Download October 2012 Monitoring International Trends

MONITORING INTERNATIONAL TRENDS
posted October 2012
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; and
 Global regulatory and blood practice trends; and
 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.
1. Products Here the NBA follows the progress in research and clinical trials that may
within a reasonable timeframe make new products available, or may lead to new uses or
changes in use for existing products.
a. Clotting factors.
 Biogen Idec and Swedish Orphan Biovitrum (Sobi), have designed their
recombinant factor IX Fc fusion protein (rFIXFc) to last longer in circulation than
existing clotting factors for treating Haemophilia B1. The companies announced in
September that the therapy met its primary efficacy and safety goals in a phase
III trial, and a marketing application will be filed with the US Food and Drug
Administration (FDA) in the first half of 20132.
 The B-LONG study, for up to 77 weeks in 123 teenage boys and men,
produced the following annualized rates of breakthrough bleeding: :
(a) Weekly treatment3, starting dose 50 IU/kg: 2.95 bleeding episodes per
year
(b) Dosing 100 IU/kg at variable intervals4: 1.38 episodes per year
(c) Dosing only after bleeding episodes began: 17.69 episodes per year
 "Overall, 90.4 per cent of bleeding episodes were controlled with a single
injection of rFIXFc," the companies said. They reported that for 12 patients
receiving rFIXFc in association with surgery, bleeding control was excellent or
good in all cases. No patients appeared to develop anti-rFIXFc antibodies.
Adverse effects reported in 5 per cent or more of patients included
nasopharyngitis, influenza, arthralgia, upper respiratory infection,
hypertension, and headache.
 A pharmacokinetic study in some of the participants found a mean
approximate terminal half-life for rFIXFc of 82 hours, compared with 34 hours
for current therapy BeneFIX. The companies are also conducting an openlabel extension study of participants in these trials.
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Biogen’s Fc fusion technology uses a natural pathway to recycle rFIXFc in circulation so it remains
in the body longer. Fc fusion technology is used in seven FDA-approved products for the long-term
treatment of chronic diseases including rheumatoid arthritis, psoriasis and platelet disorders. Using
the same Fc fusion technology, Biogen Idec and Sobi are also developing a long-lasting recombinant
Factor VIII Fc fusion protein (rFVIIIFc) for the control and prevention of bleeding episodes and routine
prophylaxis in haemophilia A.
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An ongoing trial in children younger than 12 must be completed before applications in Europe.
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drug dose adjusted to produce trough levels in circulation minimally adequate to prevent bleeding
4 dose constant but the interval between doses was adjusted to achieve minimally adequate trough
levels. The interval began at 10 days for all patients, but the median interval was 14 days during the
last 6 months of the study.
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Baxter International has submitted a biologics license application (BLA) to the
FDA for approval of BAX 326, a recombinant factor IX (rFIX) protein for the
treatment and prophylaxis of bleeding episodes for haemophilia B patients over
the age of 12. This follows a Phase III study conducted in 10 countries. The
prospective, controlled, multicentre study evaluated the pharmacokinetics,
efficacy, safety and immunogenicity of BAX 326 in 73 patients with severe or
moderately severe haemophilia B previously treated with other FIX therapy. The
study met its primary goals. Baxter expects to file its application for BAX 326 in
Europe in 2013.
 Pro Bono Bio Group (PBB) in May took out an exclusive, global license to
PolyTherics’ TheraPEG™ platform to develop and commercialize a TheraPEGFVIII product designed to have a longer half-life than existing FVIII products.
 In September, Novo Nordisk ceased work on a drug it had hoped would replace
Novoseven. Some patients in clinical triaIs of haemophilia candidate vatreptacoq
alfa developed antibodies to the drug. Novoseven lost patent protection in the US
in 2010 and in Europe in 2011. NovoNordisk still has other haemophilia drug
candidates in Phase III studies. The group's sales of Novoseven rose by 15 per
cent in the second quarter of this year compared with the same quarter last year.
b. Other
 Oxygen Biotherapeutics has agreed with the US Naval Medical Research Unit
that it will study its perfluorocarbon-based drug candidate Oxycyte and
haemoglobin-based oxygen carriers as potential resuscitation treatments for
haemorrhagic shock. The US Navy is already investigating the potential of
Oxycyte in decompression sickness and traumatic brain injury.
 Pluristem Therapeutics in August announced that its placental stem cell therapy,
Placental eXpanded (PLX), saved a woman’s life at Hadassah Medical Centre in
Jerusalem. This was the second successful treatment of a patient with bone
marrow failure. Pluristem said it was preparing to apply for orphan drug status for
its PLX cells with the FDA for the treatment of aplastic bone marrow.
 A trauma patient at Royal Perth Hospital refused a blood transfusion for religious
reasons and was given Hemopure, a US product containing bovine haemoglobin.
 Symphogen has published in the journal Blood its Phase II experience with its
polyclonal antibodies for immune thrombocytopenia purpura (ITP). Symphogen’s
rozrolimupab is a human recombinant mixture of 25 antibodies which all are
manufactured simultaneously from a single batch. The data demonstrates
rozrolimupab’s safety profile and its induction of an increase in platelet counts.
The trial demonstrated that at 300µg/kg, 8 of 13 patients responded at day 7.
