Cysteine cross-linking chemically traps two positions together, forcing them to
come together in space, even in the absence of the drug ligand. Using this
technique, the researchers were able to switch the dopamine receptor “on”
when cross- linking mimicked the activity of an agonist drug, or switch it
“off” when cross-linking replicated binding with an antagonist compound.
Thus, the study provided the first structure-based demonstration of how drugs
work on the receptor and affect the GPCR interface; and it confirmed and
elaborated on the role dimerization plays in this process.
“Based on our experiments, we now propose — although we haven’t proven
this — that the activation or inactivation of this entire family of receptor
involves a rearrangement of the interface, not only between pairs, but through a
shift in these rows of pairs, called oligomers,” Javitch said.
If proven true by future research, this mechanism could point to a whole new
mechanism for driving and refining the activity of GPCR-linked drugs, he noted.
NIH awards Source MDx SBIR Phase I grant to develop biomarkers to track HCV
Source MDx, Boulder, CO, announced Jan. 12 that it has been
awarded a Small Business Innovation Research (SBIR) grant by NIH to initiate the
development of a molecular diagnostic test that will characterize Hepatitis C
virus (HCV)-infected patients and their response to standard-of-care therapy.
The company said it has the ability to analyze biomarkers from a wide variety of
samples including a blood sample, which is less invasive than many current
clinical tests, such as, liver biopsy.
The development of clinically useful RNA-based biomarkers has been inhibited in
the past by the inability to measure gene expression with sufficient precision,
as well as the presumption that gene expression is too variable within and
between individuals. But Source MDx said it has successfully addressed the
issues of precision measurement and has established a normal range of human gene
expression, laying the foundation for the use of RNA-based molecular diagnostics
to monitor an individual’s health, disease status and response to therapy.
The grant provides $100,000 in funding over a one-year period. Source MDx will
use the SBIR funding to characterize gene expression patterns from whole blood
in HCV patients and monitor their response to treatment at the molecular level.
This is the fourth SBIR grant Source MDx has received.
“Although HCV targets the liver, sampling of whole blood is relatively
non-invasive and peripheral blood is representative of many systemic
processes,” said Lisa Siconolfi, Ph.D., director of clinical studies at Source
MDx. “Changes in gene expression in the blood from HCV patients could yield
important foundational information for the development of a patient care
diagnostic in the area of infectious diseases.”
“We are pleased that the National Institutes of Health continues to recognize
the potential impact of Source MDx’s enabling technology in the development of
RNA-based molecular diagnostics,” said Jim Walther, VP of business
development, Source MDx.
“This capability is valuable for many additional diseases that are
particularly difficult and expensive to diagnose and treat, such as, multiple
sclerosis, lupus and inflammatory bowel disease.”
AstraZeneca, M. D.
Anderson Cancer Center collaborate to form umbrella of scientific research
AstraZeneca, Wilmington, DE, and M. D. Anderson Cancer
Center, Houston, Jan. 12 announced entering into scientific collaboration
agreements that will allow for integrated preclinical and clinical research on
new treatments for cancer, focusing initially on aerodigestive diseases (e.g.,
lung cancer, head and neck cancers, or colorectal cancers).
These renewable, three-year, master agreements establish a framework for
collaboration on a variety of initiatives across a range of AstraZeneca oncology
products and research projects. The umbrella agreements address preclinical and
clinical research in a way that will allow the two organizations to more
efficiently and effectively work to answer future research questions, the
companies said in a press release.
“Establishing a framework for our ongoing relationship will save time and
effort when negotiating individual research projects in the future,” said Les
Hughes, global head of cancer research, AstraZeneca.
“It is vital that we collaborate effectively with the best cancer research
institutions if we are to meet our goals of finding effective treatments for
patients with cancer.”
“Integrating ideas with industry earlier in the drug development process will
enhance our ability to bring new treatments from the bench to the bedside more
rapidly,” added Robert Bast, M.D., VP for translational research, M. D.
Anderson.
