MONITORING INTERNATIONAL TRENDS
posted 4 May 2012
The NBA monitors international developments that may influence the management of blood and
blood products in Australia. Our focus is on:
 Information that may have an impact on global supply, demand and pricing, such as changes
in company structure, capacity, organisation and ownership
 Potential new product developments and applications
 Global regulatory and blood practice trends, and
 Other emerging risks that could potentially put financial or other pressures on the Australian
sector.
A summary of recent matters of interest appears below. Highlights include:
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Clinical trials are continuing on a number of new therapies for haemophilia.
 At the annual meeting of the American Academy of Allergy, Asthma and
Immunology, presentations reported on studies in treating primary
immunodeficiency and hereditary angioedema.
 A number of companies are interested in developing treatments for sickle
cell disease.
 Research continues on treating Alzheimer’s Disease with plasma
products.
The impact of transfusion on outcomes in cardiac surgery remains a research interest, as
does the relationship between age of red cells and surgical outcome.
Researchers have investigated subsets of blood ‘progenitor’ cells and the signals that cause
them to expand and develop into mature blood cells.
The American Association of Blood Banks issued new guidelines on the level at which a
patient's red blood cell count can be viewed as so low as to require a transfusion.
Scientists have developed a gene therapy strategy they say could feasibly treat both
β-thalassemia and sickle cell disease.
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. This update includes clinical trials on new therapies for
haemophilia and studies on treating primary immunodeficiency and hereditary angioedema.
a. Coagulation factors
 In January Pfizer initiated a Phase I clinical trial for PF-05280602, an investigational
proprietary, engineered variant of recombinant human Factor VIIa developed by
Catalyst Biosciences. PF-05280602 has been engineered to provide improved acute
and prophylactic treatment for haemophilia A and B patients with inhibitors. Catalyst
is also engineering next generation recombinant human Factor IX and Xa variants.
 CSL Behring announced in February the results of a Phase I study evaluating
recombinant fusion protein linking coagulation Factor IX with albumin (rIX-FP) in
patients with severe hemophilia B. Results of the study, which were presented at a
congress in Switzerland, showed that rIX-FP was well tolerated in all patients and
lasted longer in the body due to its prolonged half-life, compared with current Factor IX
treatment options. In this analysis, no serious adverse events (including no
hypersensitivity reactions), presence of inhibitors to Factor IX, or antibodies to rIX-FP
were reported. Terminal half-life (a measure of how long the drug lasts in the body)
was more than five-times longer in comparison with values associated with current
recombinant Factor IX therapy. Incremental recovery and area under the curve (a
measure of total exposure to the drug) were also significantly improved in comparison
with values associated with current recombinant Factor IX therapy. The drug received
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orphan drug status in the US1 in February 2012, having received orphan drug status
from European regulators in May 2011. The CSL Behring rVIIa-FP clinical program is
being initiated with the intention of demonstrating that an extended half-life rVIIa-FP
will result in a requirement for fewer doses, while providing adequate therapeutic
response in patients who have haemophilia A and B with inhibitors.
CSL Behring announced in March the first in human dosing of recombinant fusion
protein linking coagulation factor VIIa with albumin (rVIIa-FP). The Phase I study will
investigate in healthy volunteers the safety and pharmacokinetics of rVIIa-FP in
comparison with placebo. CSL Behring, in collaboration with its parent company, CSL
Limited, is developing rVIIa-FP, to treat hemophilia A and hemophilia B patients who
have inhibitors, as part of the PROLONG 7- FP clinical study program. CSL Behring's
technology uses albumin as the ideal recombinant genetic fusion partner for
coagulation factor proteins due to its inherently long half-life, high potential for
tolerability, known mechanism of clearance and low potential for immunogenic
reactions. CSL Behring's rVIIa albumin fusion protein is expected to exhibit a good
tolerability profile and improved pharmacokinetics that may enable prophylaxis. CSL
Behring's rVIIa-FP was previously granted Orphan Drug Designation by the European
Commission and the United States Food and Drug Administration (FDA).
Prolor Biotech in February reported positive results in a comparative study of its
longer-acting version of Factor VIIa (Factor VIIa-CTP) in a preclinical trial in mice. The
study found that the mice which received Factor VIIa-CTP showed a superior survival
rate over a longer time period following a bleeding challenge, superior and longerlasting generation of thrombin (a key pro-clotting enzyme) and significantly higher in
vivo recovery. Prolor had previously reported that Factor VIIa-CTP had increased
half-life and clotting activity compared with Factor VIIa.
CSL Behring announced in February that the first patient has been screened in its
recombinant coagulation single-chain factor VIII trial, part of the AFFINITY clinical trial
program. The Phase I/III study is an open-label, multicentre trial that examines the
crossover safety, efficacy and pharmacokinetics of recombinant coagulation singlechain factor VIII compared with recombinant human anti-haemophilic factor VIII
(octocog alpha)2. The underlying research is the result of collaboration across CSL
research sites in Germany, the US and Melbourne.
Inspiration's recombinant factor IX (IB1001) has completed pivotal Phase III clinical
testing in the US, Europe, Israel and India. To date, IB1001 has been well-tolerated
by patients and pharmacokinetic results have demonstrated non-inferiority to the one
approved recombinant Factor IX product currently marketed for treating haemophilia
B. Inspiration says the data demonstrated effective surgical haemostasis in people
with haemophilia B undergoing major surgical procedures. The data were highlighted
in a poster presentation at the 5th Annual Congress of the European Association for
Haemophilia and Allied Disorders (EAHAD) in Rome. Inspiration submitted a
Biologics License Application (BLA) to the FDA in April for the approval of IB1001.
Treatment of primary immunodeficiencies
At the annual meeting of the American Academy of Allergy, Asthma, and Immunology
(AAAAI) in Orlando in March, researchers reported that subcutaneous immune
Orphan status is given to treatments for rare diseases that affect fewer than 200,000 people in the US. It qualifies the
company for tax credits, a waiver for FDA license application fees and gives certain marketing incentives. The Orphan
Drug Designation in this case is granted for the treatment and prophylaxis of bleeding episodes in patients with
congenital haemophilia and inhibitors to coagulation factor VIII or IX.
2 Recombinant single-chain factor VIII consists of two linked protein chains – a heavy one and a light one. Under
certain conditions, these chains can dissociate, resulting in the formation of separated rFVIII chains. The CSL Behring
rVIII-SingleChain uses a strong, covalent bond that connects the light and heavy chains. In-house studies have shown
that the molecular integrity of rVIII-SingleChain is significantly increased using the single-chain design, resulting in a
homogenous product that is more stable than currently available FVIII products. In addition, in-vitro studies have
shown that rVIII-SingleChain demonstrates a very strong affinity for von Willebrand factor (vWF), resulting in a faster
and more efficient binding to vWF. The FVIII/vWF complex plays an important role in the physiological activity and
clearance of FVIII and has been shown to have an influence on the presentation of FVIII to the immune system.
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globulin (Hizentra) remains safe and effective up to two years in the treatment of
patients with primary immunodeficiency diseases. The overall rate of infections was
2.4 per patient-year among patients receiving once-weekly infusions, according to
Robert P. Nelson Jr., of Indiana University in Indianapolis. The study3 was funded by
CSL Behring.
At the same meeting, Baxter presented additional long-term data supporting the
clinical profile of HyQ, its investigational combination product for use in patients with
primary immunodeficiencies (PI). The company also introduced HyQvia [Immune
Globulin Infusion 10% (Human) with Recombinant Human Hyaluronidase], as the
submitted brand name for the investigational product, previously referred to as HyQ.
Also at the AAAAI meeting CSL Behring suggested that the bioavailability of
immunoglobulin G (IgG) therapies is consistent when patients with primary
immunodeficiencies switch from one IgG product to another by the subcutaneous
route. The analysis was a joint effort between CSL Behring and physicians at the
University Hospital of Wales and the University of South Florida. Based on an
analysis of published data, the study found that bioavailability – the percentage of
unchanged drug that reaches the circulation – was similar among four subcutaneous
IgG (SCIg) preparations and all fell within the range of 66.7+2.7% as compared with
intravenous IgG4. "Maintaining a consistent level of IgG in the blood is important for
patients with primary immunodeficiencies in order to prevent infections," said John W.
Sleasman of the University of South Florida. "This analysis provides reassurance that
regardless of current treatment – intravenous or subcutaneous – patients can switch
IgG products without undue concern about dosing or therapeutic IgG levels."
Treatment of hereditary angioedema (HAE)
At the AAAAI meeting CSL Behring presented data showing that treatment with
Berinert®, C1 Esterase Inhibitor (Human) within six hours of the onset of an acute
HAE attack provides faster relief than later treatment. A second study retrospectively
analysed patient outcomes associated with intravenous self-administration of C1
Esterase Inhibitor (C1-INH), which enables patients to treat themselves earlier, at
home. The study, conducted over a period of more than 18 months, enrolled a total of
13 HAE patients who were shown how to self-administer. The study found that selfadministration of intravenous C1-INH concentrate can be a good option for patients
with HAE. Adverse events were rare in the study, and no complications related to
home administration were reported. Berinert is derived from human plasma5.
ViroPharma and Halozyme Therapeutics announced positive data from ViroPharma’s
Phase II subcutaneous trial of Cinryze (C1 esterase inhibitor [human]) in combination
with Halozyme's Enhanze technology, a proprietary drug delivery platform using
Halozyme's recombinant human hyaluronidase enzyme (rHuPH20), in patients with
HAE. The data demonstrated that subcutaneous co-administration of Cinryze with
rHuPH20 was easy, well tolerated and resulted in sustained physiologically relevant
C1 INH functional concentrations. The combination administered subcutaneously as a
single injection will be further evaluated for the prevention of HAE attacks. Cinryze is
approved in the US for intravenous (IV) administration for routine prophylaxis against
angioedema attacks in adolescent and adult patients with HAE, and in Europe for
routine prevention, pre-procedure prevention, and acute treatment of angioedema
attacks in adolescents and adults.
Nelson R, et al. "Safety, tolerability, and efficacy of Hizentra over an extended period for the treatment of primary
immunodeficiency disease" AAAAI 2012; Abstract 314.
4 In the US study, mean serum IgG level following SCIg administration did not differ significantly between Hizentra®
(Immune Globulin Subcutaneous [Human]) and Vivaglobin® at the recommended dose dosages (1139+249 mg/dl and
1158+311 mg/dl, respectively). In the European Union, mean serum IgG levels were not significantly different between
all tested SCIg products and Hizentra when the same doses were administered (843+138mg/dl and 833+125mg/dl,
respectively).
5 In Australia, Berinert has been submitted under Schedule 4. It is currently recommended for use only in response to
acute attacks and is funded directly by hospitals.
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The AAAAI meeting was told that treatment with the bradykinin receptor blocker
icatibant (Firazyr) led to rapid resolution of all types of oedema attacks in patients with
hereditary angioedema, even the most severe. By four hours after a subcutaneous
injection of icatibant, the percentage of patients reporting severe or very severe
cutaneous involvement had fallen from 40.4% at baseline to 2%, compared with only
19.7% of those receiving placebo. Among patients with potentially life-threatening
laryngeal attacks, the percentage reporting severe or very severe difficulty swallowing
had decreased from 28.6% to 10.6% after two hours and to 1.9% by four hours6. The
data were from the FAST-1, -2, and -3 (For Angioedema Subcutaneous Treatment)
trials7. Icatibant was approved by the FDA in August 2011. It is given
subcutaneously, so patients can administer it themselves, and will know within
minutes if it is working.