2. Regulatory Matters The NBA monitors overseas regulatory decisions on products,
processes or procedures which are or may be of relevance to its responsibilities.
a. In September Hemerus Medical of Minnesota announced that it has received the
world’s first CE Mark for a 56 day red blood cell storage solution – the SOLX(®
)red blood cell additive (AS-7). Currently red blood cell storage solutions provide
42 days of storage.
b. Blood salvage technology devised at the University of Strathclyde, Glasgow has
gained the CE mark and received Canadian approval. The HemoSep device
recovers blood spilled during open-heart and major trauma surgery and
concentrates the blood cells for transfusion back to the patient. Professor Terry
Gourlay, of the University’s Department of Biomedical Engineering, said: “The
technology has distinct advantages over traditional techniques which are not only
costly but technically challenging and involve the use of a complex centrifuge and
pumping apparatus by specialist technicians”. This device consists of a blood bag
using a chemical sponge technology and a mechanical agitator to concentrate
blood from the surgical site or drained from the heart-lung machine after the
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surgery. The separated cells are then returned to the patient by intravenous
transfusion. HemoSep has been licensed to Advancis Surgical Ltd.
In September, Tangent Medical Technologies received approval from the FDA to
start selling an alternative device to traditional intravenous (IV) drug delivery
systems. The company says its new closed IV system includes a catheter,
extension tubing and a flow control clamp to “eliminate an external ‘j-loop’ based
on its redirect of the fluid path internal to the device.” The NovaCath system was
on show at the recent conference of the Infusion Nurses Society in Las Vegas.
Cerus Corporation announced in September that its South African distributor,
Ilex, had submitted the INTERCEPT Blood System for platelets for fast track
approval by the South African Medicines Control Council.
The European Medicines Agency (EMA) will hold a workshop in November to
help “define the modalities of proactive access to clinical-trial data, in a way that
best serves patients and public health”.
The Association of the British Pharmaceutical Industry has updated its guidelines
on Phase I clinical trials to reflect regulatory changes in the UK since 2007.
The need for value for money indicators in government reimbursement decisions
overseas is leading pharmaceutical companies to seek input from health
economists, according to a new study by Cutting Edge Information.
In August, the FDA approved Stribild (elvitegravir, cobicistat, emtricitabine,
tenofovir disoproxil fumarate), a new once-a-day combination pill to treat HIV-1
infection in adults who have not been treated before for the infection.
Sarepta Therapeutics in September was granted fast track status by the FDA for
two of its experimental drugs for the treatment of the Marburg and Ebola viruses.
3. Market Structure and Company News The NBA’s business intelligence
follows company profitability, business forecasts, capital raisings or returns, mergers and
takeovers, arrangements for joint research and/or development, contracts for supply of
manufacturing inputs, and marketing agreements. Companies of interest include
suppliers, potential suppliers and developers of products which may be of interest.
a. CSL in August said it will focus future investment on a range of specialty
products. It will consider another $900m share buyback.
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CSL reported a 4.5 per cent rise in net profit for the 12 months to June 30, to
$982.6m. In US dollar terms, in which CSL will report in from 2013, net profit after
tax exceeded $US1b. CSL Behring’s business contributed the largest share of
revenue with sales of $3.7b, representing 12 per cent growth. Immunoglobulin
products recorded 15 per cent growth and specialty products grew 18 per cent.
 CSL has forecast a 12 per cent rise in profit on a constant currency basis. "The
main drivers of growth are the immunoglobulin portfolios, so certainly Hizentra
and Privigen," Chairman Dr Brian McNamee told AAP. "We also believe some of
the specialty products we have will also grow." Promising specialty products
include a plasma product to minimise adverse events and bleeding associated
with surgery to repair or replace a torn aorta. A self- administered injection for
hereditary angiodema is also in the list.
 Research and development costs grew during the year by 13 per cent on a
constant currency basis
 CSL is one of five companies awarded US government contracts to prepare for
an influenza pandemic. They have $US11.3m in initial funding from the US
Department of Health and Human Services to produce and store influenza seed
stock, from which vaccines are manufactured. The five-year contract could
provide CSL Biotherapies with up to $US500m in revenue from the ongoing
manufacture of flu shots for the US stockpile, but this could rise to $US1.5b if a
significant influenza outbreak occurs. Other companies receiving contracts were
Novartis, Medimmune, Sanofi Pasteur and GlaxoSmithKline.
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b. Ipsen and Inspiration Biopharmaceuticals in August renegotiated their strategic
partnership agreement for the development and commercialization of
Inspiration’s recombinant product portfolio: OBI-1, a recombinant porcine factor
VIII (rpFVIII) for the treatment of patients with acquired haemophilia A and
congenital haemophilia A with inhibitors, and IB1001, a recombinant factor IX
(rFIX) for the treatment and prevention of bleeding in patients with haemophilia B.
Ipsen made an upfront payment to Inspiration and gains commercial rights in key
territories. Inspiration remains responsible for the world-wide development of
OBI-1 and IB1001 and can receive further investment from Ipsen.
c. Italian plasma products producer Kedrion announced in August it was planning a
$US85m expansion in Melville, New York State, having bought the factory from
Spanish company Grifols. Grifols sold the plant to satisfy federal antitrust
concerns over its 2011 merger with Talecris Biotherapeutics.
d. Candian company Cangene is selling three US plasma centres to Grifols
 Cangene in August announced the extension of an existing contract and the
signing of a new contract related to US Goverrnment biodefence programs.