“To make the most rapid progress in the era of targeted therapies, we need new
ways to organize our research and to collaborate with pharma for the benefit of
our patients.”
The companies said the specific terms of the agreements are confidential.
FDA management
FDA to commemorate centennial
FDA announced Jan. 6 it will commemorate the 100th anniversary of the
passage of its founding law, the 1906 Pure Food and Drugs Act, on June 30.
In recognition of the agency’s centennial, FDA is cosponsoring several
significant events, which include the 2006 FDA Science Forum in Washington; the
Discovery Channel’s Young Scientist Challenge in College Park, MD; and
regional celebrations in Atlanta, GA, Jamaica, NY, Dallas, Chicago,
Philadelphia, and Oakland, CA.
FDA is the oldest consumer protection agency in the nation. Andrew C. von
Eschenbach, M.D., Acting Commissioner, FDA, said: “Our goal is to host events
that:
For more information on centennial events, visit
http://www.fda.gov/centennial.
Agency announces
“FDA & You” centennial newsletter
The Center for Drugs has announced a special centennial online newsletter for
health educators and students entitled “FDA & You.” The newsletter is
available in an easy-to-print PDF format.
Resources for health and science educators included pre-packaged lesson plans
designed to generate classroom discussion. The newsletter also is intended for
secondary students and their parents.
Lessons combine the efforts of five FDA centers, CDER, the Center for Biologics,
Center for Devices, Center for Food Safety and the Center for Veterinary
Medicine.
FDA & You is published three times each school year — in August, December
and March. To visit the site or download the centennial issue, see http://www.fda.gov/cdrh/fdaandyou/index.html.
People
Xenomics strengthens
product development team with appointment of veteran molecular biologist
O’Hara
Xenomics, New York, Jan. 24 announced that it has appointed Mark
O’Hara, Ph.D., as the company’s new director of product development.
O’Hara, an accomplished biochemist, will report to David Robbins, Ph.D., who
recently joined Xenomics as VP of product development.
Among his accomplishments, O’Hara has recently conceived, designed and managed
the development of all aspects of a novel diagnostic discovery program based on
comprehensive analysis of RNA from tumor cells and endothelial cells circulating
in blood. This work resulted in the filing of 21 patent applications and the
publication of 3 recent manuscripts.
O’Hara also led development and commercialization of the CellSearch Profile
kit, a medical product line currently sold worldwide by Veridex, LLC, a Johnson&Johnson
company. In addition, he has 12 years of experience as a supervisor in the
biomarker discovery validation and development industry.
The appointments of Dr. O’Hara and Dr. Robbins are part of a larger strategic
initiative designed to reinforce Xenomics’ overall product development
operations and high-growth revenue potential as the Company moves toward the
commercialization stage of its breakthrough medical diagnostic testing
technology, Xenomics said in a press statement.
Avant
expands senior management team; appoints Ellis senior VP, R&D
Avant Immunotherapeutics, Needham, MA,
announced Jan. 23 the appointment of Ronald Ellis, Ph.D. as senior VP, R&D.
Ellis had previously been senior VP, development, for ID Biomedical Corp.,
which was recently acquired by GlaxoSmithKline (GSK).
Ellis began his industrial career at the Merck Research Labs, where he
helped in the development of several vaccines prior to their licensure,
including Varivax (varicella), Recombivax HB (hepatitis B), and PedVAXHib (Hemophilus
influenzae type b). He also provided early leadership in the development of
Merck’s Rotateq (rotavirus) and Gardasil (humanpapilloma virus) vaccines, for
which license applications have been filed.
At ID Biomedical, Ellis oversaw the development of a group A
streptococcal vaccine and a pneumococcal group-common vaccine. Ellis also
was general manager of ID Biomedical’s Northborough, MA’s vaccine
development and pilot manufacturing facility, which he had started up for a
predecessor company in 1998.
In his new role, Ellis will be responsible for development functions including
the identification of new vaccine candidates, biological and preclinical
development, assay and process development, clinical lot production, quality
control, and project management.