Treating anaemia
On 7 March Amag Pharmaceuticals reported preliminary results from the first of two
Phase III studies in its global registrational program for Feraheme (ferumoxytol) in
patients with iron-deficiency anaemia regardless of the underlying cause. The study
compared treatment with Feraheme to treatment with IV iron sucrose, and enrolled
605 patients at 74 sites in Europe, Asia Pacific and Australia8. The other study in the
US, Canada, Europe and India is evaluating Feraheme compared with placebo in 800
patients. This study is now fully enrolled with results expected in mid-2012.
A once-daily oral anaemia drug from Akebia Therapeutics met its primary endpoint in
a phase IIa trial of chronic kidney disease patients. Akebia expects to file a new drug
application for the oral anaemia drug in 2015.
Treating sickle cell disease
Adventrix Pharmaceuticals’ lead candidate is ANX-188, a rheologic, antithrombotic
and cytoprotective agent that improves microvascular blood flow and has potential
application in treating a range of conditions, such as complications arising from sickle
cell disease. Adventrix began 2012 with a cash position of $US50 million, which will
be used to fund its planned Phase III study of ANX-188 in patients with sickle cell
disease.
San Diego-based HemaQuest Pharmaceuticals has raised an additional $US13
million to support a mid-stage trial of the company’s lead drug candidate for sickle cell
disease. The company expects to complete a planned Phase IIb trial of its lead drug
by early 2014. HQK-1001, belongs to a class of compounds known as Short Chain
Fatty Acid Derivatives that have been shown to stimulate foetal hemoglobin
expression and red blood cell production in the laboratory.
Treating Alzheimer’s Disease (AD)
One major study yet to report is testing the use of IVIg for AD, and if this trial has a
positive result there would be major implications for demand and price. Thus the NBA
is also interested in the development of drugs not based on plasma products.
Pfizer research chief Mikael Dolsten told an Investor Conference in New York in
February that the experimental treatment for Alzheimer’s, bapineuzumab, was the
drug industry’s “best chance” to delay progression of the illness. His comments come
months before critical Phase III trial data for the drug is due to be published. The
development of bapineuzumab was originally a joint venture between Elan and Wyeth.
Johnson and Johnson has an 18.4% stake in Elan.
Lumry W, et al "Efficacy of icatibant in laryngeal attacks of type I and II HAE: a pooled analysis of three Phase III
trials" AAAAI 2012; Abstract 821.
7 The FAST studies were funded by Jerini AG/Shire Human Genetic Therapies.
8 The patients enrolled in the study had a history of unsatisfactory oral iron therapy, and had iron-deficiency anaemia
(IDA) associated with various conditions including abnormal uterine bleeding, cancer, gastrointestinal disorders or other
causes. Patients treated with Feraheme achieved a mean increase in haemoglobin at week five of 2.7 g/dL, compared
with a mean increase of 2.4 g/dL in patients treated with IV iron sucrose. A ≥ 2.0 g/dL increase in haemoglobin at any
time from baseline to week five was achieved in 84% of patients treated with Feraheme, compared with 81% of
patients treated with IV iron sucrose.
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Eli Lilly’s anti-beta-amyloid therapy solanezumab for the treatment of mild to moderate
Alzheimer’s disease is expected to launch in 2014.
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Promoting haemostasis (preventing blood loss)
 CSL Behring announced on 16 March that the first patient has been treated as part of
the REPLACE Phase III clinical trial evaluating the efficacy and safety of fibrinogen
concentrate (Human) (FCH) in controlling micro-vascular bleeding during aortic
aneurysm surgery. The purpose of this study is to demonstrate that FCH can reduce
intraoperative bleeding and the volume of blood products (fresh frozen plasma,
platelets, and red blood cells) needed during complex cardiovascular surgical
procedures. The study also aims to show that FCH is safe and well tolerated. The
primary efficacy endpoint measurement will be the number of units of all allogeneic
blood products transfused during the first 24 hours after administration of FCH or
placebo. "Potentially life-threatening bleeding events can occur during cardiovascular
surgery because the patient's fibrinogen levels are depleted, which delays clotting"
said Dr. Niels Rahe-Meyer, Department of Anesthesiology and Intensive Care,
Franziskus Hospital, Bielefeld, Germany and coordinating investigator of the study. Of
the 12 million units of blood used in the US each year, 15% are used in cardiovascular
surgery. Some studies have suggested that blood transfusion during or after adult
cardiac surgery is associated with increased long-term mortality.
 A new biological dressing has been designed to achieve a rapid halt to bleeding,
reducing military and civil casualties. The nanoscale spray coating of thrombin (a
blood-clotting protein) and tannic acid (a component of black tea with antibacterial
properties) was developed by a team of researchers from the Massachusetts Institute
of Technology to coat sponges, which are convenient for soldiers and medical
personnel to carry. These dressings overcome the disadvantages of some other
haemostatic materials. A tourniquet cannot be used on the neck. Chitosan bandages,
adopted by the US Department of Defense, can be used only on simple wounds.
Ferrosan sponges, which are used in some hospitals, require soaking in thrombin
solution prior to application on the wound, thus proving impractical on battlefields.
 Rotem Systems announced in February that 20 additional medical centres within the
US have acquired the ROTEM® whole blood haemostasis analyser, which monitors
the coagulation state of a blood sample in order to assist in the assessment of patient
clinical haemostasis conditions. The ROTEM results, within 10 minutes, and in
conjunction with other tests, are designed to assist the clinician manage dangerous
surgical and trauma bleeding, while reducing the need -and inherent risks- of blood
transfusions and assisting with the selection of the most appropriate blood product
required9.
h. Other
 A mobile device tool has been created for easy access to the US Centers for Disease
Control and Prevention's adverse reaction definitions used in the Hemovigilance
Module of the National Healthcare Safety Network10. The tool, which can be shared
with clinicians for categorising adverse reactions, is designed to work on iPhones,
iPads and other mobile Internet-access devices.
 Flinders University researchers have developed a device to warm blood for
emergency transfusions in the field. The device is now in its first stage of
commercialisation. The Intraheat device will not need a power source. The
ambulance officer or combat medic "pulls the rip cord" on the portable, disposable unit
to trigger a chemical reaction which heats the blood and other intravenous fluids as it
flows from the bag to the patient.
9Ganter,
M.T., Spahn, D.R., University of Zurich, Switzerland: “Active, Personalized and Balanced Coagulation
Management Saves Lives in Patients with Massive Bleeding.”, Anesthesiology 2010, 113:5.
Goerlinger, K., “Reduction of blood transfusion rate by point-of-care coagulation management in liver transplantation,
visceral and cardiac surgery”. International Forum on Quality and Safety in Healthcare, Berlin. Mar. 2009.
10 Initiated in 2006, the US Biovigilance Network is a collaboration between the US Department of Health and Human
Services, including the Centers for Disease Control and Prevention, and organizations involved in blood collection,
transfusion, tissue and organ transplantation, and cellular therapies.
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University of Tasmania Professor Emily Hilder's new MilliSpot paper means a spot of
blood can be used in place of vials of blood to provide accurate test results. Blood
spots, which dry quickly, become non-hazardous and do not need refrigeration; but
storing on paper, though useful for newborns since the 1940s, has not been reliable
for drug testing. This new paper is a porous polymer-based material.
After three tours in Afghanistan as a trauma surgeon, and inspired by a simple hair
clip, Canadian Dr Dennis Filips designed a clamp which stops bleeding from wounds
within seconds. His Innovative Trauma Care (ITC) firm based at the Edmonton
Research Park aims to launch the device later this year to hospitals, ambulances and
the military in Canada, the US, Australia and New Zealand.
CSL Behring in March announced that the first patient has been enrolled in the
PATH11 study, an international clinical trial designed to evaluate the efficacy, safety,
and tolerability of two different doses of subcutaneous immunoglobulin (SCIg),
compared with placebo, in maintenance treatment of chronic inflammatory
demyelinating polyneuropathy (CIDP).
Biotest announced in April the publication of clinical data12 reporting on the efficacy of
the company’s new investigational IVIg product, a 10% liquid product, which does not
contain any sugar.
On 21 February CSL Behring announced that thought leaders from the medical
community in Europe and the US examined the pros and cons of using albumin in
treating liver disease and sepsis, in cardiac surgery and in burns patients, during CSL
Behring’s Key Issues Dialogue – “Albumin in Clinical Fluid Management.”
German company AiCuris announced trial results for Letermovir (AIC246). It met
primary efficacy endpoints in Phase II for human cytomegalovirus (HCMV) prophylaxis
in human blood precursor cell recipients. The company said the trial showed dosedependent effect on the prevention of HCMV re-activation/re-infection and an
excellent tolerability.
Vical announced in April that the company and Astellas Pharma had finalised the
general design of a pivotal, multinational Phase 3 trial of TransVax, the companies'
therapeutic cytomegalovirus, or CMV, vaccine for transplant recipients. The companies
expect to begin the Phase 3 trial of TransVax for hematopoietic stem cell transplant
recipients in the second half of 2012, and initiate a Phase 2 efficacy trial of TransVax for
solid organ transplant recipients shortly thereafter. If such a vaccine proves successful,
there would be implications for the demand for cmv immunoglobulin for transplant
patients.
On 17 April, Medgenics filed a new drug application to FDA so that it can start a
Phase II trial for the Biopump. The multi-centre trial comprising 100 patients is
designed to evaluate the safety and efficacy of sustained erythropoietin (EPO)
therapy, which is delivered by Medgenic’s EPODURE Biopump, for the treatment of
anaemia in dialysis patients with end-stage renal disease. EPODURE is a small
tissue implant made from the patient's own skin tissue. The company says a previous
study provided positive data which demonstrated that a single administration of
EPODURE can raise and maintain haemoglobin levels for many months without any
injections of EPO or other stimulating agents.
2. Regulatory Matters.
Here the NBA follows overseas regulatory decisions on products,
processes or procedures which are or may be of relevance to its responsibilities.
a. In January the FDA approved Baxter’s fibrin sealant Tisseel to include general
haemostasis in surgery when control of bleeding by standard surgical techniques is
ineffective or impractical. Tisseel is approved by Australia’s Therapeutic Goods
11
PATH = Polyneuropathy And Treatment with Hizentra
Wasserman et al.,"Safety, Efficacy and Pharmacokinetics of a New 10% Liquid Intravenous Immunoglobulin (IVIG)
in Patients with Primary Immunodeficiency." Journal of Clinical Immunology (Http://dx.doi.org/10.1007/s10875-0129656-5).
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Administration (TGA). The NBA notes that fibrin sealants are one of the most commonly
requested products for addition to the supply plan with strong interest from clinicians.
Novo Nordisk received a complete response letter from the FDA for its recombinant factor
XIII (rFXIII) needing additional data. The candidate has been studied for the treatment of
congenital FXIII deficiency.
Octapharma in February submitted to the FDA a biological license application (BLA) for
Octaplas LG, for managing preoperative or bleeding patients who require replacement of
multiple plasma coagulation factors. The application also seeks approval for the
substitution of removed plasma, such as plasma exchange in thrombotic
thrombocytopenic purpura (TTP), a disorder that causes clot formation in small blood
vessels. The product features solvent/detergent inactivation against enveloped viruses
and immune neutralisation against non-enveloped viruses. Octaplas has been used in
Europe for 15 years.
