Download April 2013 Monitoring International Trends (doc)

Monitoring International Trends
posted April 2013
The NBA monitors international developments that may influence the management
of blood and blood products in Australia. Our focus is on:
 Potential new product developments and applications;
 Global regulatory and blood practice trends;
 Events that may have an impact on global supply, demand and pricing, such as
changes in company structure, capacity, organisation and ownership; and
 Other emerging risks that could potentially put financial or other pressures on the
Australian sector.
A selection of recent matters of interest appears below.
Table of Contents
Products................................................................................................................................ 1
Regulatory matters ................................................................................................................ 2
Market structure and company news ..................................................................................... 3
Country- specific events ........................................................................................................ 4
Safety and Patient Blood Management ................................................................................. 5
Research………………………………………………………………………………………………5
Infectious Diseases ............................................................................................................... 6
Appendix: Alzheimer’s Research .......................................................................................... 9
1. Products
a) At the American Academy of Neurology meeting in March, Shawn Kile from
the Sutter Neuroscience Institute in Sacramento reported that recent studies
suggested that even a short course of intravenous immunoglobulin (IVIg)
could slow brain atrophy in early Alzheimer’s disease and improve cognitive
function. Octapharma supported the study.
b) Caltech1 engineers, in collaboration with Israeli company LeukoDx have
invented a portable device to count white cells of varying types2. The device
1
California Institute of Technology
2
Each of the five subtypes of white cells has a different function. Lymphocytes use
antibodies to attack certain viruses and bacteria; neutrophils are combat bacteria;
eosinophils target parasites and some infections; monocytes respond to inflammation and
replenish white blood cells within bodily tissue; and the rarest subtype, basophils, attack
certain parasites. The work is described in the April 7, 2013 issue of the journal Lab on a Chip.
1
c)
d)
e)
f)
g)
h)
3
4
works on only a pinprick of blood, and gives results in a few minutes, which
closely match results from hospitals.
A researcher at Washington University in St. Louis has found a way to use
light and colour to measure oxygen in individual red blood cells in real time.
The technology may have a use in determining how oxygen is delivered to
normal and diseased tissues, or the impact of specific treatments on oxygen
delivery throughout the body3.
Staff at the US Army’s Institute of Surgical Research are developing an
“intelligent tourniquet”, which has a pump and sensor system that can be
controlled by wireless. When activated it can determine how much pressure it
needs on the limb to stop beeding. The wireless vital sign monitor keeps
track of heart rate and blood pressure. Wirelessly connected to a laptop,
tablet, or smartphone it will give a more detailed readout. The vital signs
monitor has been approved by the FDA, but the “intelligent tourniquet” is still
in the prototype phase.
Entegrion is collaborating with Kedrion Melville, Inc. for clinical development
and commercialization of Entegrion’s dehydrated pathogen-inactivated
plasma product, Resusix. It is portable and overcomes the cold chain
restrictions of fresh frozen plasma (FFP), which is the current standard of
care. Entegrion will begin human clinical trials with Resusix in 2013, funded
primarily through contracts with the US Department of Defense. Kedrion will
make an equity investment. The early development of Resusix was
supported from The Office of Naval Research. The program will now be
managed by the US Army combat casualty care directorate.
The Defense Advanced Research Projects Agency (DARPA) has awarded the
Wyss Institute for Biologiclly Inspired Engineering a $US 9.25 million contract
to advance its blood-cleansing technology to treat sepsis-bloodstream
infections that are the leading cause of death in critically ill patients and
soldiers injured in combat. The patient’s blood is mixed with magnetic
nanobeads that are coated with genetically engineered human blood protein
that bind to a variety of bacteria, fungi, viruses, parasites and toxins. It then
passes through microchannels in the device where magnetic forces pull out
the pathogens without removing human blood cells, proteins, fluids, or
electrolytes -- similar to how the human spleen does. The cleansed blood then
goes back to the patient.
The addition of rituximab to a dexamethasone regimen was associated with
improved platelet response rates in a cohort of patients with immune
thrombocytopenia, according to results of a randomized, open-label, phase III
trial.