 It is expanding the scope of work under its contract with the US Department of
Health and Human Services for the development and supply of Anthrax Immune
Globulin Intravenous. This hyperimmune antibody product specific for Bacillus
anthracis bacteria, was developed to treat inhalational anthrax and was first
accepted into the US Strategic National Stockpile in 2007.
 Cangene’s new contract is for the supply of Vaccinia Immune Globulin
(Intravenous) into the US Strategic National Stockpile. This product was first
accepted into the US Strategic National Stockpile in 2002.
e. Cerus Corporation in September agreed with both the American Red Cross and
Blood Systems Incorporated to commercialize INTERCEPT plasma for the
orphan indication of thrombotic thrombocytopenic purpura, or TTP, in the US.
Manufacturing INTERCEPT plasma through these bodies controls distribution of
the treated plasma to meet FDA requirements.
 Cerus Corporation announced that Hemakim, its distributor for Turkey, has
signed an agreement with the Florence Nightingale Hospital to supply the
INTERCEPT Blood System for platelets and plasma.
f. German company Biotest said in September it is keen to acquire its governmentowned British peer as it seeks to become more regionally diversified
g. Haemonetics, which recently purchased Pall Corp.’s whole-blood collection
business, moved to acquire Hemereus Medical, which has developed a way to
make donated red cells last longer5. Haemonetics has also developed an
automated whole-blood collection system, to be rolled out in three phases, over
three years, starting March 2013.
h. Novartis Pharmaceuticals has an exclusive option to acquire Selexys and its antiP-selectin antibody SelG1, following a Phase II clinical study in patients with
sickle cell disease. The drug treats vaso-occlusive crisis.
i. Ten drug companies announced in September the formation of a non-profit
organization to speed up research and development of new drugs. Abbott,
AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly,
GlaxoSmithKline, Johnson & Johnson, Pfizer, Roche, and Sanofi are together
forming TransCelerate BioPharma Inc. This is designed to define and resolve
common issues. Each of the companies will combine financial and other
resources, such as personnel, to meet industry wide challenges.
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Hemerus’ SOLX solution, which would be mixed with the blood to make it last longer, still needs
FDA approvals although it has the CE Mark. The technology was derived from Army-funded research.
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4. Overseas Events The NBA is interested in relevant safety issues which
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arise in particular countries, and also instances of good practice. We monitor
health issues in countries from which Australia’s visitors and immigrants come.
United States
Immunetics has received a two-year, $US3.7m contract from the US National
Institutes of Health (NIH), to fund clinical trials of a new blood test for Babesia
infection. The company said that there is currently no licensed test available for
Babesia, which is transmitted by the same ticks that transmit Lyme disease and
can be passed on through blood transfusions. Although healthy people who are
infected with Babesia often have no symptoms, it is potentially fatal to people with
weakened immune systems. Approximately 20 per cent of transfusionassociated cases are fatal.6 Nationally, there have been over 120 reported cases
of transfusion-transmitted babesiosis since the year 2000. Since reporting of
transfusion-associated babesiosis has been mandatory only since January, 2011,
earlier case numbers would probably be an underestimate. Although there is no
FDA-licensed donor screening assay, donors are asked about tick bites and a
history of babesiosis. Donors from hyper-endemic areas may be seasonally
excluded.
In August the US Centers for Disease Control and Prevention (CDC) said the
country might be on track for the worst whooping cough year in five decades. A
study suggests that the safer vaccine introduced in the 1990s loses effectiveness
much faster than previously thought. The protective effect falls rapidly after
children receive their fifth injection about age 6.
A recent study7 found that industry sponsorship of clinical trials negatively
influences physicians’ perceptions of the study quality and their readiness to alter
practice based on the results.
AABB has categorized dengue as a high priority agent threatening transfusion
recipient safety in the US. Dr Michael Busch, Director of Blood Systems
Research Institute and Vice-President for Research and Scientific Affairs of Blood
Systems, Inc., discussed in a recent editorial8 the need for further research on the
risk posed by transfusion-transmitted dengue. He said: “Scientists in the blood
community are currently gathering the key data that is needed to determine,
based on prospective studies and sound evidence, whether or not dengue donor
screening needs to be implemented to protect blood recipients in the US and
throughout the world.”
 Dr. Busch’s editorial discussed four major studies evaluating dengue virus in
the blood supply in Puerto Rico and Brazil, areas that experienced recent
dengue outbreaks9. In Brazil, scientists identified dengue RNA from healthy
donors and found that 0.4 per cent of the tested blood donors have circulating
DENV-3, one strain of dengue. Researchers in Puerto Rico examined the
prevalence of dengue over a 16 year period and found that, on average, 7 out
of every 10,000 blood donations contain the virus. Another study also based
in Puerto Rico, showed that 92 per cent of 300 randomly selected Red Cross
blood donors had been previously exposed to dengue. Lastly, a study tested
Vannier E, Krause PJ. “Human babesiosis”. N Engl J Med 2012;366: 2397-407.
In the New England Journal of Medicine in September
8 Lanteri M, Busch M. “Dengue in the context of “safe blood and global epidemiology: to screen or not
to screen?” Transfusion 2012.
