MONITORING INTERNATIONAL TRENDSposted January 2013

The NBA monitors international developments that may influence the management of blood and blood products in Australia. Our focus is on:

Potential new product developments and applications; and Global regulatory and blood practice trends; and Events that may have an impact on global supply, demand and pricing, such as changes in

company structure, capacity, organisation and ownership; and Other emerging risks that could potentially put financial or other pressures on the Australian

sector.A selection of recent matters of interest appears below:

ProductsHere the NBA follows the progress in research and clinical trials that may within a reasonable timeframe make new products available, or may lead to new uses or changes in use for existing products.

a) The 54th Annual Meeting and Exposition of the American Society of Hematology (ASH) was held in Atlanta, Georgia in December 2012. Amongst the presentations:

a. Baxter International announced Phase I/III study results evaluating the safety and efficacy of BAX 326, an investigational recombinant factor IX (rFIX) protein, for the treatment and prophylaxis of bleeding episodes for patients with hemophilia B over 12 years of age. BAX 326 was recently granted orphan-drug designation by the U.S. Food and Drug Administration (FDA), a special status given to a product that when approved, will address an unmet need for people with a rare disease or condition. Data supporting the prophylaxis indication, which is the basis for the orphan drug designation, was included in the biologics license application (BLA). The Phase I/III prospective, controlled, multicentre study investigated the pharmacokinetics, efficacy and safety of BAX 326 in 73 previously-treated patients with severe or moderately severe hemophilia B. Results from the study showed that twice-weekly prophylactic treatment with BAX 326 achieved a median annualized bleed rate of 1.99 with 43 percent of patients experiencing no bleeds1.

b. Inspiration Biopharmaceuticals announced interim clinical results for two products- its intravenous recombinant porcine factor VIII (OBI-1) for treating serious bleeds in acquired hemophilia A2; and rFIX (IB1001) for treating and preventing bleeding in haemophilia B in children under 123.

1 No inhibitors were detected and no cases of anaphylaxis were reported in any patients. Mild and transient treatment-related adverse events were reported in 2 of the 73 patients. 2 The poster Recombinant B-domain deleted porcine FVIII (OBI-1) safety and efficacy in acquired hemophilia A: interim results referred to the prospective Phase II/III trial of OBI-1 in serious bleeds. Sixteen acquired haemophilia A (AHA) subjects were all judged by the investigator to have had either effective or partially effective control of serious haemorrhage 24 hours after the initial dose, and subsequent resolution of their bleed. There were 11 serious adverse events to September 2012 and 5 deaths were reported, with none of the deaths being attributed by the investigator to OBI-1. One serious adverse event (pneumonia and atrial fibrillation) was deemed by the investigator to be probably not/remotely related to OBI-1. Antibodies to OBI-1 developed in 3 subjects. No specific treatment was given for the anti-OBI-1 antibodies. These interim results were interpreted as suggesting that in this study OBI-1 was well-tolerated and effective in the treatment of serious bleeding episodes in AHA.

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i. Inspiration will file a BLA for OBI-1 in the first half of 2013. OBI-1 has orphan drug designation in the US and EU, has fast track designation from the FDA. This designation is for a drug intended to treat a serious disease and which has a potential to fill an unmet medical need. It may receive priority review (eight months).

ii. Inspiration filed a marketing authorization application in Europe for IB1001 late in 2011 and a BLA license application in the US for IB1001 in the first half of 2012. Regulatory reviews are ongoing4.

iii. Ipsen and Inspiration made some changes in their partnership arrangements in 2012. In January 2013, Baxter announced it will be acquiring OBI-1 and related assets.

c. Alnylam Pharmaceuticals presented new pre-clinical data from its RNAi therapeutic program for the treatment of haemophilia and other bleeding disorders. Data showed that ALN-AT3, a subcutaneous RNAi therapeutic targeting antithrombin (AT), delivers “potent, dose-dependent, and durable knockdown of AT in non-human primates with an up to four-fold increase in thrombin generation”. The company said the drug is expected to be subject to an investigational new drug filing in mid-2013.

d. AesRx announced data from its Phase I study for its drug Aes-103 shows the treatment is safe and well-tolerated for patients with sickle cell disease. The drug has orphan drug status from the FDA.

e. Emmaus Medical discussed its sickle cell research. It had earlier announced the completion of patient enrolment for its Phase III trial to study L-glutamine as a treatment for sickle cell anemia and beta-thalassemia. L-glutamine therapy for these conditions is a patent protected treatment, which has orphan drug status in both he US and Europe. It has fast track designation from the FDA.

f. Acetylon Pharmaceuticals announced results from a preclinical study of a selective histone deacetylase (HDAC) 1/2 inhibitor for the treatment of sickle cell disease and beta-thalassemia. The study results suggest that selective inhibition of the epigenetic regulators of gene expression, HDACs 1 and 2, could represent a refined and targeted approach for the treatment of both conditions through the induction of disease-corrective foetal hemoglobin in human red blood cell progenitors.

3 The poster IB1001, an investigational recombinant factor IX, pharmacokinetics in pediatric patients with hemophilia B reports preliminary pharmacokinetic data from 7 subjects. Compared with findings previously reported by Martinowitz U, et al. in subjects 12 years of age and older, these pediatric subjects demonstrated a more rapid metabolism of rFIX with a shorter terminal half-life and a lower in vivo recovery. Results resemble those reported by Berntorp, et al (Haemophilia, 7, 2001) with nonacog alfa. 4 The FDA placed a clinical hold on IB1001 in July 2012 when a number of study subjects developed antibodies to the host cell protein, Chinese hamster ovary cell proteins (CHOP). No clinical sequelae were associated with these antibodies and they were claimed not to limit the clinical effectiveness of the product. Inspiration said it has made significant progress in addressing the situation, and intends to submit data to the FDA in the first part of 2013.

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g. Amgen presented data from several studies5. These included data evaluating long-term use of Nplate (romiplostim) in paediatric chronic immune thrombocytopenia (ITP).

h. Noxxon Pharma presented Phase 1 results for its anti-hepcidin NOX-H94 to treat anaemia associated with chronic disease. Excessive concentrations of the peptide hepcidin occur in chronic diseases such as cancer, renal disease, and inflammatory diseases. These concentrations lead to iron restriction, or functional iron deficiency where iron is trapped in its cellular stores and is unavailable for haemoglobin synthesis. NOX-H94 binds to and inactivates hepcidin. The Phase I program consisted of a comprehensive single and multiple ascending dose study in healthy volunteers and a subsequent human pharmacodynamic study to assess the ability of NOX-H94 to prevent endotoxin-induced hypoferraemia in healthy subjects. This study delivered the first clinical evidence that NOX-H94 is capable of neutralizing high levels of hepcidin in humans and maintaining higher serum iron concentrations compared with subjects receiving placebo. Noxxon Pharma has begun a Phase IIa clinical trial in Europe in anaemic patients with cancer.