Scientists at Temple University and the University of Delaware have reported4
on the effect of Fucoidan on platelets. Fucoidan is a sulfated polysaccharide,
derived from the brown seaweed Fucus vesiculosis, which has demonstrated
decreased bleeding and clotting time for people with haemophilia and is now
in clinical trials. It activates platelets rather than increases a particular clotting
factor.
The research was published in PNAS Online Early Edition, March 25, 2013
in the Journal of Biological Chemistry
2
2. Regulatory
a) Baxter and Halozyme Therapeutics announced in March that the European
Medicines Agency's Committee for Medicinal Products for Human Use (EMA
CHMP) gave a positive opinion on the use of HyQvia as replacement therapy
for adult patients with primary and secondary immunodeficiencies. HyQvia, a
solution for subcutaneous use, combines human normal immunoglobulin
(10%) and recombinant human hyaluronidase, which facilitates the dispersion
and absorption of the immunoglobulin.
b) The European Commission granted CSL Behring marketing authorization for
the use of Privigen (immune globulin intravenous [human], 10 percent liquid)
in the treatment of patients with chronic inflammatory demyelinating
polyneuropathy (CIDP). CIDP is a neurological disorder of the peripheral
nerves characterized by progressively worsening weakness in the arms and
legs.
c) Cangene Corporation of Winnipeg had its botulism antitoxin (heptavalent)
approved by the US Food and Drug Administration (FDA). It was developed
under a contract with the US Department of Health and Human Services as a
precaution against possible bioterrorism.
d) Bayer announced CHMP had recommended its anti-clotting drug Xarelto for
approval in the European Union when preventing cardiovascular death or
stroke after an acute coronary syndrome in adult patients with elevated
cardiac biomarkers.
e) Fenwal received FDA clearance for a functionally closed disposable set used
with the Autopheresis-C system to collect plasma for processing into FFP for
transfusion. The closed design permits thawed plasma to be stored for up to
an additional four days.
f) Terumo BCT in April received 510(k) clearance from the FDA to collect
platelets on the Trima Accel system for storage in Isoplate platelet additive
solution, which replaces a portion of the plasma in blood products. Blood
centres in the US can now collect platelets on the Trima Accel system in 65
percent less plasma volume and store platelets in Isoplate for up to five days,
which reduces the single-donor plasma volume in the transfused platelet
product.
g) Biotest’s Florida plant recalled one lot of Bivigam intravenous immunoglobulin
10% liquid, 100ml vials because visible particles were observed.
h) The FDA has granted Acceleron Pharma orphan designation for ACE-536 to
treat beta-thalassemia and myelodysplastic syndromes.
3. Company structure and market news
a) German company Biotest said in March it is interested in taking over British
government-owned Plasma Resources UK (PRUK). The British government
reaffirmed in January it would sell most or all of its shares in PRUK. PRUK's
Bio Products Laboratory Ltd (BPL) makes plasma products from collections at
32 centres in the US operated by DCI Biologicals Inc. American
biopharmaceutical companies and private equity firms are also reported to be
interested.
b) Biotest’s group sales last year amounted to 422 million euros, up by 4.3 per
cent on 2011, while profits after tax rose by 23.5 per cent year-on-year to 23.1
3
c)
d)
e)
f)
million euros. The company said it expects the group's sales in the financial
year 2013 to grow 10 per cent to 15 per cent year-on- year.
CSL Limited on 27 March 2013 closed a new US$500m Private Placement in
the US. The Private Placement was foreshadowed in CSL's half year
announcement in February 2013. It has four maturity dates, an average life of
8.5 years, and a weighted average interest rate of 2.81 per cent. The
proceeds from the Private Placement will be used to fund the Group's capital
management plan, including on-market buybacks, and for general corporate
purposes.
CSL is reviewing its non-plasma businesses, with its incoming CEO Paul
Perreault interested in assessing their growth prospects, to see if the
businesses need to be improved, spun-off or sold. The Commonwealth
Serum Laboratories were established during World War I when Australia
became isolated from global supplies. CSL was incorporated in 1991 and
listed on the Australian Stock Exchange in 1994. bioCSL, which was formed
in January, includes vaccine, pharmaceutical and diagnostics businesses. It
is the only manufacturer of flu vaccine in the Southern Hemisphere; its other
vaccines include a vaccine for Q fever. The company produces anti-venom for
Australian snakes and spiders. CSL sells the Gardasil human papilloma virus
vaccine, which protects against cervical cancer, in Australia and earns
royalties on Merck’s sales of the vaccine overseas.