Takeda's new treatment for symptomatic anaemia
associated with chronic kidney disease was accepted in February for European Medicines
Agency (EMA) review. Peginesatide is intended for adult patients undergoing dialysis.
Positive data from two Phase III trials supported the submission.
The FDA in March approved a new injectable drug from
Affymax to treat anaemia in adult patients on dialysis. Peginesatide will be sold under the
brand name Omontys. It is given only once a month rather than multiple times a week, as is
required with the well-established drug Epogen.
Bovie Medical Corporation announced it has received 510K
clearance from the FDA to market its J-Plasma handpiece with retractable cutting feature
to be used for soft tissue coagulation during surgery.
Bayer HealthCare in April submitted an application for
marketing authorization to the European Medicines Agency (EMA) for the oral
anticoagulant Xarelto® (rivaroxaban) for the treatment of pulmonary embolism (PE) and
the prevention of recurrent deep vein thrombosis (DVT) and PE in adults.
In March the FDA approved Avioq HTLV-I/II Microelisa
System, a test designed to detect antibodies to viruses in donors of human blood and
blood components that are associated with several diseases, including some forms of
leukemia and neurologic diseases.
Baxter in March recalled one lot of its GAMMAGARD
LIQUID 10%, 20g because the labels on the unit carton and product vials indicate an
incorrect manufacturing date and expiry date.
In April the FDA cleared for marketing a new source plasma
collection system developed by Fenwal. The Aurora™plasmapheresis system, can
support two-way, wireless data communication and eliminate manual steps. The FDA
also cleared Fenwal to market a therapeutic plasma exchange protocol for the company’s
Amicus® separator. The TPE protocol is also available for the Amicus separator in
Europe and Latin America.
OraSure Technologies announced the FDA Blood Products
Advisory Committee will consider the company's application for the approval of its
OraQuick Rapid HIV-1/2 test for sale in the US over-the-counter market at a meeting
scheduled for 15 May.
Since 2008, the FDA has been working on a program that
would allow it to outsource inspections of active pharmaceutical ingredient manufacturing
operations in other countries to other regulators and then reciprocate with inspections it
conducts. It is already working with European Medicines Agency (EMA), the European
Directorate of the Quality of Medicines and Healthcare, and Australia's TGA. On 1 March,
the FDA published its terms of reference- and expects other agencies will want to join.
The World Health Organization (WHO) joined after the terms were issued. There are
provisions for asking each other to look into specific areas of concern. In testimony before
a congressional subcommittee, Peter Beckerman, a senior policy advisor to the FDA, said
the FDA needs to be able to share information on manufacturing processes with other
regulators, but confidentiality agreements with companies under trade secret legislation
prevent it from giving full disclosure. The FDA was severely criticised by Congress for
allowing contaminated heparin marketed by Baxter International into the US in 2008. Yet,
it has had trouble getting additional funding so that it can increase oversight in other
countries where inspections have averaged once every 9 years, instead of once every 30
months as in the US.
p.
The full clinical study reports of drugs authorized for human
use should be publicly disclosed to allow independent re-analysis of the benefits and risks
of the drugs, experts said in April, basing their assertions on their experience with Tamiflu
(oseltamivir)13. A recent Cochrane review on Tamiflu has declared that even more than
ten thousand pages of regulatory evidence were not sufficient to clarify major
discrepancies regarding the effects and mode of action of the drug. In a Perspective
article accompanying the analysis four drug regulators (representing the EMA, the Agence
Française de Sécurité Sanitaire des Produits de Santé, the UK's Medicines and
Healthcare Products Regulatory Agency, and the Medicines Evaluation Board in The
Netherlands) responded: "We consider it neither desirable nor realistic to maintain the
status quo of limited availability of regulatory trials data". They suggested "establishing
rules of engagement to follow the principle of maximum transparency whilst respecting the
need to guarantee data privacy and to avert the potential for misuse”.
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Baxter International and Halozyme Therapeutics announced
on 17 April that regulators will take more time to review their immune disease drug HyQ.
The FDA wants more information about long-term use of HyQ. HyQ is a combination of
immune globulin and recombinant human hyaluronidase, which is designed to temporarily
break down a substance in the body that forms a barrier between cells so drugs can be
absorbed faster. That would allow some drugs to be delivered by an injection instead of
an IV drip. HyQ was developed for patients with primary immunodeficiencies. An
application in the European Union, filed in the third quarter of last year, is also pending.
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A March report analysing biologics recalls issued or
reported with the FDA and its agencies concluded that immunoglobulins and vaccines are
involved in more recalls than other drug classes.
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 February CSL announced that first-half net profit fell 3.4% as the high Australian
dollar put pressure on its earnings. The unfavourable foreign exchange impact was
A$95 million. On a constant currency basis, which removes the impact of exchangerate movements, net profit grew 16%. However, the company also upgraded its fullyear profit guidance, citing "vigorous" demand for its products. "We now anticipate
profit will grow approximately 13%, using fiscal 2011 exchange rates, to around
A$1.06 billion, despite continuing economic pressures in Europe and the US and the
return of a competitor to the market" said Chief Executive Brian McNamee. "Demand
for our immunoglobulin products Privigen, Hizentra as well as our lyophilised product,
Carimune, has been vigorous, despite economic pressures in Europe and the US" he
said. North America was CSL’s biggest market, accounting for 42% of revenue,
followed by Europe with 32% and Australia with 10%. CSL said it plans to begin
reporting in US dollars in the year starting 1 July, in line with industry practices and to
reflect the predominance of the company’s global sales. The company made a
13
Doshi P, Jefferson T, Del Mar C (2012) The Imperative to Share Clinical Study Reports: Recommendations from the
Tamiflu Experience. PLoS Med 9(4): e1001201. doi:10.1371/journal.pmed.1001201
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provision of about €11 million ($A15 million) in the first half in case of delays or
defaults in payments by southern European customers.
 CSL Behring in March was the recipient of a 2012 EURORDIS Award for its
pioneering work in developing and manufacturing therapies used to treat rare and
serious medical conditions. CSL Behring received the National Organization for Rare
Disorders 2011 Corporate Award for new treatments for rare diseases brought to
market in the US.
Baxter
 Baxter announced on 14 February that the company had completed its acquisition of
Synovis Life Technologies. The acquisition adds biological and mechanical products
used for soft tissue repair and microsurgery.
 In 2011, Baxter generated cash flow in excess of $US2.8 billion. It returned $US2.3
billion of this cash to shareholders through dividends of $US709 million and $US1.58
billion in share repurchases. Management expects foreign currency experience to
hold revenue growth to about 2% for 2012.
 Baxter International reported its first quarter earnings on 19 April 2012. Its results
exceeded its previously issued revenue and earnings per share guidance.
Grifols
 In January, Grifols began seeking $US3.4 billion in leveraged loans to refinance debt
used to support the acquisition of Talecris Biotherapeutics in 2010.
 Grifols, the world's third largest plasma product manufacturer, has acquired 51% of
the equity of Zaragoza-based company Araclon Biotech, which specialises in the
research and development of therapies and diagnostic methods for neurodegenerative
diseases. It currently focusses on AD14. Grifols recently launched a second medical
trial for the treatment of AD with plasma derivatives, combining haemapheresis with
the administration of albumin and IVIg, at different intervals and in varying doses:
three hundred AD patients with mild to moderate symptoms, divided into three
treatment groups, plus a fourth control group of around 100. In September 2009
Grifols published preliminary results of another trial with 42 patients. These
intermediate results, suggested a tendency to stabilise the illness in patients receiving
treatment.
NovoNordisk
 Increased earnings were reported in the fourth quarter 2011 compared with prior-year
earnings. Total revenues were up 12% (in local currencies), including a significant
increase in NovoSeven (recombinant factor VIIa) sales where it is the sole supplier,
although this could change with products currently in the development pipeline. Novo
Nordisk increased its sales growth guidance for 2012 to 7%–11% in local currencies.
In local currencies, operating profit growth is expected to be around 10%. Novo
Nordisk initiated share repurchasing.
Octapharma
 The Group in April released figures for the year ending 31 December 2011. Net sales
at €732 million were 2% above the 2010 figure. The last months in 2011 indicated a
significant improvement in profitability for 2012. Gross profit in 2011 was €205 million,
or 28% of net sales and an increase of €31 million compared with 2010. Operating
expenses were almost 6% less than in 2010. This includes €43 million investments
into Research and Development. Earnings before interest and tax (EBIT) were €64
million, a 164% increase compared with 2010.
ProMetic
 In a report to shareholders in March, ProMetic said it will continue to assist
Macopharma, with the adoption of the P-Capt® filter in the UK. In line with SaBTO's
recommendation, in November 2009, for adoption of the P-Capt® filter for children
born after 1 January 1996, the Company is hopeful that sales may commence after
In diagnosis of AD, Araclon has kit patented for the detection of amyloid beta peptides (AB) 40 and 42 in the blood.
Its research on treatment is based on immunotherapy, specifically developing a series of patented vaccines which have
yielded positive results in various animal models and on which clinical trials will start soon.
the reporting of the PRISM clinical study results. ProMetic will also continue to
support Octapharma in the adoption of OctaplasLG® for the US market following the
recent submission of its Biological License Application.
g. LFB
 Christian Béchon, Chairman and CEO of LFB since July 2006, was reappointed by a
decree from the French President in March.
h.
Pharming Group
 Last December the Group announced in the Netherlands that it has signed a service
agreement with Renova Life (RLI) based in Maryland. The agreement covers the
development and supply of founder transgenic rabbits from RLI to Pharming to enable
Pharming to start the commercial production breeding process. The first protein to be
expressed in the rabbits will be recombinant human Factor VIII (rhFVIII) for the
treatment of haemophilia A. Pharming says the recent European approval of its rh C1
inhibitor (Ruconest) has demonstrated its ability to produce industrial volumes of high
quality recombinant human protein through a method which requires significantly
lower capital investment and manufacturing costs than current cell based
technologies. Ruconest (Rhucin outside Europe) is a recombinant human C1 inhibitor
approved for angioedema attacks in patients with HAE in all 27 EU countries plus
Norway, Iceland and Liechtenstein, and is distributed in the EU by Swedish Orphan
Biovitrum.
i.
Biotest
 Unaudited financial results for 2011, show a slight year-on-year increase in sales.
j.
Shire and Sangamo BioSciences
 The companies have agreed to develop therapeutics for haemophilia and other
monogenic diseases. The products will be based on Sangamo’s zinc finger DNAbinding protein technology. Shire further announced in Dublin in March that it has
signed an agreement to acquire FerroKin BioSciences. This adds a product in
development (iron chelator FBS0701) with global rights, in a global market worth over
$900 million, treating patients for iron overload following numerous transfusions.
k.
Bayer
In July 2008, MAXY sold its haemophilia program assets to Bayer for $US90 million
upfront and a potential milestone payment of $US30 million. That payout will occur if
Bayer initiates a Phase II trial of MAXY-VII. The drug is claimed to be an improved
form of Novoseven, and an effective therapy for patients with inhibitors to FVIII or FIX.