b) Arsenal Medical won a $US15.5 million contract from the US Defense Advanced Research Projects Agency (DARPA) to develop a foam for battlefield use to stem internal bleeding for at least an hour while a patient is transferred to a field hospital. This is to support late-stage development as well as funding work to achieve FDA approval. Arsenal’s long-term goal is to develop the product for civilian use for severe trauma. Pre-clinical data was presented at the 2012 annual meeting of the American Association for the Surgery of Trauma in Kauai. The data demonstrated the foam can treat severe haemorrhage for up to three hours in a lethal model of liver injury. The product could reduce blood loss six-fold and increase survival three hours later from 8 percent to 72 percent.

c) Bayer's BAY 86-6150, a recombinant factor VIIa, is the subject of a Phase II/III study called TRUST (TReatment with Unique recombinant rFVIIa STudy). This will evaluate the safety and efficacy of the compound in patients with haemophilia A or haemophilia B who have developed inhibitors (neutralizing antibodies to clotting factor therapies). Part A of the trial involves sequential dose escalation and assessment of dose response and the pharmacokinetics and pharmacodynamics evaluation. Part B is to confirm efficacy and safety.

d) Kamada announced positive results of the Phase I/II clinical trial of its Alpha-1 Antitrypsin (AAT) protein, the active ingredient in its drug, Glassia, for the treatment of type 1- juvenile onset- diabetes. Analysis of the results found that the AAT protein

5 Long-Term Use of Open-Label Romiplostim in Children with Chronic/Refractory Immune Thrombocytopenia (ITP): Results from an Open-label Phase 1/2 Randomized Double-blind Placebo-controlled Study. Lead Author: James B. Bussel, Department of Pediatrics, Division of Hematology, Weill Medical College of Cornell University, New York, NY; Abstract No. 621Integrated Analysis of Long Term Safety in Patients (pts) with Chronic Immune Thrombocytopenia (ITP) Treated with Romiplostim: Results from a Safety Analysis of Pooled Data from ITP Romiplostim Clinical Studies. Lead Author: Douglas B. Cines, Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA; Abstract No. 2185A Systematic Literature Review and Meta-Analysis of the Risk of Thromboembolic Events in Patients with Immune Thrombocytopenia (ITP) in Observational Studies: Results from a Systematic Review and Meta-Analysis of Randomized Controlled Trials of Thrombopoietin-receptor Agonists (TPOr). Lead Author: Wendy Langeberg, Amgen, Thousand Oaks, CA; Abstract No. 2187Romiplostim for the Treatment of Adults with Primary Immune Thrombocytopenia (ITP) in Routine Clinical Practice – Interim Results From a Large, European, Observational Study. Lead Author: Dominik Selleslag, Department of Hematology, AZ St-Jan, Brugge, Belgium; Abstract No. 3316. Abstracts were made available on the ASH website at www.hematology.org

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may halt the progression of diabetes. It enables the pancreas beta cells to continue excreting insulin, providing better glucose balance, thereby lowering or even preventing serious future complications of the disease. In view of the success of the trial and its results, Kamada is preparing further development of injectable AAT for the treatment and curing of juvenile onset diabetes, and to move for regulatory approval. Most patients in the trial reported reduced use of insulin, and there was a corresponding reduction in the level of specific diabetes antibodies, which may indicate a reduction in the autoimmune response in the pancreas.

e) Novo Nordisk in November introduced HemaGo, a mobile application for people with haemophilia and their carers to monitor medications and dosing, details of their bleeds, their pain, and the impact of haemophilia on the rest of their lives.

b) FibroGen and Astellas Pharma in December announced the commencement of a Phase III trial of FG-4592/ASP1517 for treatment of anaemia in chronic kidney disease (CKD) patients. The inhibitor of hypoxia-inducible factor prolyl hydroxylase demonstrated the potential to maintain haemoglobin levels, without any intravenous iron supplementation, in CKD patients who are not on dialysis, and in end-stage renal disease patients on dialysis.

f) Halozyme Biotherapeutics works with human enzymes to modify biotechnology medicines for administration by injection rather than intravenously. Its recent agreement with Pfizer includes a licence to develop two specific treatments, and the right for Pfizer to select up to four other targets.

g) CSL, which markets Beriplex, a four-factor prothrombin complex concentrate (PCC), sponsored a study which found Beriplex superior to plasma for urgent reversal of warfarin and other vitamin K antagonists in patients experiencing major bleeding. Dr. Joshua N. Goldstein of the University of Rochester, NY, told the annual meeting of the American College of Emergency Physicians that Beriplex had a higher rate of INR6 reversal than did plasma at 30 minutes after the start of infusion, based on the Phase IIIb prospective, multicentre, randomized clinical trial. Beriplex was also shown to be superior to plasma at early replacement of depleted coagulation factors and was noninferior to plasma in terms of blinded investigator–rated haemostatic efficacy in the first 24 hours7.

Regulatory MattersThe NBA monitors overseas regulatory decisions on products, processes or procedures which are or may be of relevance to its responsibilities.

6 International normalized ratio, a laboratory test measure of blood coagulation.7The study included 202 adults on warfarin or another vitamin K antagonist who presented with acute major bleeding. The objectives were to correct their INR as quickly as possible and thereby reduce their blood loss. Participants were randomized to INR- and weight-based dosing of the PCC or to plasma on top of background vitamin K given by slow intravenous infusion in all cases. Thirty minutes after the start of the infusion, the mean INR was significantly lower in patients on the PCC than in those given plasma. The higher the baseline INR, the greater was the benefit of the PCC. One hour after the start of infusion, roughly 70 percent of PCC recipients had corrected their INR as defined by an INR of 1.3 or less, compared with less than 5 percent of plasma recipients. Median factor levels were below 50 percent at baseline. Levels increased significantly more within 30 minutes of starting PCC infusion than with plasma. Dr Goldstein observed this wasn’t particularly surprising, since the PCC contains factors II, VII, IX, and X, along with proteins C and S. Blinded investigators rated haemostatic efficacy in the first 24 hours as good or excellent in 72 percent of the PCC group and in 65 percent of patients on plasma, a nonsignificant difference. Thromboembolic event rates through 51 days of follow-up were 7.8 percent with the PCC and 5.5percent with plasma. Dr. Goldstein serves as a consultant to and advisory board member for CSL Behring.