Cerus Corporation announced that the TILAK, University Clinics, Regional
Hospital Innsbruck (LKI) in Austria and ZIT GmbH Hamburg in Germany,
signed one and four year purchase agreements, respectively, for the
INTERCEPT Blood System for platelets. Implementation of the latter
agreement is expected to occur upon ZIT Hamburg’s receipt of regulatory
approval from the Paul-Ehrlich-Institut to produce INTERCEPT-treated
platelets.
Prices charged by the three largest producers of plasma therapies- CSL,
Baxter and Grifols have 70 per cent of the market- have increased in the US
by up to 4 per cent for the second consecutive year and analysts are
predicting further price rises. Julien Dormois, a Paris-based analyst at Exane
BNP Paribas, noting a 5 per cent rise in Grifols share price in response to
predictions of more price increases, raised his stock- price estimate by 21 per
cent to $45.
4. Country- specific events
United States
a) A 9-year-old Georgia boy has developed a rare tick-borne bacterial infection
called ehrlichiosis from a blood transfusion, according to the Centers for
Disease Control and Prevention (CDC). The infection is serious and can be
fatal. It can remain undetected because routine tests don't look for it, and
many people do not realize they were bitten by a tick. In this case, the boy's
condition deteriorated for ten days before a pathologist identified the
condition. Ehrlichiosis is easily treatable with the antibiotic doxycycline, but as
this is not a powerful drug it is not always the first choice when doctors are
dealing with a serious but unknown infection. In this case the boy was treated
4
with broad-spectrum antibiotics on admission to hospital, but remained ill.
The infected donor was traced, but had no symptoms.5
b) Memorial Blood Centers in April announced the receipt of a second round of
funding from The Foundation for America's Blood Centers to continue
research on blood donor safety. The Iron Depletion and Replacement in
Donors Study is a two year study being conducted jointly with the Mississippi
Valley Regional Blood Center. Across the US, a low haemoglobin level is the
most common medical reason for donor deferral. Previous studies have
evaluated the efficacy of iron replacement in deferred donors but this study
includes testing of ferritin--a measure of iron stores--and also offers iron
replacement to donors who qualify for donation but may be at risk of iron
deficiency. Participant data is being compared with data collected under
current testing protocols to discover if education and iron replacement reduce
rates of subsequent donor deferral.
c) At the National Kidney Foundation’s 2013 Spring Clinical Meetings,
researchers reported that red blood cell transfusion rates have increased
since the introduction of the Medicare prospective payment system
(“bundling”) for end-stage renal disease care and changes to drug labelling for
erythropoiesis stimulating agents.
Canada
d) Health Canada is opening up a comment period on its website for people to
express support or concern about paid plasma donations and their potential
impact on the nation’s blood system. Canadian Plasma Resources wishes to
operate commercial collection centres in Toronto and Hamilton. Health
Canada’s responsibilities include the safety of the blood supply. Whether
donors are paid falls under provinicial legislation. As part of its consultation,
Health Canada convened a meeting in Toronto on 10th April with key
stakeholders, including patient advocacy groups, academia, provincial and
federal government representatives the Canadian Blood Services, the nonprofit agency that oversees the blood supply in Canada, except Quebec. Also
participating was Héma-Québec, which oversees the blood system in
Quebec.
e) On April 17th, World Haemophilia Day, the Canadian Haemophilia Society
marked its sixtieth anniversary as the World Federation of Haemophilia
celebrated its fiftieth. Both were founded in Montreal by Frank Schnabel, a
businessman with haemophilia.
Other
f) In New Zealand, a decline in the demand for red blood cells from District
Health Boards means the New Zealand Blood Service has been able to
reduce the number of times a year it calls on some donors. The Auckland
DHB, for instance, has run a campaign on "Why use two when one will do?"
g) In India, the proposal from five years ago to set up the National Blood
Transfusion Authority (NBTA), to streamline regulations in the blood banking
sector, appears to have been dropped by the government.