Bayer reported last September on a successful Phase I human study with the modified
FVIIa product, BAY 86-6150. The goal of the study was to demonstrate increased
thrombin burst generation and reduced clearance. A pivotal Phase II/III study is
following.
Other
 The CEO of Elan in March postponed retirement to take responsibility for the ultimate
outcome of the Phase III program for the AD drug bapineuzumab. Although Johnson
& Johnson and Pfizer took over driving bapineuzumab some time ago, Elan retains a
25% share.
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l.
4. Overseas events.
The NBA is interested in relevant safety issues which arise in
particular countries, and also in what can be learned from instances of good practice by
others. It follows health issues in countries from which its visitors and immigrants come.
a.
United Kingdom
 In the UK, experts advising the Department of Health believe patients who have
received more than 80 blood transfusions are most at risk of developing CreutzfeldtJakob disease (vCJD). They would expect to see 150 cases among the group of
around 30,000. Discussion centred on whether following patients without their
consent is 'ethically problematic'.
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b.
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c.
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d.
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e.
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f.
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The UK National Health Service (NHS) announced in February that four teaching
hospitals are participating in a Blood Management System Pilot to track and compare
the use of blood.
London's Air Ambulance is now carrying blood supplies – the first such service in the
UK to do so15. Blood will also be carried on the service's rapid response cars.
In May, a test for West Nile Virus (WNV) will be introduced in England and North
Wales for blood from donors who have returned from countries where WNV is
prevalent16 and immediate donation allowed if appropriate. Previously donors had to
wait 28 days after return.
In the UK, new guidelines issued in April allow men to donate more frequently. They
can now give four times in 12 months, as long as they wait 12 weeks between
donations. Women can still donate only every 16 weeks, as they have lower levels of
stored iron than men. There is no upper age limit for donors who have donated in the
last two years.
New Zealand
The New Zealand Parliament's health select committee was told in April by the Office
of the Auditor General that the New Zealand Blood Service is safe, efficient and well
run.
Canada
In February, Canadian Blood Services marked Black History Month by urging
Canadians of African and Caribbean heritage to celebrate their unique culture through
blood and stem cell donation. Sickle cell disease is an inherited disease of red blood
cells, predominantly affecting people of African descent. “Individuals with African
heritage possess certain minor blood groups that may make it difficult to find
compatible blood when repeated transfusions are needed as in sickle cell disease
treatment" said Dr Isaac Odame, Medical Director of the Global Sickle Cell Disease
Network at Sick Kids Hospital in Toronto.
The Canadian media reported in April that Canadian Blood Services is buying an
increasing supply of blood plasma products from the United States while shutting
down its only Canadian plasma collection facility in Thunder Bay.
The Middle East
A 90-bed blood disease centre is being built in Bahrain’s main hospital. It is expected
to be of particular help to those suffering from sickle cell disease.
The number of people having premarital genetic screening in Dubai has risen by more
than a third in two years. Screening is required before a couple can be issued a
marriage certificate in the United Arab Emirates. The screening process looks for
thalassemia, sickle-cell anaemia, hepatitis B and C, syphilis and rubella. If both
parents carry the trait for a recessive genetic disease, with each pregnancy there is a
25% chance that a child will be born with the disease, 50% chance the child will be a
carrier and 25% chance the child will be unaffected.
Qatar has expanded its newborn screening program to test for severe combined
immune deficiency.
India
India announced in April that it will initiate a national programme to prevent and
manage hereditary blood disorders, beginning with a registry.
China
Blood transfusions will not be sold at a profit at Chinese hospitals, a deputy from the
National People's Congress clarified in March. Patients will have to pay only for the
price of supplying, storing or processing and not for the donated blood.
5. Safety Issues.
At present, the impact of transfusion on outcomes in cardiac surgery
remains an interest, as does the relationship between age of red cells and surgical outcome.
15
Some services in Australia do carry blood.
These include the USA, Canada, Italy, mainland Greece, Romania, Former Yugoslav Republic of Macedonia,
Turkey, Albania, Israel and some areas of Russia.
16
a.
b.
c.
d.
e.
f.
Patients given packed red blood cells had an increased risk for major infection after
cardiac surgery, according to study results presented at The Society of Thoracic Surgeons
48th Annual Meeting17.
At a professional update on paediatric and congenital cardiovascular disease in
February, researchers reported that in paediatric heart transplantation, increasing
amounts of blood transfused appears to be associated with worsening outcomes18.
The duration of red blood cell storage did not adversely affect outcomes in ventilated
patients receiving transfusions, according to a small randomized trial. There was no
difference in short-term pulmonary, immunologic, or coagulation status between 50
patients who received fresh red blood cells (median storage of four days) and 50 who
received standard-issue red blood cells (median storage duration of 26.5 days), reported
Daryl Kor, from the Mayo Clinic in Rochester, Minnesota19. The study was done at a
single centre, tertiary-care facility in a small patient population. The follow-up period was
short, so delayed responses to the transfused red blood cell units were not identified. The
investigators noted that their results differed from earlier study results that have found
storage duration and adverse clinical outcomes. One possible reason is that patients in
this study received a similar red blood cell dose, while earlier researchers did not adjust
for dose, they suggested. Also, pre-storage leukocyte reduction was used for all red
blood cell units transfused – including fresh ones – in this study, and they explained this
has been shown to lessen the accumulation of bioactive substances. The authors
concluded that the study offers proof that larger clinical trials randomising patients to fresh
red blood cell units or prolonged storage units are ethical and possible.
In March, the American Association of Blood Banks issued new guidelines on the level
at which a patient's red blood cell count can be viewed as so low, as to require a
transfusion. Previously US physicians might see patients with a haemoglobin threshold of
9 or 10 as being sufficiently anaemic to require a transfusion. After reviewing recent
research the Association concluded most patients would do just as well if the threshold
were at 7 or 8 grams per deciliter in hospitalized, stable patients.
In the February issue of Nature Genetics, University of Vermont biologist Bryan Ballif
and his colleagues report on their discovery of two proteins on red blood cells responsible
for two lesser-known blood types, the Langereis blood type and the Junior blood type.
“Only 30 proteins have previously been identified as responsible for a basic blood type”
Ballif notes, “but the count now reaches 32. More than 50,000 Japanese are thought to
be Junior negative and may encounter blood transfusion problems or mother-foetus
incompatibility”. Both of the newly identified proteins are also associated with anticancer
drug resistance.
Health-care provider Kaiser Permanente said in California in January that it will no
longer purchase intravenous solution bags made from PVC or that contain the plasticizer
DEHP, or IV tubing that contains DEHP. Six years ago, the two companies that control
90% of the IV bag market in the US – Hospira and Baxter – began selling non-PVC IV
bags.
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. The brief
reports which follow include the Australian research which has investigated subsets of blood
Horvath KA. “Do blood transfusions affect the risk of infections after cardiac surgery? Experience of the NIH/CIHR
Cardiothoracic Surgical Trials Network”. Presented at: The Society of Thoracic Surgeons 48th Annual Meeting; Jan.
28-Feb. 1, 2012; Fort Lauderdale, Fla.
18 Howard-Quijano K, et al, "The effect of red blood cell transfusions on pediatric heart transplant patients" PCCD
2012; Abstract 43. : Annual Update on Pediatric and Congenital Cardiovascular Disease, Orlando, February 2012.
19 Kor DJ, et al "Fresh red blood cell transfusion and short-term pulmonary, immunologic, and coagulation status: A
randomized clinical trial" Am J Respir Crit Care Med 2012.
17
‘progenitor’ cells and the signals that cause them to expand and develop into mature blood
cells; the discovery that the abundance of plasma proteins may differ between male and
female plasma; and the study to determine whether the rate at which a person’s red cells
decay is an inherited trait.
a.
On the horizon
 In January, Cambridge scientists announced they are a step closer to making ‘off the
shelf’ veins and arteries which could revolutionise treatment for heart attacks and
strokes20. A biotechnology firm in California managed to grow whole blood vessels in
a lab for the first time last June and implanted them into three kidney dialysis patients.
However, the Cambridge team say they are the first to grow multiple types which
could have more medical uses.
 A research team from the Walter and Eliza Hall Institute, led by Drs Ashley Ng and
Maria Kauppi, investigated subsets of blood ‘progenitor’ cells and the signals that
cause them to expand and develop into mature blood cells21. The researchers were
surprised to find that progenitor cells believed to be able only to produce
megakaryocytes22 were also able to develop into red blood cells23. “This research is
the first step in the future development of treatments for patients with blood diseases”
Dr Ng said. “This may occur either by limiting blood cell production when too many are
being made, as with myeloproliferative disorders, or stimulating blood production when
the blood system is compromised, such as during cancer treatment or infection.”
 Scientists from the Queensland Institute of Medical Research claim a breakthrough in
the treatment of throat cancer using a patient's blood to grow special white blood cells
that recognise and fight infected cancer cells.
 In February, Oxygen Biotherapeutics of North Carolina and Aurum Biosciences of
Glasgow, announced their agreement to develop a better tool for defining the extent of
injury in acute ischemic stroke and for treating this emergency in the important early
hours after the attack. Oxygen Biotherapeutics' proprietary, perfluorocarbon-based
Oxycyte emulsion, was developed to deliver large amounts of oxygen to the brain,
while the diagnostic work depends on Aurum's proprietary GOLD (Glasgow Oxygen
Level-Dependent) Magnetic Resonance Imaging (MRI) technology, which has been
designed to map potentially salvageable tissue in the brain after stroke in the brain.
b.
Impact of genetics
 University of Iowa researchers are using 14 sets of twins (identical and non- identical)
to investigate whether the rate at which red blood cells decay is inherited. If the
results (due in May) show that it is, a larger study will follow to identify specific genes
involved.
 Two recent US studies have examined two specific health issues faced by AfricanAmericans:
20
They can grow all three main types of cells which make up the walls of a blood vessel. Implanting laboratory- grown
blood vessels may be an alternative to heart bypass treatment and stenting. Test tube blood vessels could also be
used to treat kidney dialysis patients, and to fix damaged arteries after accidents for those who might otherwise lose a
limb. The researchers used patients’ own skin cells to make different types of vascular smooth muscle cells. They
could be used to build an artificial artery in a test tube or the stem cells could be injected straight into the heart and they
could form within it.
21 Their results were published 30 January 2012 in the journal Proceedings of the National Academy of Sciences of the
United States of America.
22 A type of bone marrow cell that gives rise to blood-clotting platelets.
23 “We were able to clearly demonstrate that these mouse megakaryocyte progenitor cells have the potential to develop
into either megakaryocytes or red blood cells in response to cytokines such as thrombopoietin and erythropoietin,
which was quite unexpected” Dr Ng said. “In addition, we discovered that other progenitor populations thought to really
make only neutrophils and monocytes [other immune cells], were capable of making red blood cell and platelets really
well. In effect, we will have to redraw the map as to how red cells and platelets are made in the bone marrow.” Dr
Kauppi said the researchers found they could regulate whether the progenitor cell became a megakaryocyte or a red
blood cell by using different combinations of cytokines. “Now that we have properly identified the major cells and
determined how they respond to cytokine signals involved in red blood cell and platelet production, the stage is set for
understanding how these progenitors are affected in health and disease” she said. “We can also better understand, for
instance, how genetic changes may lead to the development of certain blood diseases.”