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a) In a Safety Communication on 13 November 2012 the FDA updated information on the risks of thrombosis and haemolysis potentially related to administration of intravenous, subcutaneous and intramuscular human immune globulin products. This follows the FDA Interim Statement Regarding Immune Globulin Intravenous (IGIV), of August 22, 2002, regarding thrombotic events following infusion. The FDA says it continues to investigate whether or not specific characteristics of immune globulin products such as excipients, concentration, or trace procoagulant activity account for an increased risk of thrombosis.

b) Biotest received FDA approval for its polyspecific intravenous immunoglobulin Bivigam for the treatment of patients with primary humoral immunodeficiency. The approval was based on a Phase III study in 63 patients. Participants received 300–800mg/kg of IVIg every three or four weeks for a year. The primary efficacy endpoint was demonstration that the rate of acute serious bacterial infections was <1.0 per person-year. The study achieved its primary endpoints for safety, efficacy, and tolerability. Bivigam will be available in a 10% liquid in 50mL and 100mL vials.

c) The FDA approved Cangene’s Varizig for reducing the severity of chicken pox in high risk individuals when given within four days of exposure. Varizig is a varicella zoster immune globulin preparation.

d) The FDA approved GlaxoSmithKline’s Promacta (electrombopag) for the treatment of thrombocytopenia (low blood platelet counts) in patients with chronic hepatitis C to permit them to initiate and maintain interferon-based therapy.

e) Novartis received approval from the European Commission for Exjade, its oral drug used to reduce iron overload in patients undergoing chelation therapy for non-transfusion-dependent thalassemia, or NTDT, syndrome. The pivotal study, THALASSA, showed a significant dose-dependent decrease in concentration of iron-burden in the body as well as liver in patients on Exjade, compared with placebo. The overall adverse event rate for Exjade was similar to the placebo arm.

f) Medgenics, the developer of the Biopump, which sustains production and delivery of therapeutic proteins using a patient's own tissue, announced a patent from the US Patent and Trademark Office for the use of Medgenics’ EPODURE technology for delivery of erythropoietin (EPO). The USPTO also recognised claims for a similar method for delivery of FVIII, underpinning Medgenics’ HEMODURE Biopump technology for sustained prophylaxis in haemophilia. Claims covering EPODURE and HEMODURE were recently recognised in Australia, Japan, China, and Korea.

g) The European Medicines Agency (EMA) held its promised workshop on access to clinical-trial data and transparency. Participants included representatives of the European Federation of Pharmaceutical Industries and Associations, and the Cochrane Collaboration, which has campaigned for Roche to publish the complete raw dataset on its antiviral Tamiflu (oseltamivir). The EMA said it "is committed to proactive publication of clinical-trial data, once the marketing-authorisation process has ended. We are not here to decide if we publish clinical-trial data, but how". The EMA wants r "to build trust and confidence in the system by allowing re-analysis of clinical-trial data by stakeholders". The commitment to publication will apply only to drugs that receive marketing authorisation process from a set date, probably 1 January 2014.

h) In December the European Parliament voted in favour of introducing a unified patent system in 2014. If ratified, the new system is expected to reduce application costs and make Europe more competitive.

i) Ethicon Biosurgery received FDA approval for its EVARREST fibrin sealant patch. This is an adjunct to haemostasis for soft tissue bleeding during open retroperitoneal, intra-abdominal, pelvic and non-cardiac thoracic surgery, when control of bleeding by standard surgical methods (e.g., suture, ligature, or cauterization) is ineffective or

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impractical. EVARREST is placed upon the bleeding wound surface and manually compressed for three minutes. The human thrombin and fibrinogen initiate a fibrin clot, which integrates into the patch. EVARREST remains in the patient's body supporting the wound site as it is bio-absorbable. The patch is not for use in babies under one month of age, and is not for use in place of sutures or other forms of mechanical ligation in the treatment of major arterial or venous bleeding.

j) Amag has submitted a supplemental new drug application to the FDA for its intravenous Feraheme. The company has asked the FDA to extend the indication for the drug to all iron-deficiency anaemia patients who have failed on, or could not tolerate, oral anaemia drugs, not just to iron-deficiency anaemia patients with CKD. The application is based on data from two Phase III trials (1,400 patients).

k) Anti- coagulant Eliquis has been approved for use in the 27 European Union (EU) countries in patients who have an irregular heartbeat (atrial fibrillation) and are at risk for strokes or systemic embolisms. Eliquis, developed by Bristol-Myers Squibb and Pfizer, had already been approved in the EU in May 2011 for preventing dangerous clots from forming in deep veins after hip or knee replacement surgery. The FDA in December approved Eliquis after earlier rejections and requests for more trial data. The FDA approved the oral treatment for atrial fibrillation, in patients at risk for strokes or dangerous clots, but warned that patients with artificial heart valves should not take the drug as it had not been studied in that population.

l) Boehringer Ingelheim’s anti- coagulant Pradaxa (dabigatran) continues to attract discussion.

a. In November 2012, the FDA issued a Drug Safety Communication informing the public that the Agency has evaluated new information about the risk of serious bleeding associated with use of the anticoagulants Pradaxa and warfarin. Following the approval of Pradaxa, the FDA had received a large number of post-marketing reports of bleeding among Pradaxa users. As a result, the FDA had investigated the actual rates of gastrointestinal bleeding and intracranial hemorrhage for new users of Pradaxa compared with new users of warfarin. The indications were that bleeding rates associated with new use of Pradaxa did not appear to be higher than bleeding rates associated with new use of warfarin, consistent with observations from the RE-LY trial used to approve Pradaxa. The FDA is continuing to evaluate multiple sources of data in the ongoing safety review of this issue.

b. In December Boehringer Ingelheim said it would inform physicians that Pradaxa is contraindicated in patients with mechanical heart valves. This followed advice from regulators.

c. Australia's Pharmaceutical Benefits Advisory Committee (PBAC) advised the government that, because of new information about Pradaxa,"it is of a mind to rescind its March 2011 recommendation" that the drug be available on the Pharmaceutical Benefits Scheme (PBS). A report on the use of anticoagulant therapy was prepared for the government by Emeritus Professor Lloyd Samson. The report says more work is needed before new oral anticoagulants (NOACs) such as Pradaxa can be listed on the PBS. He found actual use of Pradaxa had not matched the clinical trial evidence presented to the PBAC in March 2011, including the average age of patients, the dosage, and the treatment they would otherwise be receiving. In light of this clinical information, the review concluded that the net benefit of NOACs in clinical practice and the subsequent impact on cost-effectiveness "is uncertain." Boehringer Ingelheim and the sponsors of other NOACs will be able to make submissions to the March meeting.

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m) Cerus Corporation said the FDA had accepted its proposed modular pre market approval application for the INTERCEPT Blood System for plasma. A PMA shell outlines the structure, content and timing of each module, and will allow Cerus to leverage its existing regulatory dossier from European approvals. It will begin the INTERCEPT plasma submission early in 2013. Carol Moore, Cerus' Vice President, Regulatory Affairs, Quality and Clinical, said: "FDA's agreement with our proposal means that we can target completing all four modules in 2013, putting us in a position to receive US approval as early as 2014.”

n) Australia’s Therapeutic Goods Administration(TGA) has approved a 30-minute test for HIV for use in sexual health clinics.

o) The EMA’s Committee for Medicinal Products for Human Use (CHMP) recommended new instructions for fibrin sealants such as Tisseel, Tissucol, Artiss and Beriplast P to ensure their safe use when applied as spray during surgery. This follows reports of gas embolism with Evicel and Quixil in association with the use of spray devices that use a pressure regulator. Amongst the recommendations were that product information advise recommended pressure and distance for spray use.