Xoma announces
senior management appointments
Xoma, Ltd., Berkeley, CA, Jan. 12 announced four senior management
appointments: Robert Gundel, Ph.D., VP, scientific corporate development; Mary
Haak-Frendscho, Ph.D., VP, preclinical R&D; Mark White, VP, cell and
analytical development; and Paul Goodson, senior director, investor relations.
In his new role, Gundel will provide leadership in corporate messaging, business
development and specialized projects. Gundel has more than 20 years experience
in the biotechnology and pharmaceutical industries including management
positions at Chiron Corp., Boehringer Ingelheim Pharmaceuticals and Bayer
Corp. Gundel joined Xoma in 2002 and most recently served as Xoma’s VP,
preclinical development.
Haak-Frendscho, who has over 15 years experience in the biotechnology industry,
most recently at Abgenix, Fremont, CA, joined Xoma in 2003 as senior
director, cell and analytical biology. In her new role, Haak-Frendscho will lead
Xoma’s antibody platform enhancement effort and direct the antibody discovery
and preclinical development of Xoma’s drug candidates.
White was appointed as Xoma’s VP, cell and analytical development in November
2005. In his new role, White provides strategic leadership in developing and
implementing Xoma’s cell expression and pharmaceutical/bioanalytical
capabilities. He has 15 years of experience, which includes multiple scientific
and management positions with increasing responsibility. Most recently he was
senior director, cell and analytical development, where he successfully
integrated Xoma’s cell biology and pharmaceutical development groups.
Goodson is an investor-relations executive with more than 20 years of investor
relations and general management experience. Prior to founding Shareholder
Value Partners, Goodson was VP of investor relations at Invitrogen Corp.,
Carlsbad, CA, and was previously president of two R&D firms. As Xoma’s
senior director, investor relations, he is responsible for developing and
managing programs that communicate Xoma’s messages to the financial community.
Ohio woman honored as a medical pioneer
Columbus, OH-resident Mary Starke Harper, M.D., widely known for her scientific
research that helped improve medical care for the elderly and minorities, Jan.
10, received the “Secretary’s Award” — a top award from HHS,
“WorldNow” of Raycom Media reported.
“I’m proud of the federal government giving me 60 years of service. This
great country has created me and sustained me. Thank you. Please pray for me. I
have cancer now,” Starke Harper told the press during a gala in her honor.
Starke Harper is fighting breast cancer. Other accomplishments include having a
hospital named after her in Tuscaloosa, TN. She also worked with four presidents
including President’s Carter, Reagan, Clinton and Bush. And, Starke Harper
established a foundation that helped 15,000 persons earn Master’s or Doctorate
degrees.
Trial news updates
A.P. Pharma, Redwood City, CA, announced Jan. 24 its submission of a
protocol to FDA for a single pivotal Phase III clinical trial with the
company’s lead product candidate APF530. The proposed trial will compare the
safety and efficacy of Aloxi (APF530 with palonosetron) for the treatment of
acute and delayed chemotherapy-induced nausea and vomiting (CINV) in patients
receiving either moderately or highly emetogenic chemotherapy. A.P. Pharma said
the Phase III protocol is based on collaborative and directional discussions
with FDA officials during a recent end of Phase II meeting, while chemistry,
manufacturing and controls matters were agreed upon in writing. The company is
undertaking activities to prepare for initiation of the Phase III trial
following protocol review by FDA, with enrollment planned to commence at the
beginning of April 2006. Enrollment of patients is expected to be completed
within nine months of initiation in up to 100 sites across the U.S. The proposed
Phase III pivotal trial protocol design includes approximately 1,200 patients
comprised of two groups, including roughly equal numbers of those receiving
either moderately or highly emetogenic chemotherapeutic agents. In each group,
three sets of approximately 200 patients will be treated with APF530 containing
5 mg or 10 mg of granisetron, compared with the currently approved dose of
palonosetron. The study’s primary endpoint is to establish the efficacy of
APF530 for the prevention of acute onset (first 24 hours) and delayed onset
(four to five days) CINV in patients receiving either moderately or highly
emetogenic chemotherapy. No other 5HT3 antagonist is currently approved for the
prevention of both acute and delayed CINV for both moderately and highly
emetogenic chemotherapy. A.P. Pharma’s decision to move into a Phase III
clinical trial with APF530 is based on the positive safety and efficacy data
from the open label Phase II study of APF530, in which all clinical endpoints
were achieved, including an evaluation of safety, pharmacokinetics (PK),
tolerability and efficacy. There were no serious clinical adverse events
attributed to the formulation and injections of APF530 were well tolerated.