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Research at the Beth Israel Deaconess Medical Center, led by Dr Martin Pollak, is
shedding light on why kidney disease is far more common among AfricanAmericans than other ethnic groups. Finding the gene they believe responsible
(APOL1) is the first step of many in developing treatments24. It is a variant that
wards off sleeping sickness, a disease mainly borne by tsetse flies that kills tens of
thousands of people in Africa each year. The gene is carried by as many as 12%
of African-Americans.
 Researchers have found five previously unknown gene mutations believed to be
associated with elevated blood platelet counts in African-Americans. The findings,
they say, could lead to the development of new drugs to help prevent coronary
artery disease. The study25 is believed to be the first of its size to focus on platelet
genetics in African Americans, who have a higher risk of stroke than other racial
groups. They also have relatively higher platelet counts and average platelet
volume, and worse outcomes after a heart attack. Study leader Rehan Qayyum,
of Johns Hopkins University School of Medicine cautions that there are believed to
be many more genes involved in platelet function that remain unknown. Studies
have shown that the greater the platelet volume or count in the blood, and the
larger the platelets, the greater the risk of dangerous clot formation. Qayyum
notes that the number of platelets in a given amount of blood (platelet count) and
the size of these platelets (measured as average platelet count) vary from person
to person in much the way that height, weight and eye colour differ. One goal of
the research is to identify new targets for drugs that decrease platelet aggregation
in the arteries and prevent clot formation. Blood thinners—including aspirin,
clopidogrel and warfarin—are widely used anti-platelet medications, but have side
effects, which include bleeding, bruising and gastrointestinal upset.
In a small study, researchers have compared plasma proteins in male and female
blood, and found, of the 231 proteins identified, there were differences in abundance
between genders. They suggest that if these are confirmed in further work, male or
female plasma could be selectively transfused to patients, depending on their
condition.26
Researchers have identified an elusive gene responsible for Thrombocytopenia with
Absent Radii (TAR). This research is being transformed into a test allowing prenatal
diagnosis and genetic counselling in affected families. TAR syndrome combines low
platelet count and prominent bleeding, especially in infancy, and skeletal abnormalities
affecting the upper limb, ranging from absence of the radial bone in the forearm to
absence of the upper limb.
Alnylam, an RNAi therapeutics company, focusses on development and
commercialisation of novel RNAi therapeutics for the treatment of genetically defined
diseases. Its core programs in clinical or pre-clinical development include: ALN-APC
for the treatment of haemophilia; ALN-HPN for the treatment of refractory anaemia,
24
Though African-Americans are 12% of the US population, they represent about a third of the kidney failures. Kidney
disease is about five times more likely to affect African-Americans than other groups. In the US they represent about
35% of the people waiting for transplants.
25 Published in the online journal PLoS Genetics and reported 5 March. Rehan Qayyum and his colleagues conducted
a meta-analysis and genomewide association study, looking at genetic data from 16,000 African-American participants
in seven studies. Comparing information from each study, they tracked 2.5 million single possible changes in the
human genetic code to see which genes stood out across the entire group as significantly associated with increased or
decreased platelet counts. Across the studied genomes, the researchers found five such alterations – involving the
addition or deletion of a single piece of genetic code – that had not been identified in other populations. When they
checked their findings against data from Caucasian and Hispanic groups, they found three of the novel gene mutations
in those populations too. Four of the previously unknown gene mutations were later found in the genetic code of
platelet cells, but one was not; that one, however, was found close to a gene that is known to be essential in the
formation of normal platelets. The exact role played by each of these mutations still needs to be determined, Qayyum
says.
26
"Proteomic analyses of human plasma: Venus versus Mars" Transfusion 2012, 52, 417-424.
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c.
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and ALN-TMP for the treatment of haemoglobinopathies, including beta-thalassemia
and sickle cell anaemia.
Scientists have developed a gene therapy strategy they say could feasibly treat both
β-thalassemia and sickle cell disease. The technology is based on delivery of a
lentiviral vector carrying both the human β-globin gene and an ankyrin insulator to
improve gene transcripton and translation, and boost levels of β-globin production.
The Weill Cornell Medical College-led team that reports on the development27 has in
parallel devised a simple assay to predict how well individual patients are likely to
respond to the treatment.
Patient blood management
In a recent presentation28 Dr Mark Pagnano of the Mayo Clinic said that administering
fluids first rather than transfusing patients, and using an antifibrinolytic agent such as
tranexamic acid, can reduce blood loss and the need for transfusion in patients
undergoing hip or knee arthroplasty. He said “most of the postoperative clinical
symptoms…traditionally attributed to anaemia are, in fact, a volume problem, not a red
blood cell problem” and “Traditional indicators of the need for transfusion –
hypotension, elevated heart rates and low urine output – almost always respond to IV
fluids alone and do not need blood most of the time. Most patients can function quite
safely with relatively low hemoglobins, if they have sufficient intravascular volume.
There is comprehensive ICU data that morbidity for patients is only increased with
very, very low hemoglobins in the six or under range. Another way to reduce blood
loss and the need for transfusion is using an antifibrinolytic medication such as
tranexamic acid or aminocaproic acid. These medications are easy to obtain,
inexpensive and have a long history of use in cardiac and dental surgery and
tonsillectomy” Pagnano said. Of the two medications, Pagnano recommends
tranexamic acid because of extensive studies in patients undergoing total knee or total
hip procedures proving its ability to decrease blood loss and transfusion. The
medication has not been associated with higher rates of deep vein thrombosis or
pulmonary embolism. “It works by inhibiting the activation of plasminogen to plasmin,
thus preventing the breakdown of fibrin” Pagnano said. At his institution, patients are
administered one gram of tranexamic acid mixed with 50 mL of saline through an IV
preoperatively at the time of prophylactic antibiotics and another gram mixed with 50
mL of saline at wound closure. He advises against using tranexamic acid if patients
have had a recent cardiac stent.
In February, a research team led by Gavin Murphy, Reader in Cardiac Surgery at the
University of Bristol, was awarded £297,000 by the British Heart Foundation to
develop blood transfusion methods that reduce the risk of organ injury during cardiac
surgery.
A study29 has found that patients who have robot-assisted surgeries on their kidneys
or prostate have shorter hospital stays and a lower risk of having a blood transfusion
or dying. The analysis compared increasingly common robotic surgery with two other
techniques and found that direct costs can be up to several thousand dollars higher for
the robotic type.
Researchers report that prophylactic erythrocyte transfusion decreases perioperative
anaemia and erythrocyte transfusions, and may reduce plasma iron levels.30 The
study included 60 anaemic patients undergoing cardiac surgery with cardiopulmonary
Stefano Rivella, and colleagues report in PLoS One: “Therapeutic Hemoglobin Levels after Gene Transfer in βThalassemia Mice and in Hematopoietic Cells of β-Thalassemia and Sickle Cells Disease Patients.”
28 Pagnano M. Minimizing blood loss: An acid trip in 2011. Paper #38. Presented at the Current Concepts in Joint
Replacement 2011 Winter Meeting. Dec. 7-10. Orlando, Fla. Mark W. Pagnano, can be reached at the Mayo Clinic,
200 First St. SW, Rochester, MN 55944; 507-284-5276; email: pagnano.mark@mayo.edu (he may make an interesting
speaker on the subject of patient blood management).
27
29
30
Published in the Journal of Urology and reported by Reuters 5 March.
in the March issue of Anesthesiology (maybe March 13).
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d.
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bypass who were given either a prophylactic transfusion, which included two units of
erythrocytes transfused one to two days before surgery, or a standard transfusion.
A recent study31 from the London School of Hygiene and Tropical Medicine has
concluded that the use of tranexamic acid (TXA) in the treatment of traumatic bleeding
has the potential to prevent many premature deaths every year. A large proportion of
the potential health gains are in low and middle income countries.
Immunoglobulin and hyperimmunes
The US National Institutes of Health (NIH) is set to launch a large trial using antibodies
to test a way to prevent birth defects, such as blindness and deafness, caused by
mothers passing a common virus to their unborn babies. CSL will donate $US2.5
million worth of cytomegalovirus (CMV) antibodies from human plasma to the NIH for
the trial. Analysis is expected in 2016. There is no vaccine available yet to prevent
CMV infection, the most common infection that causes birth defects. It affects 1-2% of
women for the first time during their pregnancy, and one-third of those pass it to their
unborn babies. More babies are born with CMV infection than Down Syndrome and
almost as many as with cerebral palsy, said Bill Rawlinson, senior medical virologist at
the University of New South Wales. Babies infected with CMV can be born with
serious problems, including mental and physical disabilities. In rare cases it can be
fatal. About 1% of babies in the US are born with CMV infection, with about 11% of
those showing symptoms at birth and a small portion having effects later. Scientists
have studied using antivirals and vaccines, but immunoglobulin appears to be the
most promising therapy for pregnant women. “I think this (trial) is a good way of doing
it because we’ll get a definitive answer” Rawlinson told reporters. The clinical trial will
screen around 150,000 pregnant women over four years to come up with 400 to test
the injected antibodies and 400 to receive a placebo. Infants will be followed for two
years. CSL’s chief scientific officer, Andrew Cuthbertson, said if the trial was
successful, the therapy could be available within this decade.
The Society of Hospital Medicine meeting in San Diego in April was told that
resistance to standard treatment with IVIg appears to be more prevalent among
children with Kawasaki32 disease, and that additional and alternative treatments are
being explored for resistant cases.
A large trial in the US is testing intravenous immunoglobulin (Baxter’s Gammagard) as
a treatment for AD. As mentioned above, If a positive result is obtained, the
implications for immunoglobulin demand and price will be substantial. Accordingly,
the NBA takes an interest not only in this trial, but in AD research more generally.
 The New York Genome Center, in collaboration with Illumina, announced in
February the initiation of a whole genome sequencing project with the Feinstein
Institute for Medical Research. The project aims to understand the genetic basis
of susceptibility to Alzheimer’s disease, and to define the molecular pathways
responsible for neuronal degeneration. Whole genome sequencing efforts will
begin with 130 Alzheimer’s patient samples, for whom there is detailed clinical
data and brain pathology available. Over a four-year period, up to 1,000 genomes
of patients with Alzheimer’s will be sequenced and compared with the genomes of
a control group of elderly individuals. All data resulting from this project will be
made freely available to the scientific community.
 Neuroscientists at Case Western Reserve University School of Medicine showed
that use of bexarotene in mice reverses the pathological, cognitive and memory
deficits caused by small soluble forms of amyloid beta. Within six hours of
Katharine Ker, Junko Kiriya, Pablo Perel, Phil Edwards, Haleema Shakur and Ian Roberts: “Avoidable mortality from
giving tranexamic acid to bleeding trauma patients: an estimation based on WHO mortality data, a systematic literature
review and data from the CRASH-2 trial”, BMC Emergency Medicine 2012, 12:3 doi:10.1186/1471-227X-12-3
Published: 1 March 2012
32 Kawasaki disease is an acute self-limited vasculitis of uncertain etiology and is a frequent cause of acquired pediatric
heart disease. Tremoulet, A, et al "Kawasaki Disease: Finding the needle in the haystack" SHM 2012. Adriana H.
Tremoulet is from the Kawasaki Disease Research Center at the University of California San Diego.
31
e.
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33
administering bexarotene, soluble amyloid levels fell by 25%; the effect lasted as
long as three days.