Market Structure and Company NewsThe 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 considered include suppliers, potential suppliers and developers of products which may be of interest.

a) The first of CSL’s new buildings from a $A250 million investment at Broadmeadows will begin production of biopharmaceuticals early this year. rF IX is scheduled for 2013, with the immunoglobin Privigen scheduled to be produced in 2015. CSL’s Australian plasma business, previously within CSL Biotherapies, is now part of CSL’s global plasma business, CSL Behring, creating a globally-integrated supply chain for the complete portfolio of plasma and recombinant protein products. Other areas of CSL Biotherapies’ business - vaccines, pharmaceuticals and in-vitro diagnostics – are now operating as bioCSL. CSL Behring in Australia will be led by Dr Simon Green and bioCSL by Dr John Anderson.

b) Sanguine, an innovator in perfluorocarbon (PFC) based therapies, in December announced its intention to acquire New Alliance Pharmaceuticals. New Alliance holds an exclusive license for Oxygent, a PFC product with 20 clinical studies and around 250 preclinical studies already completed.

c) Grifols’ shareholders in December approved a bonus share issue.d) Cerus signed a two-year agreement with two Swiss Red Cross Blood Services -

Lausanne and Zurich- for deployment of the INTERCEPT Blood System for plasma. These two centres supply around 15,000 plasma units annually.

e) Cangene Corporation in December reported financial results for the quarter which ended on October 31, 2012. Revenues for the quarter were $C36.5 million, compared with $C21.5 million in the same quarter of the previous year. The increase was largely attributable to revenue from US government stockpiling contracts. There were lower research and development expenses because of the cancellation of intravenous immunoglobulin development.

f) Johnson & Johnson has invested in biological sealant developer Lifebond as part of the company's $US 20 million third financing round. Lifebond’s co- chairman is Robert Taub, who founded Omrix Biopharmaceuticals which Johnson and Johnson

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acquired for $US425 million in 2006. Lifebond's flagship product is a surgical sealant for tissue after surgery to shorten the bowel. It partly competes with Omrix.

g) Amgen agreed to buy the genetic-research company DeCode Genetics for $US415 million to help it develop new medicines that target defective DNA. The all-cash deal will give Amgen access to Iceland-based DeCode’s technology used to sequence human genomes. DeCode’s research enables it to identify genetic variants that may be linked to a disease or disorders such as cancers or heart disease.

h) The Medicines Company and Bristol-Myers Squibb have signed a global licence and two year collaboration for Recothrom. Recothrom is a recombinant thrombin approved by the FDA for use as a topical haemostat to control non-arterial bleeding during surgical procedures. As part of the agreement, The Medicines Company will make Bristol-Myers Squibb an upfront collaboration payment, an upfront option fee and a tiered royalty on annual net revenues from Recothrom during the two-year collaboration period. Bristol-Myers Squibb will manufacture Recothrom and act as exclusive supplier to The Medicines Company during the agreement term.

i) Eisai is collaborating with University College, London in drug discovery and development, focussing on neurological diseases such as Alzheimer’s, Parkinson’s and other related disorders. Meanwhile, Biogen Idec has leased some of Eisai's facility in Research Triangle Park in North Carolina to manufacture oral solid dose products for both companies The 10-year lease agreement gives Biogen the option to purchase the plant. Some 50 Eisai personnel are expected to become Biogen employees in early 2013.

Country- specific EventsThe NBA is interested in relevant safety issues which arise in particular countries, and also instances of good practice. We monitor health issues in countries from which Australia’s visitors and immigrants come.

a) The Australian Competition and Consumer Commission (ACCC) decided to authorise Medicines Australia’s latest Code of Conduct for two years - rather than the five years sought. Under the Code’s new edition member companies will, for the first time, disclose aggregate payments made to doctors and consumer groups.

b) The Scottish Government has approved the business case for a £36.4 million centre for the Scottish National Blood Transfusion Service, to be constructed at Heriot Watt Research Park near Edinburgh, and to be completed in 2017. It will centralise the testing and processing of blood and tissue donations.

c) Victor Grifols has said that he is not willing to invest any more in Spain “if things don’t change.” In media comments, Sr Grifols said that unless there is change, he envisages moving to the US.

d) In the US, a meningitis outbreak arising from tainted steroid injections prepared by a compounding pharmacy had reached 620 cases by 17 December with 39 fatalities.

e) Fewer black women in the US are being infected with HIV, but the number of young gay and bisexual men infected is rising, the Centers for Disease Control and Prevention announced in December.

f) The US PreventiveServices Task Force in November said everyone aged 15 to 65 should be tested for the virus that causes AIDS. Previously it recommended screening only those at high risk, but percent of people with HIV don't know, and early treatment can prolong lives and greatly reduce spread of HIV.

g) In November Canadian Blood Services revealed that it expected to replace the lifetime ban on gay men donating blood with a deferral system. The plan submitted

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to Health Canada proposed that men who had not had sex with other men for somewhere between five to ten years would be eligible.

h) Mexico has implemented new blood donation regulations screening donors based on sexual history rather than sexual orientation. HIV- and hepatitis- negative gay or bisexual men who have histories of safe sex and are not sex workers or injecting drug users may become donors.

Safety IssuesWe follow current issues in patient safety.

a) In a study reported in the December issue of Anesthesiology8, researchers found that inhaled nitric oxide decreased tissue injury and improved short-term survival in mice who suffered haemorrhagic shock and were then resuscitated with a transfusion of stored blood.

b) Dr Michael Stark, from the University of Adelaide's Robinson Institute, has told the media that premature babies given blood transfusions have elevated levels of chemicals which can cause bowel and lung problems. "We believe that the bioactive components of packed red blood cell transfusions are initiating or amplifying these inflammatory processes in the body," he said. Researchers in January began a two-year trial at the Women's and Children's Hospital to "wash" blood in a solution just before being administered to the baby to reduce the risk of complications because their immune systems are still not fully developed.

c) Officials from the World Health Organisation (WHO), International Haemovigilance Network (IHN) and International Society of Blood Transfusion met at the Global Consultation on Haemovigilance in Dubai in November. IHN will hold a seminar in Brussels in February 2013. It will highlight achievements of countries with well- developed haemovigilance systems and will give the opportunity for others to present their challenges.

d) The British Heart Foundation is funding University of Hull researchers to investigate part of the process of blood clotting. Although clotting is normal after injury, the clumping together of platelets is also the last stage in the process that leads to a clot blocking a blood vessel in the heart or brain, leading to a heart attack or stroke. Hull researchers have found a protein called thrombospondin-1 can disrupt the action of prostacyclin, which is released by the cells lining blood vessels and helps prevent platelets from becoming too sticky. Using mice they will test whether tackling thrombospondin-1 offers prospects as an anti- clotting treatment.

e) Amongst six research proposals funded by the US National Blood Foundation in October was Identifying Innate Immune System Pathways Critical for RBC Alloimmunization from Stephanie Eisenbarth, of Yale University. Every unit of allogeneic red blood cells contains antigens foreign to the transfusion recipient. Why do only some patients become alloimmunized after transfusion? Eisenbarth and her colleagues will examine the initial stages after transfusion of allogeneic red blood cells, seeking to "nail down the critical antigen-presenting cell that dictates when you get an alloimmune T-cell response to RBCs", as she put it.