9 Petersen LR, Tomashek KM, Biggerstaff BJ. “Estimated prevalence of dengue viremia in Puerto
Rican blood donations, 1995 through 2010.” Transfusion 2012. and Mohammed H, Tomashek KM,
Stramer SL, Hunsperger E “Prevalence of anti-dengue immunoglobulin G antibodies among American
Red Cross blood donors in Puerto Rico, 2006”. Transfusion 2012 and Dias LL, Amarilla AA, Poloni
TR, Covas DT, Aquino VH, Figueiredo LT. “Detection of dengue virus in sera of Brazilian blood
donors”. Transfusion 2012
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more than 15,000 donor blood samples from the Red Cross in Puerto Rico,
and demonstrated high rates of viraemia within blood donors10.
In the US in the fiscal year 2011, there were 69 fatalities among transfusion
recipients, 30 definitely attributable to the transfusion. The number of transfusionrelated fatalities due to transfusion related acute lung injury declined from 18 in
the previous year to 1011 in 2011.
United Kingdom
The Health Protection Agency estimates about 24,000 people in the UK are
carrying the agent that can cause Creutzfeldt Jakob disease (CJD), twice the
number scientists previously estimated. This figure is based on a study of 30,000
appendixes removed in operations, which were tested for the presence of the
prion, or misfolded protein, that causes the condition. Although carriers will not
necessarily develop the disease there is a theoretical risk they could spread it
through blood transfusions or surgical instruments.
The Emergency Blood Bikes Service on September 1 took on a challenge to ride
from Skegness to Lands’ End and back in 24 hours, to raise money for their first
motorcycle. The volunteer service service plans to transport blood, blood
products, samples, donor breast milk and any other urgently required medical
items to hospitals during nights, evenings, weekends and public holidays. The
service would be free of charge.
Canada
A study of 11 hospitals, together transfusing less than 10 per cent of blood
products nationally, found “high-severity” errors in the blood-transfusion process.
A report by the Public Health Agency of Canada also said they posed a
“staggering” cost in terms of wasted blood. Many of the mistakes involved
mislabelling of blood samples taken from patients for testing, leading to the
possibility of the wrong blood type being administered to a sick person. Agency
officials commenting on the report said most of the errors were “near misses.”
The report analysed data from 2005-2007. It identified 31,989 errors; just under
3,000 of them were of high severity, with the potential for patient harm. The report
said 23 patients were actually harmed, meaning they suffered allergic reactions
or fevers after receiving the wrong blood type or product. There were no deaths.
Ireland
The National Haemovigilance Office based at the Irish Blood Transfusion Service
(IBTS) reviewed and accepted 161 mandatory serious adverse events in 2011
relating to the quality and safety of blood under the EU Blood Directive
2002/98/EC. These reflected 61 per cent of all adverse events. 130 serious
adverse reactions were reported in the ‘Acute Allergic’, ‘Anaphylactic Transfusion’
and ‘Febrile Non-Haemolytic Transfusion Reactions’ categories.
The Irish Blood Transfusion Service incurred a budget deficit of €5,036,000 in
2011, compared with a surplus of €1,510,000 the year before, and in September
warned that 2012 was proving more difficult. The Department of Health had
decided that the IBTS should no longer manage the products for haemophilia
patients and this had adversely affected the Service’s income stream.
Other
Global pharmaceutical companies are increasingly out-sourcing clinical trials to
countries in Asia, Latin America and Eastern Europe to save time and money.
Stramer SL, Linnen JM, Carrick JM, Foster GA, Krysztof DE, Zou S, Dodd RY, Tirado-Marrero LM,
Hunsperger E, Santiago GA, Munoz-Jordan JL, Tomashek KM. “Dengue viremia in blood donors
identified by RNA and detection of dengue transfusion transmission during the 2007 dengue outbreak
in Puerto Rico”. Transfusion 2012.
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FDA Center for Biologics Evaluation and Research. Fatalities Reported to the FDA Following Blood
Collection and Transfusion: Annual Summary for Fiscal Year 2011, 2012
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To ensure the safety of plasma derivatives, a number of countries screen for
human parvovirus B19V genomic DNA in donated plasma using a pooling
strategy. Researchers investigated the prevalence of B19V DNA and anti-B19V
antibodies in Chinese plasma pools, plasma derivatives and plasma donations to
evaluate the risk posed by B19V12.They concluded that “despite the
implementation of some inactivation/removal methods designed to prevent viral
contamination, B19V DNA was detectable in Chinese plasma pools and plasma
derivatives. Thus, the introduction of B19V screening and discard donation with
high viraemic concentration for Chinese plasma donors would be desirable”.
In Pakistan, scientists at the National Institute of Blood Diseases report that
hydroxyurea reduces the need for blood transfusion in some thalassemia
patients13.
In Switzerland the Incidence of hepatitis C virus infections has increased 18-fold
in HIV-positive gay men in Switzerland since 1998. Half of all infections in gay
men occurred between 2008 and 2011. In contrast, incidence of hepatitis C fell in
HIV-positive injecting drug users and remained stable in HIV-positive
heterosexuals.
5. Safety Issues We follow current issues in patient safety.
a. Australian scientists are developing a blood test for Creutzfeld-Jacob disease in
humans and “mad cow disease” in cattle14. The test is expected to be
commercially available within five years. It may allow more Australians who have
spent time in the UK to donate blood if they test negative for the disease.