Biogen Idec, Cambridge, MA, and Elan Corp., Dublin, Ireland,
announced Jan. 23 that they have received notification from FDA that the
agency’s Peripheral and Central Nervous System Drugs Advisory Committee will
review Tysabri (natalizumab) for the treatment of multiple sclerosis (MS) on
March 7. On Sept. 26, 2005, the companies announced they submitted to FDA a
supplemental BLA for Tysabri. Subsequently, FDA designated Tysabri for priority
review.
Cardiogenesis, Foothill Ranch, CA, announced Jan. 19 it has received approval from the FDA on the clinical
trial protocol for the company’s minimally invasive Percutaneous Myocardial
Channeling (PMC) procedure. The protocol is approved under an IDE. Prior to
receiving the protocol approval, the company entered into a binding Letter of
Agreement with the FDA to ensure that key scientific and clinical issues
regarding the PMC technology and trial are clearly understood and agreed to
prior to commencing the study. Following receipt of the protocol approval,
Cardiogenesis said it plans to continue its search for a strategic partner and
begin the U.S. trial this year.
Cubist Pharmaceuticals, Lexington, MA, Jan. 23 announced that the
supplemental NDA to expand the indication for Cubicin (daptomycin for injection)
as therapy for the treatment of patients with bacteremia with known or suspected
endocarditis caused by Staphylococcus aureus (S. aureus) will be the
focus of the next public meeting of the Anti-Infective Drugs Advisory Committee
on March 6. The Cubicin Phase III trial included in the supplemental NDA is the
first study of its kind in bacteremia and infective endocarditis caused by S.
aureus. The meeting will take place at FDA’s Center for Drugs in
Rockville, MD.
CytRx Corp., Los Angeles, Jan. 23 announced it has submitted a protocol
to FDA reflecting its plans to treat patients in an open-label extension of its
ongoing Phase II clinical trial with its orally administered, small molecule
product candidate arimoclomol for the treatment for amyotrophic lateral
sclerosis (ALS or Lou Gehrig’s disease). CytRx said it expects to provide all
patients who complete the ongoing Phase II trial with the opportunity for
treatment with arimoclomol at the highest dose level three times daily for an
additional six months. In the currently underway 80-patient, 10-center,
double-blind Phase II study, patients are receiving either placebo or one of
three dose levels of arimoclomol capsules three times daily for a period of 12
weeks. The open-label extension trial is designed to provide additional safety
and tolerability data in combination with the current Phase II trial. CytRx
expects to report final data from its ongoing Phase II trial with arimoclomol
for ALS in the third quarter of this year, followed by initiation of a pivotal
Phase IIb clinical trial subject to FDA review and acceptance. The company
believes that successfully demonstrating safety and efficacy in this latter
Phase II clinical trial could be sufficient to support product registration with
FDA. In 2005, CytRx announced that arimoclomol was granted orphan drug status
and fast track designation by FDA for the treatment of ALS. Arimoclomol is one
of CytRx’s three orally administered, small molecule compounds. This small
molecule drug candidate is believed to function by stimulating a normal cellular
protein repair pathway through the activation of “molecular chaperones.”
Since damaged proteins called aggregates are thought to play a role in many
diseases, CytRx believes that activation of molecular chaperones could have
therapeutic efficacy for a broad range of diseases.