5
The case report was published in the journal Clinical Infectious Diseases, March 19, 2013.
5
5. Safety and patient blood management
a) Vel-negative blood contains an antibody that can cause violent rejection of
transfused blood, and further transfusions can trigger kidney failure and
death. The blood type has been difficult to identify and supply. Scientists led
by Bryan Ballif of the University of Vermont and Lionel Arnaud of the French
National Institute of Blood Transfusion have found the culprit, a small protein
molecule called SMIM1, and identified two rapid DNA tests for identifying Velnegative blood in patients6.
b) At the 15th International Haemovigilance Seminar in Brussels, Swissmedic
and the Swiss Red Cross presented the results of a haemovigilance study
reflecting two years of experience with routine transfusion of 62,500
INTERCEPT-treated platelet components. Dr. Markus Jutzi told the meeting:
“As expected, in routine use, we observed that INTERCEPT-treated platelet
components prevented septic transfusion reactions. Furthermore, we detected
no increased risk for pulmonary adverse events. The introduction of the
INTERCEPT procedure also obviated the need for gamma irradiation.” 7
c) In the US, the Cleveland Clinic is using new protocols to make doctors think
again before ordering transfusions. Costs for external blood purchases
dropped to $US26.4 million in 2012 from $US35.5 million in 2009. Savings
elsewhere in the hospital included blood storage and processing costs and
the cost of transfusion-related complications. Robert Lorenz, medical director
of blood management for the Cleveland Clinic, says the guidelines encourage
physicians to give some patients iron before surgery, and to accept some
level of anaemia and a higher heartbeat before resorting to transfusions. The
Cleveland Clinic uses low volume test tubes when samples are collected and
minimizes the number of blood draws performed on patients.
6. Research
a) Scientists at the Albert Einstein College of Medicine of Yeshiva University and
the Icahn School of Medicine at Mount Sinai have discovered in mice that
macrophages -- white blood cells essential in the immune response -- also
help to produce and eliminate the body's red blood cells. The findings could
lead to novel therapies for human conditions where the red blood cell
production is out of balance such as haemolytic anaemia and polycythaemia
vera, bone marrow transplants and chemotherapy8.
b) A team at Lund University (Sweden) have rejuvenated the blood of mice by
re- programming the stem cells that produce blood. "Our ageing process is a
consequence of changes in our stem cells over time", said Martin Wahlestedt,
lead author of the report in the journal Blood. "Some of the changes are
6
Their results were published online in the journal EMBO Molecular Medicine on March 18, 2013.
The poster abstract has been published as P-11 in Blood Transfusion, Supplement No. 1, February
2013, ISSN 1723-2007 and is available for download at
http://www.bloodtransfusion.it/scarica.aspx?tipo=A&id=002454&riv=81.
7
8
Andrew Chow et al, "CD169+ macrophages provide a niche promoting erythropoiesis under
homeostasis and stress." Nature Medicine, 2013 DOI: 10.1038/nm.3057. Another study reported in
the same issue by Stefano Rivella and colleagues at Weill Cornell Medical College will also be of
interest.
6
irreversible, for example damage to the stem cells' DNA, and some could be
gradual changes, known as epigenetic changes, that are not necessarily
irreversible, even if they are maintained through multiple cell divisions. When
the stem cells are re-programmed, as we have done, the epigenetic changes
are cancelled."
c) A team led by Dr Anna Randi at the National Heart and Lung Institute,
Imperial College London used a new approach to investigate von Willebrand
disease (vWD). This disease is caused by a deficiency of von Willebrand
factor (vWF), a blood component essential to clotting. vWF is produced by
endothelial cells, which line the blood vessels. Dr Richard Starke, lead author
of the study, took blood samples from eight patients, extracted stem cells
called endothelial progenitor cells, and grew them in the lab to yield large
numbers of endothelial cells. The team then analysed each patient’s
disease. Dr Randi believes that endothelial progenitor cells could become an
invaluable resource for testing new drugs for vWD and other diseases. “We
will be able to test the effects of a range of compounds in the patients’ own
cells, before giving the drugs to the patients themselves,” she said. Professor
Mike Laffan, in charge of patients with VWD at Hammersmith Hospital in West
London, hopes to apply the team’s findings to reduce severe bleeding in these
patients.