Researchers from the University of Melbourne say it's hoped further research
may help detect other brain diseases such as Alzheimer’s and Parkinsons. These
other neuro- degenerative diseases also release evidence into the bloodstream.
b. A recent study 15 showed that for patients with chronic liver disease who require
an invasive procedure as part of their routine care, the oral thrombopoietinreceptor agonist eltrombopag reduces the need for platelet transfusions, but also
results in an increased incidence of portal-vein thrombosis.
c. Researchers testing reversal agents for two of the newer anticoagulants
discovered all the agents affected some quantitative and kinetic parameters of
thrombin generation. For rivaroxaban, for example, two prothrombin complex
concentrates had a significant effect on the quantitative parameters, while
recombinant factor VIIa had a stronger effect on kinetic parameters16.
d. An ultrashort pulsed laser technology has been developed to provide efficient and
chemical-free inactivation of a broad spectrum of bacterial and viral pathogens in
pharmaceuticals, blood products, and attenuated or inactivated vaccines.17
e. Even small doses of intravenous immune globulin (IVIg) can cause acute, severe
anaemia, researchers warned. Two such cases in Guillain-Barré syndrome
patients after a total dose of only 125 to 225 g of IVIg each were reported.18
12
Wei ZhangLing KeChangqing LiYan ZhangWuping Li Journal of Translational Medicine 2012,
10:194
13 American Journal of Pediatric Hematology/ Oncology
14 The study was published in Nucleic Acids Research.
15 published in the Aug. 23 2012 issue of the New England Journal of Medicine.
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The study was published in Thrombosis and Haemostasis, August 2012. Marlu R, Hodaj E, Paris A,
et al. “Effect of non-specific reversal agents on anticoagulant activity of dabigatran and rivaroxaban. A
randomised crossover ex vivo study in healthy volunteers”. Thromb Haemost 2012; 108:217-224 and
Levi M. “Reverse engineering for new oral anticoagulants: Non-specific reversal agents and the
anticoagulant activity of dabigatran and rivaroxaban”. Thromb Haemost 2012; 108:201-202
17 Shaw-Wei D TsenTzyy Choou WuJuliann G KiangKong-Thon Tsen: Journal of Biomedical Science
2012, 19:62
18 Pintova S, et al "IVIG -- A Hemolytic Culprit" N Engl J Med 367; 10:974-76.
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f.
Exposures to the phthalate DEHP, used sometimes in blood bags and medical
tubing, change how rat heart cells use fuel, a new study reports19. By making
heart cells more dependent on fatty acids than usual, DEHP may ultimately
increase the risk of heart attack and heart failure. The findings raise concerns
about similar effects in humans. DEHP leaches into blood during transfusions or
dialysis procedures and goes straight to the patient’s bloodstream. There is
special concern for pregnant women, premature babies and young children,
because of heightened sensitivity to chemical exposures during early
development.
g. Triclosan, which was introduced in the 1970 and is an ingredient in many
antibacterial soaps is now reported20 as capable of damaging both skeletal and
heart muscle cells.
6. Research A wide range of scientific research has some potential to affect the use of
blood and blood products. However, research projects have time horizons which vary
from “useful tomorrow” to “at least ten years away”. Likelihood of success of particular
projects varies, and even research which achieves its desired scientific outcomes may
not lead to scaled- up production, clinical trials, regulatory approval and market
development.
a. The Harvard Clinical Research Institute dual antiplatelet therapy study has
enrolled 26,000 patients. It aims to establish the combination of aspirin and
antiplatelet treatments necessary to optimize the benefits of the drugs while
limiting bleeding. Final results from the study are expected late in 2014.
b. Researchers at Case Western Reserve University have found that nanoparticles
tailored to attach to blood platelets rapidly create clots and almost double the
survival rate in the critical few hours after injury. They are developing synthetic
platelets for first responders to carry to stabilise trauma patients until they reach
hospital. These synthetic platelets do not need to be refrigerated21.
c. University of Utah researchers have received a grant of $US16m from NIH to
study blood clots and how they threaten people suffering diabetes, obesity or
other metabolic disorders. The research will develop ways to diagnose, prevent
and treat clotting, and disseminate the findings.
d. The National Heart, Lung, and Blood Institute, part of NIH, has awarded
$US10.8m for a multi- institutional 22 five-year study of haemoglobin toxicity that
may complicate blood transfusions and reduce the effectiveness of blood
substitutes. The goals are making blood transfusions safer and more effective
and matching patients with the transfusion strategy best suited to them.
Haemoglobin toxicity occurs when cells break open and spill directly into the
bloodstream.
e. At the European Society of Cardiology Congress 2012 research was presented23
from Brigham and Women's Hospital, suggesting that adding platelet blocker
vorapaxar to standard antiplatelet therapy significantly reduces the long-term risk
of recurrent cardiovascular events beyond one year in patients who have had a
19
Posnack, NG, LM Swift, MW Kay, NH Lee and N Sarvazyan. 2012 “Phthalate exposure changes
the metabolic profile of cardiac muscle cells”. Environmental Health Perspectives
http://dx.doi.org/10.1289/ehp.1205056.