f) A meta-analysis of 10 studies concluded that receiving a blood transfusion among patients with myocardial infarction (heart attack) was associated with increased all-

8 Chong Lei, Binglan Yu, Mohd Shahid, Arkadi Beloiartsev, Kenneth D. Bloch, Warren M. Zapol. “Inhaled Nitric Oxide Attenuates the Adverse Effects of Transfusing Stored Syngeneic Erythrocytes in Mice with Endothelial Dysfunction after Hemorrhagic Shock”. Anesthesiology, 2012; 117 (6): 1190 DOI: 10.1097/ALN.0b013e318272d866

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cause mortality compared compared with not being transfused during a heart attack9. If the transfusion was large, the risk increased by 12 percent.

g) The Journal of the American Medical Association (JAMA) published a summary of the systematic review of the 19 clinical trials that compare higher versus lower haemoglobin thresholds in red blood cell transfusion. “Our systematic review of these clinical trials resolves that the use of a restrictive approach to blood transfusions is safe for most patients,” said Jeffrey L. Carson, lead author. “The evidence provided in the synopsis can be used to treat anaemic patients in both critical and acute care settings without concern of causing undue harm.” The 19 studies included more than 6,000 patients with a mean age of 63 years. The systematic review not only showed that death did not increase in patients given a lower threshold blood transfusion, but showed there was not a significant difference in major complications like pneumonia, pulmonary oedema, stroke, or infection10.

9 Arch Intern Med. Published online December 24, 2012. Includes comment by

Anti- coagulants and antiplatelet drugs have improved how acute coronary syndrome is treated, but may increase the risk for bleeding, anaemia and transfusion. A team led by Dr Saurav Chatterjee of Brown University reviewed ten studies published between January 1966 and March 2012. They included 203,665 participants. One study was a randomised trial, the rest were observational studies. “Analyses of blood transfusion in myocardial infarction revealed increased all-cause mortality associated with a strategy of blood transfusion vs. no blood transfusion during myocardial infarction, the researchers said. Other statistical analyses suggest that blood transfusion was associated with a higher risk for mortality independent of baseline haemoglobin level, nadir haemoglobin level and change in haemoglobin level during the hospital stay. It appeared blood transfusion was alo associated with a higher risk for subsequent heart attack. “Additional outcomes data are needed from randomised clinical trials that investigate important outcomes with adequate sample size and with low risk for bias," the researchers concluded. In a related commentary Jeffrey L. Carson and Paul C. Hébert said of the meta- analysis “because of its many limitations, as physicians, we should not use the results of this review to justify or limit the use of red blood cells…..…..For researchers and decision makers, we can now appreciate how little reliable information is available to inform clinical and policy decisions involving red blood cell transfusions in patients with acute coronary syndrome. Given that real risks and potential benefits exist as to how we choose to use the valuable resource of blood transfusion, we believe that high-quality research is long overdue."10 Jeffrey L. Carson, Paul A. Carless, MMedSc; Paul C. Hébert, “Outcomes Using Lower vs Higher Hemoglobin Thresholds for Red Blood Cell Transfusion”, JAMA. 2013;309(1):83-84. doi:10.1001/jama.2012.50429. See http://jama.jamanetwork.com/article.aspx?articleid=1555108Dr. Carson developed the blood transfusion guidelines along with specialists in cardiology, paediatrics, critical care medicine, trauma and anesthesia that were issued last March by the AABB (formerly the American Association of Blood Banks). He was lead author on two of the clinical trials included in this Clinical Evidence Synopsis.

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h) Debate continues on red blood cells (RBC) and the storage lesion11, and whether patient outcomes are better when transfused RBC are fresher.

Patient Blood ManagementThe NBA is committed to appropriate use of blood and blood products and improved outcomes for patients.

a) In Ontario, Canada, the Peterborough Regional Health Centre’s is one of 25 hospitals with a Blood Conservation Management Program. In 2011-2012, 4.8 percent of patients who underwent knee surgery received a blood transfusion, compared with 10.1 percent across the province; the comparison in hip surgery was 4.8 percent against 12.8 percent; and in prostate cancer surgery 1.6 percent against 7.7 percent. The conservation program targets surgeries where typically more than 10 percent of blood is lost. Weeks before the surgery, a nurse will check a patient’s iron level, and if it’s low, they’ll prescribe iron pills or have the patient undergo iron transfusions to get levels up. A cell saver is mostly used during cardiovascular surgeries. Patients who avoid transfusion usually leave the hospital 1.5 days earlier, and have a decreased chance of contracting an infection.

b) Orthopaedic surgeons and anaesthetists with Jewish Orthopaedic Care, a part of KentuckyOne Health, have reduced the number of total joint replacement patients who require a blood transfusion. They now use transexamic acid for patients undergoing total hip and knee surgeries. This reduces the number of patients who need blood transfusions from 14 percent to 2 percent.

c) Robotic-assisted laparoscopic surgery for invasive bladder cancer was associated with 50 precent less blood loss and allowed patients to return home sooner with no difference in oncologic outcomes compared with conventional surgery (open radical cystectomy), investigators reported in a small pilot study12.

d) The EMA has initiated a review of hydroxyethyl starch (HES) used to manage hypovolaemia13 and hypovolaemic shock14 in critically ill patients. The review will look particularly at its use in patients with sepsis15. Safety concerns follow the publication of recent studies comparing HES with other volume expanders in critically ill patients with severe sepsis.

11Heddle et al. (INFORM-P study) report on a single-site random controlled trial (RCT) iwith more than 900 patients. Mortality was slightly higher in patients receiving "fresh" RBC units. Similarly, the ABLE Study showed a slight increase in mortality in the "fresh" group, but confidence intervals were high. Both these studies were intended to be pilot studies. The ARIPI Study found no significant adverse outcomes in stable pediatric ICU patients when "older" RBCs were transfused. But the meta-analysis by Wang and colleagues found the relative risk of death associated with older blood to be as high assixteen percent. Data from the RECESS Study and the NIH study of RBC units used in CVS are yet to come.The INFORM-P study defined fresh vs. old as 12 days vs. 26 days on average. The ABLE Study defined <8d as fresh. Aubron et al. comment that three studies imply a 14-day "rule" yet their two-site RCT defined 12 days vs. 23 days, plus or minus several days. The studies also differed in terms of storage solutions for red cells and in leucodepletion. See Heddle N et al. Transf 2012; 52:1203 ;LaCroix J et al. Transfus Med Rev 2011; 25:197; Fergusson D et al. JAMA 2012; 308:1443; Wang D et al. Transf 2012; 52:1184; Assmann S 2010; http//clinicaltrials .gov/ ; Koch C 2011; http//clinicaltrials.gov/ ;Aubron C et al. Transf 2012; 52:1196 12 Dipen Parekh, of the University of Miami, and colleagues in the Journal of Urology online13 low blood volume caused by dehydration or blood loss14 a steep fall in blood pressure caused by drop in blood volume15 damage to organs caused by bacteria and their toxins in the blood following an infection