GSK’s low-dose, over-the-counter (OTC) version of
the prescription obesity drug Xenical (orlistat) moved closer to FDA approval
Jan. 23 after a health advisory panel endorsed the idea. Called Alli, the drug
is generally safe and effective for adults when used for six months, FDA’s
advisers said. The drug helps prevent fat from being absorbed by the body. FDA
now will consider the panelists’ advice as it decides whether to allow OTC
availability. If approved, it would be the first proven weight-loss drug to be
sold OTC at a time when two-thirds of Americans are overweight or obese. GSK
studies have shown that patients taking Alli lost about four to five pounds more
than those taking a placebo after six months. Some panelists voiced concerns
about repeated and long-term use, such as, abuse among teenagers and people with
eating disorders. The product also has several unpleasant side effects,
including oily stools, rectal discharge and excess gas.
Medarex, Princeton, NJ, and PharmAthene’s, Annapolis, MD,
drug Valortim (MDX-1303), a treatment for anthrax, has been granted fast track
designation by FDA. Valortim is an investigational, fully human antibody created
using Medarex’s UltiMAb human antibody development system that targets the
bacillus anthracis protective antigen. Preclinical studies suggest that Valortim
has the potential to provide significant protection against anthrax infection
when administered prior to the emergence of symptoms of anthrax infection, and
also may increase survival when administered therapeutically, or once symptoms
become evident. In these studies, Valortim was shown to protect both rabbits and
monkeys against the lethal effects of anthrax infection when administered at the
time of exposure at doses as low as 1 mg/kg. When administered to rabbits after
the development of symptoms, Valortim also improved survival as late as 48 hours
post-exposure as compared to controls. Valortim is currently being evaluated in
a Phase I open-label, dose-escalation clinical trial to evaluate the safety,
tolerability, immunogenecity and PK of a single dose of Valortim administered
intravenously or intramuscularly in healthy volunteers.
Nuvelo, San Carlos, CA, Jan. 23 announced that it has been
granted fast track designation by FDA for its lead product candidate,
alfimeprase, for the treatment of acute peripheral arterial occlusion (PAO), or
“leg attack.” Alfimeprase is currently being studied in Phase III clinical
trials for the potential treatment of acute PAO and catheter occlusion (CO), and
may have utility in a wide range of additional thrombotic-related conditions
such as stroke, deep venous thrombosis and myocardial infarction. Collectively,
these disorders are among the most common causes of death and morbidity in the
Western world, the company noted. Alfimeprase is being studied in an ongoing
Phase III program known as the NAPA (novel arterial perfusion with alfimeprase)
program, for the treatment of acute PAO. The program consists of two overlapping
randomized, double-blind, multi-national trials comparing 0.3 mg/kg of
alfimeprase versus placebo in a total of 600 patients. The primary endpoint in
both trials is avoidance of open vascular surgery within 30 days of treatment.
Open vascular surgery includes procedures such as surgical embolectomy,
peripheral arterial bypass graft surgery and amputation, but does not include
catheter-based procedures such as percutaneous angioplasty or stenting. A
variety of secondary endpoints are also being evaluated, including safety
endpoints such as the incidence of bleeding, and pharmacoeconomic endpoints such
as length of hospital and intensive care unit (ICU) stay. The first trial in
this program, NAPA-2, is expected to complete enrollment in the second half of
2006 and the second trial, NAPA-3, is expected to begin enrollment in early
2006. Alfimeprase also is being studied in an ongoing Phase III clinical program
known as the SONOMA (Speedy Opening of Non-functional and Occluded catheters
with Mini-dose alfimeprase) program, for the treatment of CO. The program
consists of two overlapping, multi-national trials. The first trial, SONOMA-2 is
an efficacy study comparing 3 mg of alfimeprase versus placebo in 300 patients
with occluded central venous catheters, evaluating restoration of function to
the catheters at 15 minutes. SONOMA-2 is expected to complete enrollment in the
second half of 2006. The second trial, SONOMA-3, will be an open label,
single-arm trial evaluating alfimeprase alone in 800 patients. This study’s
primary endpoint is safety; however, efficacy will also be evaluated. SONOMA-3
is expected to begin enrollment in the first half of 2006.