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Researchers from the University of California, Davis, the University of Colorado, and the
Department of Veterans Affairs, Northern California Health Care System published their findings
online ahead of print on August 13 in the Proceedings of the National Academy of Sciences (PNAS).
21 Research was presented on August 20 at the 244th National Meeting & Exposition of the American
Chemical Society.
22 Including Albert Einstein College of Medicine of Yeshiva University, Rice University, the University
of California, San Diego and the FDA
23 published simultaneously in the Lancet.
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heart attack. Researchers also identified a low bleeding risk group among whom
the clinical benefit of vorapaxar was especially favourable.
Southeast Asian ovalocytosis, an inherited disorder in which red blood cells are
oval, instead of round, seems to protect its sufferers from malaria24. Ivo Mueller
from the Walter and Eliza Hall Institute and his team genotyped Researchers at
Duke University Medical Center may have found why people with sickle cell
disease get milder cases of malaria than individuals who have normal red blood
cells. They believe that very small units of genetic material in sickle red cells
reduce the parasite's ability to propagate. 25
Scientists at the University of Liverpool are developing a simple, rapid and robust
bedside test of a small sample of blood for early diagnosis of sepsis.
Researchers suggest that patients with type A, B, or AB blood are at significantly
greater risk for coronary heart disease than those with type O blood26.
Human stem cells can be used to produce red blood cells, and researchers say
the method has the potential to provide cells of any blood type for transfusion27.
Eric Bouhassira of the Albert Einstein College of Medicine said the team
"combined different cell-expansion protocols into a 'cocktail' that increased the
number of cells we could produce by 10- to 100-fold".
At the American Chemical Society meeting in Philadelphia in August, Xiaole
Shao of the University of Missouri-Columbia described how her team created
sensors that might eventually facilitate non-invasive and long-term monitoring of
blood chemistry. Since infra-red light will penetrate skin it can trigger fluorescent
molecules circulating in the blood, and this fluorescence can be picked up by an
external monitoring device, which can also pick up changes in the molecule’s
fluorescence. Since fluorescent dyes can be toxic, and short-lived in the body,
the team encapsulated the sensors in red blood cells.
The US Army has given Worcester Polytechnic Institute $US1.9m to develop
sensors to monitor soldiers’ condition, including whether they are wounded and
bleeding. The work, in collaboration with the University of Massachusetts Medical
School, will develop miniature wireless sensors for soldiers to wear in combat.
They will use light to measure physiological signs. The same monitoring
capabilities will be installed on smartphones, for army medics to use in diagnosis.
The sensors rely on the technology behind pulse oximeters, the devices clipped
onto a patient’s finger to determine blood oxygen levels.
Dr. Sivaprakash Ramalingam has been funded by the Maryland Stem Cell
Research Commission to apply zinc finger nuclease, or ZFN, to try to cure sickle
cell anaemia. With ZFN, Ramalingam is able to target and replace problematic
sequences of the human genome with healthier genetic material.
Clinicians, patients and carers are awaiting the next round of results from a large
clinical trial of Baxter’s Gammagard as a treatment for Alzheimer’s disease(AD).
If immunoglobulin is found to be effective and safe in this indication, the
implications for global demand and price are significant.
 Two drugs in clinical trials for AD have recently failed to meet their goals.
(a) Bapineuzamab was being trialled by Pfizer, Johnson and Johnson and
Elan. The drug failed to meet primary endpoints in patients with mild to
moderate AD whether or not they carried the ApoE-4 genotype (which
significantly raises the risk of developing AD). However an ongoing Phase
II study is continuing to look at a subcutaneous formulation, which the
company may take into a Phase III study in a pre- AD population. At a
PLOS Medicine (5 September).
Reported in Cell Host and Microbe, August 2012.Influenza
26
Qi L, et al "ABO blood group and risk of coronary heart disease in two prospective cohort studies"
Arterioscler Thromb Vasc Biol 2012; DOI: 10.1161/atvbaha.112.248757.
27
according to a study published in the journal Stem Cells Translational Medicine
25
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neurology meeting in Stockholm on September 11 it was reported that in
a study of patients who carry the ApoE4 gene mutation bapineuzumab
significantly reduced levels of the protein beta amyloid on the brain scans
of patients, compared with those who were given a placebo. The drug
also significantly reduced the amount of a toxic form of the protein tau in
spinal fluid, a sign of brain cell death.
(b) Eli Lilly’s Solanezumab also failed to meet its target. This raised the
question of whether it is worthwhile attacking beta- amyloid after the toxic
deposits have already damaged the brain. Eli Lilly said that trial data
suggested that people with only mild AD might have experienced a
slowing of cognitive decline.
Following these disappointing trial results, Roche more than doubled the size
of a trial of its monoclonal antibody gantenerumab. Roche believes this to be
the most advanced of the drugs currently in development for AD (one report
says there are 83 of these with variable prospects).
EnVivo Pharmaceuticals presented data at the Alzheimer’s Association
International Conference (AAIC) 2012 suggesting statistically significant
improvement in cognition and clinical function in a Phase IIb clinical trial of
EVP-6124 in patients with mild to moderate AD. En Vivo plans to move to
Phase III development.