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e) In a small randomized controlled study of patients undergoing elective thoracic or thoracoabdominal aortic replacement surgery with cardiopulmonary bypass (CPB), nearly half those receiving fibrinogen avoided the need for blood transfusion, whereas all patients on placebo required a transfusion. In an editorial accompanying the report in Anesthesiology, Nauder Faraday (Johns Hopkins University School of Medicine) cautions: "Enthusiasm for the administration of fibrinogen as a clinical therapy for bleeding in surgical patients must remain tempered at this time…..The administration of fibrinogen concentrates demonstrates clear potential to improve hemostasis more rapidly and at lower risk of immunologic reactions, infection, and volume overload than conventional allogeneic blood products……(but) future studies should develop more clinically relevant treatment algorithms and use modern randomization strategies that adhere to intention-to-treat principles.‘’

f) Biotest has begun a clinical development programme of human fibrinogen concentrate to treat serious, life-threatening bleeding. It has approval to conduct a Phase I/II clinical trial.

g) At the 2012 American Society of Hematology (ASH) Annual Meeting and Exposition in Atlanta in December Dr Tiziano Barbui reported on a large-scale randomized trial to examine the efficacy and safety of efforts to maintain hematocrit levels among patients with polycythemia vera16. The standard approach of maintaining hematocrit levels less than 45 percent was associated with a lower risk of thrombosis than the less aggressive strategy of maintaining levels between 45 percent and 50 percent, according to the data presented.

h) Results presented at the ASH Meeting suggested that the effectiveness of prophylactic platelets to prevent bleeding in patients with haematologic malignancies is unclear17. While patients given no-prophylaxis platelet transfusion had more days with grade 2 or higher bleeding and a shorter time to first bleed than patients who received prophylaxis, rates of bleeding among patients who did receive prophylactic platelet transfusion were still high.

i) Dr. Marcos de Lima led a study18 from the University of Texas M.D. Anderson Cancer Cente which concluded that multiplying umbilical cord-blood cells in the laboratory might improve recovery for patients needing blood stem cell transplants to treat blood- borne cancer. The approach involved expanding normal blood cells from donated cord blood in conditions similar to those in bone marrow, to increase the supply needed for transplant. Since umbilical cord blood is more easily matched in patients than donor bone marrow, the recovery period is safer and shorter.

m) Omega-3 fatty acid (n-3FA) supplements do not correlate with higher perioperative blood loss during spinal fusion procedures, according to a study published in the December issue of the European Spine Journal.

16 In polycythemia vera (PV) bone marrow produces too many red blood cells, increasing the risk of deep vein thrombosis, pulmonary embolism, stroke and heart attack. Patients with PV usually have hematocrit levels that range from 50 percent to 70 percent, compared with less than 50 percent in the wider population.17 Researchers screened 1,093 patients from 14 UK and Australian hospitals from August 2006 to August 2011 for the randomized, parallel group, open-label, non-inferiority TOPPS trial. Stanworth SJ. Abstract #1. Presented at: the 2012 ASH Annual Meeting and Exposition; Dec. 8-11, 2012.18 Marcos de Lima, M.D., professor, medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio, formerly M.D. Anderson Cancer Center, Houston; Kanti Rai, M.D., hematologist/oncologist, North Shore-LIJ Health System, New Hyde Park, N.Y.; Dec. 13, 2012, New England Journal of Medicine

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ResearchA wide range of scientific research has some potential to affect the use of blood and blood products. However, research projects have time horizons which vary from “useful tomorrow” to “at least ten years away”. Likelihood of success of particular projects varies, and even research which achieves its desired scientific outcomes may not lead to scaled- up production, clinical trials, regulatory approval and market development.

a) Scientists at the University of Liverpool are leading a new study of immunoglobulin in complex regional pain syndrome (CRPS). Results are expected to be published in 2016/17. CRPS is an ongoing condition usually diagnosed after trauma to a limb.

b) Dr Seth Masters from the Walter and Eliza Hall Institute in Melbourne and his team have discovered how the body reacts under stress from a severe infection. The immune system switch destroys blood stem cells and researchers have discovered how to turn the switch off. They hope this may mean faster recovery rates from blood infections and from chemotherapy.

c) Researchers have found a way to turn a patient’s own blood into usable, personalized stem cells19. The University of Cambridge team says they can take regular, adult blood cells and turn them into stem cells, which is much easier than using adult tissue samples. Furthermore, using the patient’s own blood tricks the body and there is no rejection involved. The team found that the red blood cells do not have to be converted immediately; they could freeze and store the regular blood cells for later use, and then convert them to induced pluripotent stem cells (iPSC) the patient might need later on. One of the team, Dr. Amer Rhana also said of their findings: “Tissue biopsies are undesirable, particularly for children and the elderly – whereas taking blood samples is routine for all patients.”

c) A study in Anesthesiology has pinpointed a gene that may help determine the sepsis survival rate. Evidence suggests the gene NFKB could be a genetic pathway for amplifying inflammation in sepsis, a leading cause of hospital deaths. The study could determine if anti-inflammatory sepsis treatment should be tailored for patients with certain genetic sequences. Lead author was Dr Michael Adamzik of the University of Duisberg-Essen, Germany.

d) Advanced Cell Technology of Massachusetts has initiated the process for regulatory approval of a human trial involving stem cells created by reprogramming adult cells back to an embryonic-like state. It wants to begin clinical testing of stem-cell derived platelets that can be used to help treat people with leukemia and other conditions.

e) EpiVax has a $US 55,000 grant to explore using tregitopes as an immuno-modulator in chronic inflammatory demyelinating polyneuropathy (CIDP), a nerve disease treated with intravenous immunoglobulin (IVIg). Tregitopes are linear sequences of peptides contained within the framework of monoclonal antibodies and immunoglobulin-G, which activate natural regulatory T cells. They seem to suppress tissue-destroying immune cells that cause 'organ-specific autoimmune diseases', and they can modify immune responses to biotherapeutics (including FVIII).

f) At the ASH meeting In December, researchers at Dana-Farber/Children's Hospital Cancer Center (DF/CHCC) announced that they had demonstrated in an animal model the feasibility of activating a form of haemoglobin unaffected by the sickle cell mutation.

g) An international team has used a combination of genetic analysis in people and subsequent research in fruit flies to identify genes linked to red blood cell biology

19 Imbisaat Geti, Mark L. Ormiston, et.al. “A Practical and Efficient Cellular Substrate for the Generation of Induced Pluripotent Stem Cells from Adults: Blood-Derived Endothelial Progenitor Cells” in the on-line journal, Stem Cells: Translational Medicine.