 Alzheimer’s researchers remain divided on whether AD is a widespread, slowly
building defect in brain biochemistry, affecting neurons for memory and cognition,
or whether it stems from a localized infection that starts in the memory centres and
spreads out.
 Prana Biotechnology announced that the first patient has been dosed in the
"IMAGINE Trial" – a 12-month Phase II Imaging trial testing PBT2, the Company's
drug in development for AD. The double blind placebo-controlled trial is being
conducted on 40 patients with prodromal or mild Alzheimer's Disease. PBT2
restores neuronal health by selectively binding and redistributing brain metals
(copper, zinc) that have become imbalanced due to disease or the ageing
process. Furthermore PBT2 is able to prevent Abeta induced toxicity and promote
its disaggregation in the brain.
 US researchers replicated Alzheimer's disease neurons using induced pluripotent
stem cells from patients with the genetic and sporadic forms of the disease,
according to a report in Nature. The study found that biochemical abnormalities in
Alzheimer's neurons are caused not by beta amyloid fragments but by a precursor
to the fragments called beta-CTS, a researcher said. The neurons could help in
drug testing.
 A preliminary study33 of 46 patients found that bapineuzumab may reduce the
development of tau tangles in the brain, thought to be a hallmark of AD. The
results of another, more conclusive study are expected later this year.
 A new study34 suggests that reducing iron levels in blood plasma may protect the
brain from changes related to AD.
Other
A recent study35 concluded that a deeper understanding of the process leading to
sepsis is needed before investigators can design an effective suite of interventions.
Ongoing clinical trials are evaluating AZD9773 (AstraZeneca), an antibody against
tumour necrosis factor, and endotoxin removal by haemoperfusion through a
polymyxin B column (Spectral Diagnostics).
One potential way to overcome the problem of rejection of transplanted organs is
through the creation of a chimeric36 immune system by mixing the immune
(haematopoetic) stem cells of the recipient with that of the donor. In the context of
organ transplantation, a “chimera” can indicate both desirable and disastrous
outcomes. For example, hematopoietic chimerism, in which the immune cells in the
graft recipient come from both the host and the donor, may promote graft tolerance,
but may also cause graft-versus-host host disease (GVHD), in which the donor
immune cells attack the healthy tissue of the host. The underlying problem behind
rejection and GVHD – both of which shrink the potential donor pool – is matching. A
University of Louisville team transplanted mismatched, unrelated donor kidneys into
eight patients along with a mix of donor haematopoetic stem cells and a special
population of tolerance-inducing facilitator cells (FCs). These FCs have been shown
in animal models to improve engraftment and avoid GVHD. Five of eight kidney
transplant recipients exhibited durable chimerism and were weaned off
immunosuppressive therapies by one year after transplantation, with no signs of
GVHD or engraftment syndrome. If confirmed in larger patient cohorts, this approach
to transplantation could free some patients from the difficulties associated with lifelong
Published April 2, 2012 in Archives of Neurology. ,
Gribi O et al, in the Journal of Alzheimer's Disease Journal of Alzheimer's Disease, published April 11 2012
35 Lancet infectious Diseases, (2012;12:89).
36 According to Greek mythology, the Chimera was a fire-breathing creature made of parts from different animals: the
body of a lioness, a snake’s head at the end of the tail, and the head of the goat. Sightings of this fearsome beast
portended any of a number of terrible disasters.
34
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immunosuppression and add transplantation as a viable option for patients for whom
no matched donors exist.
Grifols presented study results in March suggesting that the plasmapheresis process
may reduce levels of low-density lipoprotein (LDL) or "bad" cholesterol as well as total
cholesterol in individuals who have high baseline levels. The study also suggests that
plasmapheresis could increase levels of "good" (HDL) cholesterol among individuals
with low baseline levels37.
The most common predictor of hospitalisation for venous thromboembolism – a
potentially life-threatening condition that includes both deep-vein and lung blood clots
– was recent exposure to an infection, according to the study released 3 April ahead
of print in Circulation38. “Over half of older Americans who were hospitalized for such
blood clots had an infection in the 90 days prior to the hospitalization,” says lead
author Mary Rogers, assistant professor in Internal Medicine at the University of
Michigan Medical School and research director of the Patient Safety Enhancement
Program at the U-M Health System and the VA Ann Arbor Healthcare System. If the
infection occurred during a previous hospital or nursing home stay, patients were
nearly seven times more likely to be admitted for a blood clot. The study also found
that other strong predictors of hospitalization for blood clots included blood
transfusions and erythropoiesis-stimulating agents, which are sometimes given to treat
anemia. The risk of hospitalisation for blood clots was nine times greater after the use
of these drugs.
A meta-analysis published online in March in Hepatology, the journal of the American
Association for the Study of Liver Diseases, says that administration of albumin
reduces morbidity and mortality in cirrhotic patients undergoing large-volume
paracentesis due to severe ascites.
In April, the Wellcome Trust, the largest non-governmental funder of medical research
after the Bill & Melinda Gates Foundation, joined a growing campaign to break the
stranglehold of academic journals and allow all research papers to be shared online.
Sir Mark Walport, director of the Trust, said that his organisation is in the final stages
of launching a high calibre scientific journal called eLife that would compete directly
with top-tier publications such as Nature and Science39. Articles in eLife will be free to
view on the web as soon as they are published. Sir Mark also said that the Wellcome
Trust, which spends more than £600m on scientific research a year, would soon adopt
a more robust approach with the scientists it funds, to ensure that results are freely
available to the public within six months of first publication.
 Walport, who is a fellow of the Royal Society, said the results of public and charityfunded scientific research should be freely available to anyone who wants to read
it, for whatever purpose they need it. The UK government has also signalled its
support for open access. At the launch of the government's innovation strategy in
December, David Willetts, Minister for Universities and Science, said he aspired to
have all government-funded research published in the public domain.
 "If you look at the way the web works and what makes effective information
dissemination on the web, then it's clear that open content spreads further, has
more influence, is used in more ways than the people who wrote it could ever
37
The study involved 663 adults and 9,153 plasma samples. "The results of our study suggest that plasmapheresis
may reduce the levels of cholesterol, although the magnitude of the effect observed depends on the baseline levels of
cholesterol and the time intervals between plasmapheresis procedures" said Dr. Marilyn Rosa-Bray, Chief Medical
Officer of the Grifols Plasma Operations. "While the results are preliminary and the study should be replicated in larger
populations, our data suggest that plasmapheresis might particularly benefit people with either high LDL or total
cholesterol levels". Dr. Rosa-Bray presented the study at the International Plasma Protein Conference (IPPC) meeting
in Madrid, Spain.
38
Citation: DOI: 10.1161/CIRCULATIONAHA.111.084467
39The
Wellcome Trust has teamed up with the Max Planck Society in Germany and the Howard Hughes Medical
Institute in the US to set up the new open-access journal.
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expect," said Cameron Neylon, a biophysicist who will take up a position as
director of advocacy at Public Library of Science, an open access publisher, in
July. The commercial success of open-access journals published by the PLoS
group, has proved that open access can make money. "PLoS ONE is now the
largest scientific journal in the world and this is ramping up," said Walport.
 In the US, academic publishers are reported to be “up in arms” about the Federal
Research Public Access Act (FRPAA) a bill intended to make publicly- funded
research available to the public.40
More than 9,000 participants from around the world are expected at the 17th
Congress of the European Hematology Association at the RAI Congress Center in
Amsterdam from 14-17 June 2012.
A study reported in April that acupuncture is an effective and safe form of pain
management for patients with haemophilia. A total of 14 acupuncture treatments were
applied to the subjects of the study and over 75% of the subjects had a significant
decrease in pain levels. The researchers note, “This study suggests that acupuncture
therapy can be a safe additional modality for pain management therapies in persons
with haemophilia, although larger randomized studies are needed for further
validation.”41
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.
Can US manufacturers favour overseas customers in a time of shortage? A US firm is
being sued because a manufacturing problem in 2009 led to rationing; and furthermore for
discrimination, in that the firm is alleged to have rationed Europe less stringently than it
did the US42.
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 in summer) 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 babesiosis43 and Lyme disease). The FDA held in November a public workshop
40
Michael P. Taylor writing in The Scientist, 19 March 2012.
Lambing,A; Kohn-Converse, B.; Hanagvadi, S.; Varma, V.”Use of acupuncture in the management of chronic
haemophilia pain”. Haemophilia, The Official Journal of the World Federation of Hemophilia and the European
Association for Haemophilia and Allied Disorders. Blackwell Publishing Ltd. 1365-2516.
42Reports in March described litigation testing whether manufacturing problems that resulted in a drug shortage can be
considered legal negligence, and whether the manufacturer can be held accountable for patients' deaths. An Idaho
widow has sued Genzyme and parent Sanofi, saying the viral contamination at a plant led to a shortage of Fabrazyme,
and rationing of the Fabry disease treatment killed her husband. The patent holder for the drug (The Mount Sinai
School of Medicine) is also named in the lawsuit. "Genzyme's rationing scheme was undertaken despite their
knowledge that less than a full dosage would not be effective and many patients would suffer catastrophic health
deterioration and even death", according to the suit. The suit says the patient started the reduced dosage in late 2009
and died March 6, 2010. This lawsuit, filed in Salt Lake County Court in Utah, follows another patient action in federal
court. Two dozen patients, including a lead plaintiff who uses Fabrazyme, allege that the FDA allows drug companies
to discriminate against US citizens, citing Genzyme's decision to ration American Fabrazyme supplies more severely
than those in Europe. Another patient group sued last year over Genzyme's handling of the shortage.
43 The first reported Australian human case of the potentially lethal tick- borne infection babesiosis has been reported in
the Medical Journal of Australia. The patient, from the South Coast of NSW, was injured in a motor vehicle accident
and was in Canberra Hospital from November 2010 to the following April, when the parasites were detected in his
blood. He died shortly thereafter. Doctors speculated that the infestation came from a tick bite and whether the tick
had come from a rodent or maybe a marsupial. (This was the first case of babesiosis found in Australia. There is no
viable automated screening test and this event has increased interest in the extent to which tick- borne lyme disease
may be present in Australian ticks).
41
on “Data and Data Needs to Advance Risk Assessment for Emerging Infectious Diseases
Relevant to Blood and Blood Products”.-a.
Infectious diseases: mosquito–borne diseases
 Over the summer Australia has seen reports of Murray Valley encephalitis, dengue,
and Ross River virus.
 In February, researchers said they hoped most dengue mosquitoes at Machan’s
Beach, north of Cairns in far north Queensland, will be unable to transmit the disease
by the end of the wet season: 49% of mosquitoes being caught were carrying the
wolbachia bacteria and they hoped to double the number. The next step was to see
whether the wolbachia stays in the mosquito population. Brazilian scientists flew to
Cairns to see the experiment, which will be extended to Brazil, Vietnam and
Indonesia.
 Oxitec's launch of genetically altered anti-dengue mosquitoes in Florida has
confronted ecological and bureaucratic obstacles. As at 7 March, Key West had not
been able to find a state or federal agency to serve as government regulator.
 Researchers at the Johns Hopkins Bloomberg School of Public Health have shown
that infection with dengue virus turns on mosquito genes that makes them hungrier
and better feeders, and therefore possibly more likely to spread the disease to
humans44.