An established treatment for epilepsy, levetiracetam (Keppra in the US), given
to mice with AD over a fortnight, improved neuronal activity, and halved
abnormal neuronal behaviour. Proteins that maintain healthy brain function
returned to normal, and learning and memory improved (based on how mice
behaved in a maze). While this research was conducted at the Gladstone
Institutes in San Francisco28, a previous trial at Johns Hopkins University saw
patients treated with Keppra twice daily for a fortnight develop improved brain
activity.
In September Eli Lilly and Company released results from the International
Alzheimer's Disease Physician Survey of nearly 1,000 physicians that
assessed physician attitudes and beliefs on the barriers to a formal
Alzheimer's diagnosis. The survey was conducted in the US, France, Italy
and Japan. Close to half of physicians surveyed said AD is "often"
misdiagnosed. Half said the diagnosis usually occurs too late to intervene in a
meaningful way. Lack of definitive tests, lack of communication between
patients and/or caregivers and physicians, and patient denial, are the most
common barriers to making a formal diagnosis of AD.
A study led by scientists at the University of Ulster, interested in the potential
of diabetes drugs for protecting brain cells from damage, has used an
experimental drug, (Val8)GLP-1, to grow new brain cells in mice29.
7. Legal actions and enquiries
The NBA is interested in the implications for
Australia of any proceedings against companies, governments and professional
practitioners in relation to blood and blood products; or of relevant public enquiries.
a. The US Securities and Exchange Commission (SEC) in August charged a US
headquartered pharmaceutical company with violating the Foreign Corrupt
Practices Act after findings that various subsidiaries bribed doctors and other
health care professionals employed by foreign governments. The SEC alleges
that employees and agents in Bulgaria, China, Croatia, Czech Republic, Italy,
Kazakhstan, Russia, and Serbia made improper payments to foreign officials to
obtain regulatory and formulary approvals, sales and increased prescriptions for
28
29
Reported in the Proceedings of the National Academy of Sciences.
Research funded by Alzheimer's Research UK; see journal Brain Research Sept 14 2012.
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its medicines; and that they improperly recorded payments as legitimate
expenses for promotional activities, marketing, advertising, conferences, clinical
trials, training, travel and entertainment, and freight.
8. Infectious diseases The NBA takes an interest in infectious diseases because:
the presence of disease in individual donors (e.g. influenza), or potential disease
resulting from travel (e.g. malaria) means a donor must be deferred; temporary disease
burden within a community (e.g. dengue in North Queensland) may limit blood collection
in the community for a time; and some people may not be permitted to donate at all (e.g.
people who lived in the UK for a period critical in the history of vCJD). Blood donations
are tested for a number of diseases (e.g. HIV and Hepatitis B), but there are also
emerging infectious diseases for which it may become necessary to test in the future
(e.g. Chagas disease, and the tick-borne babesiosis and Lyme disease).
a. Mosquito- borne diseases
 Singapore, Malaysian and Indonesian researchers are studying dengue fever
trends to track viruses and how they spread in the region.
 Sanofi’s dengue vaccine was 30 per cent effective in its first large clinical trial. 30
There are four types of dengue virus and in this Phase II trial the vaccine did not
protect against serotype 2. Sanofi is testing the vaccine in a number of other
countries, and these Phase III trials will report in 2014.
 Releases of Oxitec's genetically modified dengue- spreading Aedes aegypti
mosquitoes achieved an 80 per cent reduction of a local mosquito population in
the Cayman Islands31.
 In the US, the number of West Nile Virus cases reported through to midSeptember was the highest YTD total recorded since the disease was first
detected there in 1999. By 19 September, with 3142 confirmed cases recorded
across 48 States there had been 138 deaths. Volunteer blood donors in the US
are screened for WNV. By 5 Sept 200 donors across 28 states had tested
positive this year.
b. Influenza
 In the last five months of 2011, 12 US residents were found to be infected with an
influenza A H3N2 variant virus (H3N2v) with the matrix (M) gene from the 2009
H1N1 pandemic virus. This M gene may have increased transmissibility to and
among humans, compared with other variant influenza viruses. This virus has
been identified in pigs in a number of US states. Investigations into the human
cases revealed infections with these viruses following contact with swine as well
as some limited human-to-human transmission. In 2012, another case of H3N2v
in a child was detected in April. Then, beginning in July 2012, multiple H3N2v
human infections were identified. The CDC warned agricultural fairgoers on 3
August 2012 against contact with pigs. Three candidate vaccine viruses specific
for A(H3N2)v have been developed and could be used to produce an (H3N2)v
vaccine if needed.
 Oxford University scientists, with US and Swedish colleagues have identified a
compound to boost the effect of vaccines against viruses, including flu. This
“adjuvant” is a polymer known as PEI (polyethylenemine).32
 Inovio Pharmaceuticals announced in September that its SynCon universal H1N1
vaccine showed protective immune responses in humans against the nine key
H1N1 flu strains of the last 100 years, including the 1918 pandemic flu.
 Immune Targeting Systems announced data from two Phase I clinical trials of
Flunisyn, the Company’s lead vaccine which it said elicited potent immune
responses against multiple strains of influenza-A virus.
30
Reported in The Lancet September 2012.
Reported in Nature Biotechnology, September 2012.
32
Reported in Nature Biotechnology.