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and investigate their function. Their studies confirmed that sets of genes involved in controlling human red blood cell traits in people are also important for the formation of blood cells in flies20.

h) With IVIg being trialled as a treatment for Alzheimer’s disease, the NBA, concerned about market pressure if the trial result is positive, takes an interest in research on other possible treatments for Alzheimer’s, on the identification of genetic predisposition for the disease, and on improvements in diagnostic tools. Some recent developments are outlined in an appendix to this article.

Legal IssuesThe 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) In the US in December a federal judge accepted Amgen’s plea agreement on a charge that it misbranded its anemia drug Aranesp. The agreement will cost the company $US 150 million in criminal penalties. Amgen will also pay $US 612 million to settle civil claims by states and whistle-blowers alleging the company also illegally marketed other drugs.

Infectious DiseasesThe NBA takes an interest in infectious diseases because: the presence of disease in individual donors (e.g. influenza), or potential disease resulting from travel (e.g. malaria) means a donor must be deferred; temporary disease burden within a community (e.g. dengue in North Queensland) may limit blood collection in the community for a time; and some people may not be permitted to donate at all (e.g. people who lived in the UK for a period critical in the history of vCJD). Blood donations are tested for a number of diseases (e.g. HIV and Hepatitis B), but there are also emerging infectious diseases for which it may become necessary to test in the future (e.g. Chagas disease, and the tick-borne babesiosis and Lyme disease).

Mosquito- borne diseasesa) Reported cases of dengue on the Portuguese island of Madeira had exceeded 2,000

by mid- December. This was the first sustained outbreak of dengue in Europe since the 1920s.

b) Sanofi Pasteur announced that it would soon be bringing its dengue vaccine to market. The first commercial batches are expected to be available in 2015.

c) In December, Australian authorities eradicated a dozen potentially dangerous mosquitoes found inside a shipment of Chinese plants. Investigators from the Department of Agriculture, Fisheries and Forestry discovered the Asian tiger mosquitoes (Aedes albopictus) inside two glasshouses at a quarantine station near Melbourne. They are a known vector for arboviruses, such as dengue.

d) A group of research institutes in Georgia have won a contract of up to $US19.4 million from the National Institute of Allergy and Infectious Diseases to use a systems biology-based approach to studying how host-pathogen interactions are involved in malaria.

e) The West Nile virus outbreak in the US reached 5,245 cases, including 236 deaths, by 28 November.

20 P van der Harst et al. “75 genetic loci influencing the human red blood cell” Nature 2012

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Influenza

Avian influenzaa) Global health workers are concerned about the discovery in Indonesia of a new

strain of the deadly H5N1 avian flu that is both more dangerous and more virulent than others.The new strain has killed hundreds of thousands of ducks.

b) According to the WHO on 17 December, there had been so far in 2012 32 cases of avian A(H5N1) influenza virus infection in humans, 20 of whom had died. In Egypt there were 11 cases and 5 deaths. There were 9 cases in Indonesia, 4 in Viet Nam, 3 in Bangladesh and Cambodia, and 2 in China. In 2011 there were 62 cases, of whom 34 died.Since the emergence of H5N1 influenza in 2003, 610 people are reported to have become infected, 360 of whom have died.The annual number of human cases reached a peak of 115 in 2006 and has been followed by a gradual decline to the 32 cases recorded in 2012.

c) Scientists in China identified strains of avian flu in pigs21. “We recommend strongly that the pork industry worldwide should monitor the prevalence of influenza in pigs, considering their important role in transmitting this virus to humans,” explained Guihong Zhang of the College of Veterinary Medicine at the South China Agricultural University.

d) Scientists expressed varying views on a draft US government plan to review more stringently the funding of particular types of H5N1 avian flu research—even requiring some studies to be secret. The proposal to a meeting of the National Science Advisory Board for Biosecurity, followed the controversy around potential risk from "gain-of-function" studies.

Influenza vaccines.a) Novartis received FDA approval for Flucelvax in November, for use in people 18

years and over. This is the first cell-culture vaccine in US to help protect against seasonal influenza. Cell-culture technology offers an alternative to traditional egg-based production. Novartis has partnered with the US Department of Health and Human Services, Biomedical Advanced Research and Development Authority (BARDA), for the development of the cell-culture manufacturing technology, and for construction of the production facility in North Carolina. The facility is seen as enhancing pandemic preparedness.

b) The FDA in December approved GlaxoSmithKline's (GSK's) quadrivalent (four-strain) influenza vaccine, with two influenza B strains, in people aged three or more. This is the first injectable quadrivalent flu vaccine licensed in the US. MedImmune's quadrivalent version of the intranasal vaccine FluMist was approved by the FDA in February 2012.

c) Sanofi Pasteur applied in October for FDA approval of its quadrivalent flu vaccine.

d) Medicago announced results from a preclinical study on the cross-protection effects of its H5N1 VLP (virus-like particle) vaccine. The study was conducted in mice under the National Institute of Allergy and Infectious Diseases' (NIAID) Animal Models of Infectious Disease Program. Medicago says the results suggest that the company’s vaccines could provide broad protection against multiple influenza strains22.

21 Online ediction of Journal of Clinical Microbiology22 A single, non-adjuvanted, intramuscular dose of H5N1 VLP vaccine protected against a different H5N1 strain or a strain of a different subtype such as H2N2. However a recombinant non-VLP H5

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e) Inovio Pharmaceuticals in December reported interim results of a phase I trial that showed that a single dose of its H1N1 universal SynCon flu vaccine followed with a dose of a seasonal flu vaccine generated protective immune responses in 40 percent of trial subjects compared with a 20 percent response rate in elderly patients who received the seasonal flu vaccine alone. Individual SynCon DNA vaccine "constructs" are designed to provide broad cross-strain protection against existing and potential new strains of influenza. Preemptive protection against new strains is particularly important to the elderly and other immune-compromisd patents.

f) Researchers from Germany's Friedrich Loeffler Institute say they have found a way to make a vaccine artificially by copying the flu virus's RNA code. The synthetic vaccine was tested in mice, ferrets and pigs. Researchers found the vaccine could also protect against new strains as they emerged. The Influenza Specialist Group, representing medical and scientific specialists from Australia and New Zealand, said the development was a step in the right direction.''The work done on this to date is fairly comprehensive,'' said the group's chairman, Alan Hampson. However, he said while the research represented a valuable proof of concept in animals, there was still a long way to go before proving it could be applied to humans.