 The mosquito Culex modestus appears to be established in the North Kent Marshes,
possibly as the result of a recent introduction. The addition of this species to the
United Kingdom's mosquito fauna may increase the risk posed to the UK by West Nile
Virus45.
 Vical said in March that the US Naval Medical Research Center (NMRC), has begun a
Phase I human clinical trial of a tetravalent dengue DNA vaccine formulated with the
company's Vaxfectin adjuvant. Vical manufactured the vaccine and the adjuvant for
both the preclinical and clinical studies, and is providing regulatory and clinical
expertise to NMRC.
 Guidelines for preparedness and response for chikungunya virus introduction in the
Americas were released in February by the Pan American Health Organization/World
Health Organization, in collaboration with the US Centers for Disease Control and
Prevention (CDC). The disease is spread by the mosquitoes Aedes aegypti (which
can also transmit yellow fever and dengue fever) and Aedes albopictus – a mosquito
endemic to the Americas.
 A goat has been genetically modified to carry a malaria vaccine in her milk, a
development that has the potential to change life in impoverished countries. "Our
ultimate, ultimate idea is to continue the research to the point to where you actually
have a herd of goats that are producing vaccines, pharmaceuticals and nutraceuticals
… in their milk" Texas A&M professor Mark Westhusin said, envisioning a day when
children can "just go out and drink the milk and get vaccinated." The process from
testing to trials and approval could take ten years. The vaccine currently is in a form
that must be isolated, purified and injected, researchers said. A&M will send milk to
GTC Biotherapeutics for continued testing and trials. Most other malaria projects are
using cell culture methods to produce antigens.
 The millions of tourists in London for the Olympics will dramatically increase the risk of
a flu pandemic, according to risk analysts Maplecroft. They rank Britain second in the
world, after Singapore, in terms of the risk of an avian or swine flu outbreak spreading.
South East Asia poses the highest risk in terms of the actual emergence of a strain of
influenza, with countries such as Cambodia, China and Vietnam rated as ‘extreme
Sim S et al. (2012) “Dengue Virus Infection of the Aedes aegypti Salivary Gland and Chemosensory Apparatus
Induces Genes that Modulate Infection and Blood-Feeding Behavior”, published in the journal PLoS Pathogens.
45 N. Golding, MA Nunn, JM Medlock, BPurse, AGC Vaux and SM Schafer, West Nile virus vector Culex modestus
established in southern England, : Parasites & Vectors 2012, 5:32
http://www.parasitesandvectors.com/content/pdf/1756-3305-5-32.pdf
44
b.
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risk’. People travelling from these high risk countries for the London Olympic Games,
have the potential to heighten the risks for the UK if an outbreak were to occur.”
Infectious Diseases: Influenza/Avian Influenza
Research controversy: On 20 January, influenza researchers from around the world,
faced with a controversy over experiments dealing with potentially dangerous H5N1
viruses, announced a 60-day pause in such research to allow time to discuss its risks,
benefits, and oversight. The 39 signatories to the letter included the authors of two
then-unpublished studies that involved the generation of mutant H5N1 viruses that
spread readily in ferrets. The statement was published simultaneously in Science and
Nature, the journals to which those studies were submitted.
 In late December 2011 the US government, following a recommendation from its
National Science Advisory Board for Biosecurity (NSABB), had recommended that
the two journals delete key details from those reports before publishing, out of
concern that the findings could be misused. The journals indicated consent,
provided a way could be devised to share the details with responsible scientists
who need them. The 20 January statement from the researchers said nothing
about postponing publication of the studies, referring only to a break in research
activities.
 The lead signatory to the researchers’ letter was Ron A M Fouchier of Erasmus
Medical Centre in the Netherlands, lead author of the H5N1 study that was
submitted to Science and the one that had been discussed in greatest detail. The
third signatory was Yoshihiro Kawaoka of the University of Wisconsin and the
University of Tokyo, lead author of the study submitted to Nature.
 Both the H5N1 studies in question were sponsored by the National Institute of
Allergy and Infectious Diseases (NIAID) of the US National Institutes of Health
(NIH).
 A group of 22 international influenza experts convened by the World Health
Organization (WHO) concluded on 17 February that journals should publish the full
details of the two controversial experiments. It recommended that the moratorium
then in effect related to further work with lab-made H5N1 variants that spread in
mammals, remain in place until more discussion occurs about biosecurity and
biosafety issues.
 On 29 February, it was reported that the NIH wanted the biosecurity review board
to reconsider the fate of two unpublished studies of the H5N1 avian flu virus in
light of new data and clarifications. On 1 March it was reported that the Vice Chair
of the US House Committee on Science, Space, and Technology, sent a "factfinding letter" to White House science adviser John Holdren, asking pointed
questions about how the US government has handled the controversy – and
questioning whether it should have funded the two flu studies. He said that the
request that a government advisory board conduct a second review of the two
studies "only adds to the confusion” and that “an ad hoc approach is inadequate to
balance the priorities of public health and the free flow of academic ideas."
 In a 7 March letter to the Dutch parliament, the country's minister of Public Health,
Welfare and Sport, Dr.E.I.Schippers, said an export permit is required for
dissemination of detailed information about the H5N1 virus outside the European
Union. If such a permit were requested for the full publication of the study by
Dr.Ron Fouchier and colleagues, the government would consider the health and
safety risks of granting it.
 On 29 March the US government issued a new policy requiring federal agencies to
review federally-funded research (present and future) where it involved any of 15
pathogens/toxins deemed to be of “high consequence”.
 In late March the NSABB reversed its January decision and said that the two
papers describing experiments with the bird flu virus should be published in
uncensored form.
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At the end of April, the Dutch government granted Dr Fouchier an export licence
which allowed him to submit his paper to Science.
Influenza in birds.
 In a set of articles published in March in Nature46, influenza experts say global flu
surveillance—especially in poultry and swine—needs a major overhaul. They say
current efforts are sparse, erratic, crisis-driven and geographically imbalanced.
 At the beginning of February, several Asian countries including Hong Kong and
Japan temporarily banned some poultry imports from Victoria, following an
outbreak of avian flu at a duck farm. Japan banned poultry imports from all parts
of Australia. The ducks tested positive to a low pathogenic strain of the virus.
 Henry Wan of Mississippi State University has uncovered the first molecular
evidence definitively linking live poultry markets in China to human H5N1 avian
influenza.
 In Nature in March, influenza experts wrote that global flu surveillance—especially
in poultry and swine—needs a major overhaul. Current efforts are sparse, erratic,
crisis-driven and geographically imbalanced.
Strains circulating in humans:
 An ongoing swine flu (influenza A/H1N1pdm09 virus infection) outbreak has been
raging in Mexico. Three seasonal viruses are currently being transmitted in
Mexico – AH1N1, AH3N2 and influenza B – but the AH1N1, or swine flu, is the
predominant one, with 91% of both the infections and deaths. The US CDC has
warned that the A(H3N2)v swine flu strain that began infecting Americans last
September has potential for human-to-human transmission and resembles viruses
with pandemic potential. WHO recommendations for the northern hemisphere
influenza vaccine for the 2012-13 winter are: an A/California/7/2009
(H1N1)pdm09-like virus; an A/Victoria/361/2011 (H3N2)-like virus; and a
B/Wisconsin/1/2010-like virus.
 In February the Vietnamese Heath Ministry quoted sources from the Ho Chi Minh
City Pasteur Institute confirming that a new kind of porcine A/H3N1 influenza virus
has appeared, apparently a reassortment of the swine-related A/H1N1 influenza
virus and the A/H3N2 influenza virus. The medical sector has monitored 10
patients infected with (a) A/H3N2 influenza virus of porcine origin and found that
three of them had not had direct contact with any diseased pigs. Therefore, the
sector has not ruled out the possibility of a mutation in the (porcine) A/H3N2 strain
which could lead to transmission between humans instead of strictly from pigs to
humans as previously.
 Scientists have identified a genetic flaw that may explain why some people are
more ill with flu than others47.
Development of influenza vaccines
 Baxter announced in March that the European Commission has granted marketing
authorisation for VEPACEL in all European Union Member States, as well as
Iceland, Liechtenstein and Norway. VEPACEL is a pre-pandemic influenza
vaccine indicated for active immunization in adults 18 years and older (including
immune compromised and chronically ill patients) against the H5N1 subtype of
influenza A (A/Vietnam1203/2004), commonly known as bird or avian flu. Prepandemic vaccination provides a level of protection against an emerging highly
pathogenic influenza strain prior to an officially-declared pandemic. Prof. Hartmut
Butler D. “Flu surveillance lacking”. Nature 2012 Mar 29;483(7391):520-2 Farrar J. “H5N1 surveillance: shift
expertise to where it matters”. (Commentary) Nature 2012 Mar 29;483(7391):534-5 Guan Y, Webby R, Capua I,
Waldenstrom J. “How to track a flu virus: four experts pinpoint ways to improve monitoring of H5N1 influenza in the
field.” (Commentary) Nature 2012 Mar 29;483(7391):535-6 Nature editors. “Must try harder”. (Editorial) Nature 2012
Mar 29;483(7391):509-10
46
47
Everitt AR, Clare S, Pertel T, et al: IFITM3 restricts the morbidity and mortality associated with influenza. Nature.
2012 Mar 25. doi: 10.1038/nature10921.
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48
J. Ehrlich of Baxter’s BioScience business said “VEPACEL offers cross-protection
against a broad range of H5N1 strains. It also results in a sustained
immunological memory response, meaning that those who receive a ‘booster’ with
a different pandemic strain vaccine will gain a rapid protective response to the
pandemic virus.” VEPACEL is claimed to have the potential to generate a broader
immune response than conventional egg-derived vaccines due to its use of
Baxter’s proprietary Vero cell technology, which allows for use of the natural
influenza virus (identical in protein composition to the virus circulating in nature) in
vaccine production. Unlike traditional egg-grown influenza vaccines, eggs are not
used in the VEPACEL manufacturing process, which may be of significance for a
vaccine protecting against an avian influenza strain where the bird flocks needed
for egg-based vaccine production may be adversely affected by the virus.
A Vietnamese company said in February that it has succeeded in creating
effective human vaccines against both avian influenza A/H5N1 and A/H1N1
viruses.
Astellas Pharma and UMN Pharma announced that immunogenicity and
favourable tolerability have been observed in the Phase II clinical trial for the H5N1
recombinant influenza HA vaccine ASP7373. This vaccine has been produced by
the cell-culture manufacturing method employing the Baculovirus Expression
Vector System.
Indonesia is aiming to manufacture its first, locally produced vaccine to combat the
H5N1 avian influenza virus by 2013, with state-owned pharmaceutical company
PT Biofarma working to prepare its facilities for developing the vaccine for
production.
Inovio Pharmaceuticals announced in January that its synthetic vaccines for
influenza Type A H3N2 and Type B achieved protective antibody responses in
immunized animals against multiple unmatched strains48.
BiondVax Pharmaceuticals Ltd of Israel announced positive results from its
second Phase II clinical trial (BVX-005) of the Universal Influenza Vaccine
(Multimeric-001). The CEO said the trial confirmed that the vaccine “is not only
safe and immunogenic on its own but also enhances the performance of traditional
strain-dependent flu vaccines in the elderly when given in a prime-boost regimen."