Proacta, San Diego, announced Jan. 24 that cancer patient treatment is
underway in its Phase I study of PR-104, a hypoxia targeted small molecule
prodrug designed to improve the outcomes of current treatment regimens that can
include chemotherapy and radiotherapy. Tumor hypoxia, a condition that exists in
the majority of solid tumors, can make treatment with conventional chemotherapy
and radiation less likely to succeed. PR-104 is designed to be activated in the
low oxygen environment of hypoxic tumors. Preclinical studies have demonstrated
that PR-104 is not only activated, resulting in the death of the hypoxic tumor
cells, but also distributes to surrounding tumor cells which are also killed.
This “bystander effect” may differentiate PR-104 in targeting solid tumor
hypoxia and offers the potential promise of improving current cancer treatments.
The study is being conducted at the Waikato Hospital, Hamilton, New
Zealand, and at the Peter MacCallum Cancer Centre, Melbourne, Australia.
A third, U.S.-based, site will be added to the trial in the coming months.
Trial briefs
Avicena Group, Palo Alto, CA, announced Jan. 23 that findings
from a Phase I/II study of its proprietary drug candidate for the treatment of
Huntington’s disease (HD-02) demonstrated the drug was safe and well-tolerated
by patients at a dose of eight grams/day. Additionally, patients receiving HD-02
experienced elevated serum and brain levels of creatine. Results from this
study, which was supported by NIH’s National Center for Complementary and
Alternative Medicine (NCCAM), were published in the journal “Neurology.”
Additional findings from the trial showed that serum 8-hydroxy-2’-
deoxyguanosine (serum 8OH2’dG) levels, which are markedly elevated in
Huntington’s disease patients, were reduced for patients receiving HD-02. Some
researchers believe that this decrease in serum 8OH2’dG may suggest reduced
oxidative injury in patients with Huntington’s disease. HD-02 is a proprietary
therapeutic that incorporates an ultra-pure, clinical form of creatine that has
demonstrated the ability to improve neurological function in certain patient
populations. The 64 patients enrolled in this multi-site, double-blind,
placebo-controlled trial were randomized to receive either eight grams of HD-02
or placebo each day for 16 weeks. The treatment period was followed by an
eight-week washout period. Following the washout period, elevated serum and
brain creatine concentrations returned to pre-treatment levels for patients
receiving HD-02. The study’s investigators intend to use the findings from
this trial to design late-stage studies of HD-02 aimed at examining the drugs’
ability to slow or halt the progression of Huntington’s disease. NCCAM, and
Avicena are currently examining higher doses of the compound in a
dose-escalation study, as well as a Phase II open-label trial.
Javelin Pharmaceuticals, New York, announced Jan. 23 that Dyloject (diclofenac
sodium injection) met the primary endpoint of a linear dose-response for pain
relief over six hours as measured on the visual analog scale (VAS).
Specifically, in this phase IIb study, patients with moderate-to-severe pain
after oral surgery given a single dose of either Dyloject or Roche’s Toradol
(ketorolac tromethamine) experienced statistically significant pain relief over
six hours compared to patients who received placebo. Five minutes after
intravenous injection, Dyloject demonstrated superior onset of pain relief to
ketorolac as measured by statistically significant reductions in pain intensity
and pain relief using both the VAS and categorical scales.
LAB International, Laval, PQ, Canada, Jan. 24 announced the final and
complete safety, tolerability and PK results from the recently completed Phase I
trial for its novel asthma product, LAB CGRP (calcitonin gene-related peptide).