7. Infectious diseases
Mosquito- borne diseases
a) Arbovax has completed its pre-clinical trial of its single-dose tetravalent
dengue vaccine in primates. Inviragen has completed the first stage of its
phase II study of its two-dose DENVAx. A vavccine developed by the US
National Institutes of Health (NIH) is entering phase II.9
b) The CDC published findings that a 2010 dengue outbreak in Florida came
from a unique local strain of the virus.
c) Wageningen University in the Netherlands, the Erasmus Medical Centre and
TI Pharma have worked jointly to develop a prototype vaccine against
chikungunya10.
d) Researchers have discovered the precise structure of the chikungunya virus
while it is bound to antibodies, showing how the infection might be
neutralized. Michael Rossmann, Purdue University's Hanley Distinguished
Professor of Biological Sciences, said "This is the first time the structure of an
alphavirus has been examined in this detail." Chikungunya is an alphavirus.
The research was reported in the journal eLife.
e) Dengue has been found in Innisfail and Townsville, following the Cairns
outbreak.
f) Researchers from the University of Oxford and the Wellcome Trust reported in
the journal Nature that nearly 400 million people annually are infected with
dengue, more than triple the current estimate by the World Health
Organization (WHO).
9
Co developers came from Johns Hopkins University and the University of Vermont. The The study
appeared in the March 15, 2013 issue of the Journal of Infectious Diseases.
10Reported in the Public Library of Science journal, PloS Neglected Tropical Diseases
7
g) Hawaii Biotech has acquired from Merck, ownership of a family of patents to
West Nile virus vaccine technology, and a nonexclusive license to related
technologies. Hawaii Biotech is developing a Crimean-Congo haemorrhagic
fever vaccine through a grant from the National Institute of Allergy and
Infectious Diseases; a malaria vaccine in collaboration with academic
researchers at the University of Hawaii at Manoa; and a tick-borne flavivirus
vaccine.
Influenza
h) The flu reports currently of most interest globally concern the emergence of
H7N9 in China. The disease does not seem to be particularly challenging to
birds, but has a significant fatality rate in humans. There is at the time of
writing still debate on its source, its geographic extent, on whether it is
capable of human to human transmission, on how fast the world can prepare
for mass vaccination against a possible pandemic, on whether it is resistant to
available treatments, on how fast it is likely to mutate and even on how to
detect it in birds as well as humans. Chinese health officials report the
disease attacks the lungs, causing suffocation and organ failure.
i) The CDC has begun vaccine preparation for H7N9, using synthetic DNA,
teaming up with Novartis and the J.Craig Venter institute to reverse engineer
the virus sequence.
j) Sanofi Pasteur’s quadrivalent flu vaccine has been accepted for review for
approval in Europe
k) A new vaccine effective against the H5N1 avian influenza virus, in mice and
ferrets, and also effective against the H9 subtype of avian influenza, was
reported online ahead of print in the Journal of Virology. The print version will
appear May 2013.
l) Australian researchers say a new strain of swine flu has been detected that is
resistant to antivirals like Tamiflu, although the strain was sensitive to
Relenza. The speaker at the Annual Scientific Meeting of the Australasian
Society for Infectious Diseases was lead investigator Dr. Aeron Hurt of the
World Health Organization Collaborating Centre for Reference and Research
on Influenza in Melbourne.
m) A CSIRO Australian Animal Health Laboratory (AAHL) project is creating
genetically modified chickens to breed H5N1 resistant offspring.
n) Both common sense and Canadian research (by Dr Kamrahn Khan of St
Michael’s Hospital, Toronto) suggest that if flu screeining at airports is to be
used to slow a pandemic, then screening before travel from areas of threat is
essential, although it may be politically difficult.
Other
o) At 26 March, the World Health Organization (WHO) had been informed of 17
confirmed cases of human infection with the novel coronavirus, of whom 11
had died. Human to human transmission is thought to have occurred in a
family treated in the UK after one member had travelled to Pakistan and Saudi
Arabia.
p) Researchers continue with viral engineering which without adequate
safeguards may pose a risk to public health. Work to make H1N1
transmissible between humans had its moratorium lifted, and a Dutch scientist
8
q)
r)
s)
t)
u)
v)
w)
x)
was reported to have proposed similar experiments with other avian flu
viruses and with the new coronavirus. German and Swiss scientists reported
they had engineered the canine distemper virus to grow in human cells.