Researchers at Oxford and Southampton Universities, and Retroscreeen Virology
Ltd, have discovered a series of peptides, found on the internal structures of
influenza viruses that could lead to the development of a universal vaccine for
influenza.
Injecting vaccines just under the skin may get a better immune response. Now
virtually painless microneedle patches, tiny toothed patches loaded with vaccine,
have been designed to get the right dose to the right place49.
Inovio previously reported that its H5N1 synthetic vaccine achieved hemagglutination inhibition (HI) titers against six
unmatched strains of this influenza subtype in a Phase I human study. The new flu data was highlighted by Dr. Mark
Bagarazzi, Inovio's Chief Medical Officer, at Phacilitate Vaccine Forum Washington 2012. The H3N2, H1N1, and Type
B influenza strains represented in each year's seasonal influenza vaccine are updated annually, but protect only
against a single strain within each of these subtypes. When the selected strain(s) mutates, the annual vaccine may not
provide protection, as witnessed with the 2009 swine flu H1N1 pandemic. There is consequently a global need for a
universal vaccine able to provide longer term protection against all existing and potential new strains within the
influenza subtypes of concern to humans. "These new data for H3N2 and Type B in animal models further validate our
strategy to develop a universal vaccine to prevent known and unknown influenza strains, as well as our entire SynCon
platform. We have in animals provided protection against all of the circulating influenza strains of the last 10 years,"
said Dr. J. Joseph Kim, Inovio's President and CEO. "We expect additional H5N1 human data by the end of the first
quarter and look forward to human data from our combined H5N1 + H1N1 vaccine in the second quarter of 2012. We
expect that data from these studies, coupled with this positive data for H3N2 and Type B, will enable us to launch a
clinical study of a comprehensive universal influenza vaccine in 2013."
49 The researchers from Emory School of Medicine and Georgia Institute of Technology used the microneedle patch to
deliver a flu shot to mice, and saw a rise in cytokine (cell signalling molecules) levels in the area where the shot was
delivered. The role of cytokines is to recruit immune cells, which then respond to the antigens (viral targets) in the
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Influenza pandemics
 A recent article50 suggested that weather patterns could have an influence on the
spread of epidemics like that of the H1N1 influenza virus which broke out in
Mexico and the US in 2009. Researchers examined the four most recent human
influenza pandemics (1918, 1957, 1968 and 2009) and found that each pandemic
occurred in spring or early summer and was preceded by below-normal sea
surface temperatures, indicative of the La Niña phase51. Wild birds are thought to
be the primary reservoir of influenza A viruses and facilitate the new pandemic
lineages through the introduction of virus to domestic animals and humans.
Migratory birds, are considered to be particularly implicated in the mixing and
reassortment of influenza virus genomes.
 On 2 April, Canada, Mexico, and the United States unveiled a new "North
American Plan for Animal and Pandemic Influenza" at the North American
Leader's Summit in Washington, D.C52. Two days later health officials in Europe
released a report on changes to pandemic plans European countries are
considering based on lessons learned during the 2009 pandemic.
 How H5N1 replicates
 Recent research53 on highly pathogenic avian influenza H5N1 viruses identifies a
mechanism of virulence used by H5N1 to cause acute respiratory lung disease,
where blood and fluid seeps out of blood vessels in the lung and into the
airspaces, preventing patients from oxygenating tissues. The virus must interact
with human cells, where it replicates and is released in higher numbers. Research
shows that H5N1 replicates in cells that line blood vessels and is released into the
bloodstream, allowing the virus to spread. Of great concern is that other emerging
influenza strains will adapt the strategy of H5N1 to replicate in endothelium.
c. Infectious Diseases: Other
 Prions
 French researchers found that prions are more easily able to jump between
species than has been previously thought54. Prions from other species, implanted
in the brains of mice, showed up in other organs after a period, suggesting that
brain autopsies are not sufficient to detect the presence of the disease. British
neurology researcher Professor John Collinge has also published a perspective on
the topic in the same journal.
 In January, neurologists across Britain were told by the NHS National Prion Clinic,
part of the University College London Hospitals Trust, and the Medical Research
Council's Prion Unit that a new blood test is now available for vCJD. Until now the
vaccine. Another feature of this vaccination is that the antigens remain in the skin longer, which may help their take-up
by the immune cells, which then move away from the skin.
50 Jeffrey Sharman and Marc Lipsitch, The El Niño-Southern Oscillation (ENSO) – Pandemic Influenza Connection:
Coincident or Causal? Proceedings of the National Academy of Sciences, the official journal of the United States
National Academy of Sciences (NAS) January 2012.
51 La Niña is the cold phase of ENSO, a cyclical climate phenomenon that affects weather patterns around the world
and forms part of the system that regulates heat in the eastern tropical Pacific Ocean.
52 The North American plan for the first time extends pandemic planning framework to a broad range of sectors,
including health, agriculture, security, and foreign affairs, the US Department of Health and Human Services (HHS)
said in a press release. "Collaboration among these partners is vital for a faster response to pandemic threats," the
agency said. The 78-page plan describes how the countries will develop and implement actions to strengthen trilateral
response capabilities, including surveillance and early warning of disease outbreaks and protocols for transporting
laboratory samples. HHS said Canada, Mexico, and the United States also agree to conduct joint epidemiologic
investigations of viruses that have pandemic potential, including animal influenza outbreaks that pose zoonotic disease
threats.
53 Published in the American Society for Microbiology’s Journal of Virology in January (see
jvi.asm.org/content/86/2/667.abstract). Dr Troy Stevens, professor of pharmacology and internal medicine and director
of the Center for Lung Biology, and Dr Ron Balczon, Associate Professor of Cell Biology and Neuroscience and a
Member of the Center for Lung Biology, co-authored the article along with Dr Terrence Tumpey, a Senior Microbiologist
at the Centers for Disease Control and Prevention in Atlanta.
54 Béringue, V., Herzog, L., Jaumain, E. et al. Facilitated Cross-Species Transmission of Prions in Extraneural Tissue.
(2012). Science. 335: pp. 472-475. Accessed 23 February 2012.
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55
only way of confirming the diagnosis has been through tonsil biopsies or after the
patient has died when brain samples can be taken. Professor Collinge, who is
leading the MRC team, said that the blood test was "extremely good news".
 Scientists from the Florida campus of The Scripps Research Institute have
identified a single prion protein that causes neuronal death similar to that seen in
“mad cow” disease, but is at least 10 times more lethal than larger prion species.
This toxic single molecule or “monomer” challenges the prevailing concept that
neuronal damage is linked to the toxicity of prion protein aggregates called
“oligomers”.55
Other
 Doctors in February reported the first known case of legionnaires’ disease, caused
by a visit to the dentist56. Previous research has shown that dental waterlines can
be contaminated, but this is the first known case where illness has occurred. NSW
has recorded a number of cases of legionnaires’ this year, eight of them in
Western Sydney in February. In the six weeks to 3 April, nine cases of
legionnaires' disease were recorded in the Auckland region, where the normal rate
would be one or two cases in six weeks.
 In February, Australia’s Department of Immigration and Citizenship reported that
two people who arrived at Christmas Island on separate boats had been
diagnosed with typhoid.
 The US CDC says Clostridium difficile is a threat across all medical facilities, not
just hospitals. Hand sanitizer does not kill the bacteria.
 Viral Genetics announced in March that it has submitted a pre-IND57 briefing
document to the FDA for its Lyme Disease drug candidate, VGV-L. The company
claims it is the first novel drug candidate proposed for study in the treatment of
chronic Lyme disease post-infection in quite some time. “It represents the second
drug candidate we have developed from our licensed Targeted Peptides platform”
said Haig Keledjian, President of Viral Genetics. “Within the single Targeted
Peptides platform, we are also developing candidates for treatment of sepsis,
staphylococcus and streptococcus infection, multiple sclerosis and other
conditions, while we continue to complete IND-enabling preclinical testing for our
HIV/AIDS candidate.”
 Conflict and political struggles have caused massive human and animal
migrations in the Middle East and North Africa. A new study blames these
upheavals for the spread or re-emergence of a variety of tropical diseases.
Neglected Tropical Diseases (NTDs) traditionally affect poor countries, but are
now also prevalent in middle-income countries, such as Egypt, Saudi Arabia,
Morocco and Yemen. “Cutaneous leishmanaisis, Dengue, Rift Valley fever,
Crimean Congo hemorrhagic fever” said Dr. Peter Hotez of the National School
of Tropical Medicine, listing some of the diseases. “Neglected Tropical Diseases
disproportionately affect Egypt and Yemen. These two countries have some of
the greatest number of cases of intestinal worm infections, elephantiasis, and
schistosomiasis, as well as diseases such as fascioliasis. Researchers also
were surprised by the re-emergence of infections like cutaneous leishmaniasis,
caused by a sandfly, and infections transmitted from animals to humans, such as
brucellosis – a bacterial infection originating in cattle and sheep. Hotez said the
immediate strategy for controlling the rising infection rate is to step up mass drug
The study was published in February in an advance, online edition of the journal Proceedings of the National
Academy of Sciences. In addition to the insights it offers into prion diseases such as “mad cow” and a rare human form
Creutzfeldt-Jakob disease, the study opens the possibility that similar neurotoxic proteins might be involved in
neurodegenerative disorders such as Alzheimer’s and Parkinson diseases.
56 Ricci ML, Fontana S, Pinci F, et al. Pneumonia associated with a dental unit waterline. The Lancet 2012; 379 (9816):
684].
57 Investigational new drug
administration efforts, especially for schistosomiasis, intestinal helminthes
infections, and leprosy.

58
Vaccines
 In the US an adenovirus vaccine made by Barr Laboratories has been approved
for Department of Defense personnel entering basic training. It is regarded as
successful in reducing the number of colds with fever.
 The Bill & Melinda Gates Foundation has committed $US220 million for the next
five years to Rockville-based Aeras, a nonprofit developing new vaccines for
tuberculosis. Aeras announced that NIAID will join in support of clinical testing for
the new vaccine. Aeras, Dutch biopharmaceutical Crucell and NIAID, will partner
for the Phase II proof-of-concept clinical trial. The trial, initiated, is to evaluate the
safety and efficacy of the Tuberculosis vaccine candidate known as AERAS402/Crucell Ad35 in HIV-uninfected infants. It is scheduled to take place at three
sites in Kenya, South Africa and Mozambique. In addition, the partnership has
received support from the European and Developing Countries Clinical Trials
Partnership and from members of the European Union.
 A University of Georgia researcher believes he is close to developing the first
Chagas disease vaccine for pets, to limit the spread of disease to humans. While
“kissing bugs” are ultimately responsible for passing the disease on to humans,
the bugs that live in homes don't normally carry the disease unless they bite the
family pet. Pets are likely to become infected from bugs living in shrubs, woods,
kennels or barns. These animals then expose kissing bugs already nesting in
homes to the T. cruzi parasite.
 Inovio Pharmaceuticals announced on 13 March that it achieved strong T cell
immune responses in a Phase I clinical study of PENNVAX®-B, its product for the
treatment of the HIV subtype prevalent in North America and Europe, in HIVpositive subjects58.
These interim results were presented by Dr. Niranjan Y. Sardesai, Inovio's Chief Operating Officer, at the Vaccine
World Summit 2012 in Hyderabad, India in a talk titled, "New Development Paradigms and Vaccine Innovation for
Infectious Diseases."