CGRP demonstrated to be safe with no serious adverse events reported at all
doses tested. The randomized, double blind, placebo-controlled dose escalating
study was carried out on 10 healthy volunteers. The primary and secondary
objectives were to examine the safety and tolerability and the pharmacokinetics
of four inhaled doses of CGRP ranging from 0.025 to 5.0 mg. The results from the
administration of CGRP by inhalation demonstrated that there were no clinically
significant overall changes in safety laboratory parameters or systematic
changes in heart rate, blood pressure or ECG even at the highest dose
administrated. The mean endogenous CGRP plasma level before inhalation was 28
pg/ml. Although circulating CGRP increased in a dose- dependent manner following
inhalation at the 1mg and 5mg doses, thus demonstrating the desired lung
exposure, the CGRP plasma concentrations were not high enough to cause any
significant side effects, such as, decrease in blood pressure or flushing. CGRP
plasma concentrations at the 0.025mg and 0.1mg doses were not significantly
different from that of endogenous CGRP or placebo. Cmax of 38 pg/ml at 1mg and
78 pg/ml at the 5mg dose (31 to 125 pg/ml range) at Tmax of 5 minutes were
achieved, as compared to 28 pg/ml for placebo, a 2.8 fold increase. The AUC(0-15
min) at 5 mg dose was 2.5 higher than the placebo. GCRP is known to be a potent
vasodilative agent in the systemic circulation. LAB CGRP is a 37 amino acid
natural neuropeptide produced in the lung in response to allergic stimuli. As a
potential drug, it has demonstrated in preclinical studies a profile that could
make it an ideal anti-asthmatic drug candidate with bronchodilator,
bronchoprotector and anti-inflammatory properties.
University of Illinois at
Urbana-Champaign- and the University
of Georgia-researchers issued a news release
Jan. 9 stating that linear polymer chemical called polyphosphate aids in blood clotting. The researchers, who published
their findings in the “Proceedings of the National Academy of Science,”
believe that this finding could lead to new
treatment for diseases, such as, hemophilia. The study identified a
number of ways that polyphosphate helps in blood clotting. The polymer
accelerates two parts of the coagulation cascade — the contact-activation
pathway and factor V (a protein the forms thrombin) — that leads to fibrin and
clots, the researchers said. Polyphosphate also delays the breakdown of clots,
which causes new bleeding. Polyphosphate is present in every living organism.
However, research into it has been focused on bacteria and there has been little
data on the polymer’s activity in humans and other vertebrates, the
researchers explained.
Conferences
ExpertBriefings.com
audioconference. How
to Prepare for FDA Clinical Research Audits, Feb.
7, 2:30-3.30
pm (EST).
CROs
and clinical research personnel are often intimidated by the prospect of an FDA
inspection. There is much mystique surrounding this process. This interactive
session will relieve your anxieties by explaining how companies and sites can
prepare for FDA inspections. A
former FDA medical officer and conductor of pre-FDA audits, Jerri
Perkins, M.D., FDA Consultant, Perkins & Perkins
will reveal what to expect during an FDA audit by describing what agency
inspectors are actually looking for during a BiMo inspection…and why these
audits are crucial to the drug/device approval process. Click Here to Register via Electronic Form!
Or Click
Here to Register via Fax!
Drug Development Summit: R&D Innovation,
Acceleration & Risk Management, Feb. 12-15, Phoenix.
For more information, visit http://www.drugdevelopmentsummit.com.
CHI’s 13th International Molecular Medicine Tri-Conference, Feb. 21-24, Moscone
North Convention Center, San Francisco. For more information, please visit
Commercial Implications of Stem Cell Research, Feb. 22-24,
Moscone North Convention Center, San Francisco. Sponsored by Cambridge
Healthtech Institute. For more information, visit http://www.tri-conference.com/track6_STM.asp.
The Stem Cell Meeting, March 12-14, The Palace Hotel, San Francisco. This
Stem Cell Meeting is the premier international event bringing together
world-renowned scientists at the frontier of embryonic and adult stem cell
research with decision makers and thought leaders in policy, ethics, patient
advocacy, finance, business, and media to explore the challenge and promise of
stem cell research and the compelling potential of emerging therapies. For more
information, visit http://www.thestemcellmeeting.com/.
15th Annual Partnership with CROs, April 3-5, The Mirage
Hotel, Las Vegas. For more information, visit http://www.iirusa.com/cropartners/index.cfm.
12th National HIPAA Summit, April 9-11, Hyatt Regency on
Capitol Hill, Washington. For more information, visit http://www.HIPAASummit.com.
Check out our website at www.fdainfo.com
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