Researchers at the University of Alberta have discovered a tiny change in the
makeup of prions which appears to allow mad cow disease to adapt and
spread in other animals.
Public health experts are concerned about the threat from a tuberculosis
epidemic on Queensland’s northern border. A woman from Papua New
Guinea, who died in Cairns Base Hospital in March of extensively drug
resistant TB, is seen as the first of a wave of medical refugees entering
Queensland for treatment.
Between late December and 26 March, health authorities in Perth had
confirmed 30 cases of mumps. Most were older teenagers or young adults
who had been partially or fully vaccinated against mumps.
A Queensland boy has become Australia's third victim of the bat-borne
lyssavirus. He is thought to have been bitten by a bat while in the
Whitsundays.
A man who became Maryland’s first fatal case of rabies in nearly 40 years
contracted the infection from a kidney transplant.
Australian infectious diseases experts, like their overseas colleagues, are
increasingly concerned about the emergence of antibiotic–resistant superbugs
not only in hospitals but in the community.
Victoria had 485 cases of cryptosporidiosis notified to the health department
this year to April 1, compared with 88 for the same period last year.
At the annual meeting of the Australasian Society for Infectious Diseases in
Canberra in March, West Australia Health Department researchers presented
their study of the state’s visitors to Bali which showed that increased travel to
the island has resulted in a rising number of serious diseases. Dengue fever
was the disease most commonly brought back from Indonesia in 2012, with
415 notifications, 80 per cent of all WA dengue cases. Other diseases
acquired in Indonesia in 2012 included salmonella gastroenteritis with 263
cases, campylobacter gastroenteritis with 157 cases, chlamydia with 95 cases
and gonorrhoea with 37 cases. Also contracted were hepatitis A, HIV,
legionaires' disease, malaria, typhus and typhoid fever. 157 people needed
rabies prophylaxis after incidents with animals in Bali.
8. Appendix: Research on Alzheimer’s Disease
a) In the US, the CDC released data showing the risk of dying from Alzheimer’s
disease rose 39 per cent between 2000 and 2010 as mortality rates for
cancer, heart disease and stroke fell.
b) ORM-12741 is the first drug to target a specific subtype of adrenergic
receptors (alpha-2C) in the brain. These are thought to be involved in
modulation of brain functions under stressful conditions. In a clinical trial with
100 patients it appeared to have some positive effect on memory11.
11
Study author Juha Rouru, MD, of Orion Pharma in Turku, Finland. Published in American
Academy of Neurology, March 2013.
9
c) H. Lundbeck A/S and Otsuka Pharmaceutical Co announced a license and
development agreement for Lu AE58054, a selective 5HT 6 receptor
antagonist. The compound met its primary endpoint in a fixed dose,
randomized, placebo-controlled, 24-week clinical study in 278 patients with
moderate Alzheimer's disease, with Lu AE58054 administered as an add-on
to donepezil. The clinical data from the phase II study will be presented at the
annual Alzheimer's Association International Conference (AAIC) in Boston in
July 2013.
d) US researchers have identified two drugs already approved for human use
that act against prion disease. Astemizole is an antihistamine that crosses
the blood-brain barrier and works effectively at a relatively low concentration.
Tacrolimus is an immune suppressant used in organ transplantation.
However, although it acts as an anti-prion drug, it may cause problems with
neurotoxicity. Both compounds reduce the amount of the normal form of the
prion protein at the cell surface12.
e) Researchers at the Max Planck Florida Institute for Neuroscience reported in
The Journal of Neuroscience that the presence of amyloid beta triggers
increased levels of a signalling protein called centaurin-a1, that appears to
cause neuronal dysfunction. The FDA has granted Acceleron Pharma orphan
designation for ACE-536 to treat beta-thalassemia and myelodysplastic
syndromes.
12
The study, led by Professor Corinne Lasmezas of The Scripps Research Institute, will be published
in the journal Proceedings of the National Academy of Sciences.
10