31
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c. In the US, the Infectious Disease Research Institute is beginning human trials of
microneedles —a series of tiny needles that can be applied to a patch—to deliver
a bird flu vaccine. This could be self-administered, meaning that in a pandemic
people wanting vaccination could have it mailed. Medicago’s vaccine is made
using a virus-like particle in tobacco plants and can be altered quickly to adapt to
new bird flu strains. Microneedles deliver the vaccine just under the skin, where
many of the body's immune-system cells are found.
d. Scientists have reconstructed the genetic sequencing of the 1918 “Spanish”
influenza virus, responsible for a pandemic that killed over 50 million people.
They found that the viruses which caused pandemics in 1957, 1968 and 2009
were all partly descendants of the 1918 virus33.
e. A team led by scientists at The Scripps Research Institute and Crucell Vaccine
Institute in the Netherlands describes three human antibodies that provide broad
protection against Influenza B virus strains. The same team had previously
reported finding broadly neutralizing antibodies against Influenza A strains. One
of the newly discovered antibodies appears to protect against essentially all
influenza B and influenza A strains.
f. NanoViricides said in August that one of its anti-flu drug candidates under its
FluCide program was effective in an animal study when given orally. The
company makes nanoviricide drugs designed to attack enveloped particles in a
number of viral diseases, and dismantle them. The company retained
consultants Australian Biologics to coordinate the regulatory review and approval
for the first human trials in Australia for Flucide.
g. Theraclone Sciences on 10 September presented data from its Phase 1 clinical
trial of TCN-032 at the 52nd Interscience Conference on Antimicrobial Agents
and Chemotherapy (ICAAC) in San Francisco. The trial evaluated the safety,
pharmacokinetics and immunogenicity of TCN-032, a protective, fully human
monoclonal antibody for the treatment of influenza A infections. The company
said the drug was well tolerated with no dose-limiting toxicities or serious adverse
events, and that it demonstrated a favourable immunogenicity profile.
h. At the conference, Visterra also presented positive data from a preclinical study
evaluating the efficacy of VIS410, again a protective, fully human monoclonal
antibody for influenza A infections.
i. Other
 Scientists at The Scripps Research Institute reported34 that reducing copper in
the body delays the onset of prion disease. Mice lacking a copper-transport gene
lived significantly longer when infected with a prion disease than did normal mice.
 A new virus belonging to the same family as the SARS virus that killed 800
people in 2002 has been identified in Britain in a man who had been in Saudi
Arabia. Severe Acute Respiratory Syndrome, appeared in China in 2002 and
killed some 800 people globally. Scientists from the Health Protection Agency
compared gene sequences of the virus from the Qatari patient with samples of
virus sequenced by Dutch scientists from lung tissue of a fatal case earlier this
year in a 60-year-old Saudi national and found them to be almost identical. .
33
JK Taubenberger et al. “Reconstruction of the 1918 influenza virus: Unexpected rewards from the
past”. mBio DOI: 10.1128/mBio.00201-12 (2012).
34
“Disruption of copper homeostasis due to a mutation of Atp7a delays the onset of prion disease,”
Published online before print August 6, 2012, doi: 10.1073/pnas.1211499109Journal reference:
Proceedings of the National Academy of Sciences
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35
Pfizer, GlaxoSmithKline and NovaDigm Therapeutics are each testing vaccines
to halt methicillin-resistant Staphylococcus aureus, or MRSA, long a dangerous
infection in hospitals and other settings,
Eisai will supply the Sabin Vaccine Institute with E6020, an adjuvant that
enhances the immune effects of vaccines, to support the development of
vaccines for two neglected tropical diseases-Chagas disease and leishmaniasis.
Aeras and the Infectious Disease Research Institute (IDRI) began in August the
first clinical trial of IDRI's tuberculosis vaccine candidate, ID93 + GLA-SE. The
Phase I clinical trial will assess the safety, tolerability and immunogenicity of the
vaccine candidate in 60 healthy adult volunteers.
Researchers at the Weill Cornell Medical College screened drugs that target
dormant TB bacteria35. They found that the anti-inflammatory oxyphenbutazone,
developed to treat arthritis in the 1970s, is activated in lung conditions that induce
dormancy, and can kill dormant, active, and even resistant bacteria. The drug is
off- patent and can be bought over-the- counter, so is not an attractive subject for
a private sector clinical trial.
Abbott Laboratories and Astellas Pharma will collaborate in a Phase IIIl trial for
ASP0113 (TransVax), an investigational vaccine licensed from Vical for
preventing cytomegalovirus (CMV )reactivation in transplant patients. A herpes
virus, CMV infects half of all adults by age 40 and is the most common viral
infection in transplant recipients.
There has been an increase in the Northern Territory in the number of people
infected with meliodosis. The bacteria Burkholderia pseudomallei enter the body
often through cracks in feet. They can also become airborne when soil is
disturbed. The organism infects the blood and leads to pneumonia. The mortality
rate is around 15 per cent.
The World Organisation for Animal Health (OIE) implemented a new version of its
World Animal Health Information System (WAHIS ) to increase the speed with
which animal health information is disseminated. This version incorporates a
specific section for wildlife diseases notification.
Serum samples collected from 353 healthy Bornean orangutans in Indonesia
were screened for filovirus-specific IgG antibodies 18.4 per cent and 1.7 per cent
of the samples were seropositive for Ebola Virus and Marburg virus respectively.
published online in the Proceedings of the National Academy of Science (September 10),
13