Othera) Proteins responsible for mad cow disease have been discovered in the saliva of

cows infected as part of an experiment.

b) A 51-year-old woman from Macao who had a brain operation in Hong Kong was diagnosed with sporadic Creutzfeldt-Jakob Disease (CJD). The hospital was advised to contact other patients who had undergone surgery with the same instruments.

c) The FDA gave fast-track approval to a new tuberculosis drug, despite safety concerns about it during testing. Janssen Therapeutics, part of Johnson & Johnson, received approval for bedaquiline (brand name Sirturo). Janssen had not completed the usual three phases of clinical trials. In one trial, "nine patients who received Sirturo died compared with two patients who received placebo," according to an FDA statement. "Multidrug-resistant tuberculosis poses a serious health threat throughout the world, and Sirturo provides much-needed treatment for patients who don’t have other therapeutic options available," Edward Cox, director of the FDA’s office of antimicrobial products in the Center for Drug Evaluation and Research, said in a statement. "However, because the drug also carries some significant risks, doctors should make sure they use it appropriately and only in patients who don’t have other treatment options." Bedaquiline is for use as part of combination therapy for adults with multidrug-resistant tuberculosis lung infections. J&J applied last August for approval to market the drug in the EU.

d) NIAID is sponsoring a clinical trial to examine Astra Zeneca’s investigational drug’s early bacteria-killing activity in patients newly diagnosed with drug-sensitive pulmonary tuberculosis. In laboratory testing, the drug proved active against a wide range of drug-sensitive and drug-resistant strains of Mycobacterium tuberculosis. The clinical trial is being led by researchers at the Tuberculosis Research Unit at Case Western Reserve University in Cleveland.

e) Giant pandas produce a powerful antibiotic in their blood stream that kills bacteria and fungi. Scientists have been able to synthesis the compound in the lab by decoding the genes. Dr Xiuwen Yan, who led the research at the Life Sciences College of Nanjing Agricultural University in China, said “Gene-encoded antimicrobial

protein failed to provide similar protection against both strains. The H5N1 VLP vaccine appears to have induced mucosal immunity in the lungs and plant lipids may have intrinsic adjuvant activity.

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peptides play an important role in innate immunity against noxious microorganisms. They cause much less drug resistance of microbes than conventional antibiotics.”

f) Researchers (led by Matthew Bonds of Harvard Medical School) predicted in PLoS Biology that countries that lose biodiversity will have a heavier burden of vector-borne and parasitic diseases. "The more organisms you have out there, the more things there are that can interrupt the life cycle of disease, and the less concentration you'll have of any vector," said Bonds. A 2002 contribution in the Proceedings of the National Academy of Sciences had already reported that if there is a rich community of tick hosts, Lyme disease is diluted among them. Experience in the north- east US has shown that if ticks carrying Lyme disease have only white-footed mice as hosts, the disease risk to humans can rise dramatically.

g) CMV infection is widespread and not apparently serious for many who contract it, though they carry it for the rest of their lives. In pregnant women it can cause congentital abnormalities in their baby, and in transplant recipients it can be fatal. Inovio Pharmaceuticals announced in November that testing of multiple synthetic vaccine constructs for CMV induced robust T cells in mice, demonstrating the potential for a SynCon DNA vaccine to treat the virus.

h) Researchers at the Gladstone Institutes have identified the molecular mechanism by which cytomegalovirus (CMV) infects its hosts23 . CMV is one of a family of human herpes viruses24. It replicates fast, it evades the host's immune defence and it allows the host cell to survive long enough to produce and spread the virus to neighbouring cells. CMV applies 'braking mechanism' after initial replication inside the cell.

i) A recently formed global clinical research consortium 25 proposed a collaborative clinical research platform to assess prospectively the pathogenesis of illness and potential therapeutic interventions for patients infected with a novel coronavirus which has been causing concern in and around the Middle East and Eastern Mediterranean, and countries who have received infected travellers from the region.

j) The FDA has approved a monoclonal antibody, raxibacumab, by injection to treat inhalational anthrax, a form of the infectious disease caused by breathing in the spores of the bacterium Bacillus anthracis. It is also approved to prevent inhalational anthrax when alternative therapies are not available or not appropriate. Raxibacumab is the first monoclonal antibody approved under the FDA’s Animal Efficacy Rule, which allows efficacy findings from adequate and well-controlled animal studies to support FDA approval when it is not feasible or ethical to conduct trials in humans.

Appendix: Alzheimer’s Disease ResearchAs mentioned earlier, with IVIg being trialled as a treatment for Alzheimer’s disease, the NBA – concerned about market pressure if the trial result is positive- takes an interest in research on other possible treatments for Alzheimer’s, on the identification of genetic predisposition for the disease, and on improvements in diagnostic tools.

a) Two studies recently published in The New England Journal of Medicine identified a rare variant of the TREM2 gene as a potent risk factor for late-onset Alzheimer's

23 Melissa W. Teng, Cynthia Bolovan-Fritts, Roy D. Dar, Andrew Womack, Michael L. Simpson, Thomas Shenk, LeorS. Weinberger. “An Endogenous Accelerator for Viral Gene Expression Confers a Fitness Advantage”. Cell, 2012; 151 (7): 1569 DOI: 10.1016/j.cell.2012.11.05124 that also include Epstein-Barr virus (which causes mononucleosis) and varicella-zoster virus (which causes chickenpox25 The International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC)

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disease. Some risk variants previously reported have been linked to familial early-onset Alzheimer's disease. Others associated with late-onset of the disease have generally been identified as conferring low risk, with the well-known exception of the ε4 allele of apolipoprotein E, whose odds ratio is reportedly three. The newly-identified variant is suggested to increase disease risk by a similar factor. The two studies were led by Decode Genetics and the Alzheimer's Genetic Analysis Group respectively. In an editorial in NEJM, Harald Neumann (University of Bonn) and Mark Daly (Massachusetts General Hospital) suggested that the Alzheimer's Genetic Analysis Group found a greater number of variants in TREM2 linked to Alzheimer's disease as it drew upon a more diverse population than DeCode's Icelandic study

b) Bristol-Myers Squib terminated development of the drug avagacestat for the treatment of Alzheimer's disease. The decision is due to lack of efficacy, determined after an analysis of data from a completed Phase II study in patients with mild-to-moderate AD and an ongoing Phase II trial in predementia AD.

c) Merck has started a Phase II/III clinical trial designed to evaluate the safety and efficacy of MK-8931 versus placebo in patients with mild-to-moderate Alzheimer's. Merck says the study is important to an understanding of the potential of the BACE inhibitor mechanism and MK-8931 in multiple stages of Alzheimer's disease.26

d) The University of Minnesota's Center for Drug Design has developed a compound that, in mice, prevented the neurodegeneration associated with Alzheimer's disease. In the pre-clinical study, researchers found evidence that a synthesised compound designated psi-GSH enables the brain to use its own protective enzyme system, glyoxalase, against the disease process27.

e) Eli Lilly will conduct an additional late-stage study of its experimental Alzheimer’s treatment solanezumab. The drug failed to meet the main goal of two large studies, but it did slow progression in people milder stages of Alzheimer’s. The new study, for these patients only, will begin by the third quarter of 2013.

f) Past studies in animals have shown it is possible to prevent the formation of brain plaques, made of amyloid beta protein, which are considered by many to be a symptom and possibly the cause of Alzheimer’s disease. Now Eli says it may have found a way to remove plaque from the brains of forgetful, old mice. The deposited plaques are insoluble, whereas amyloid beta free-floating around the brain is soluble. Lilly researchers genetically engineered an antibody that could cross the blood-brain barrier and bind itself to the deposited amyloid beta. It cleared around 50 percent of pre-existing plaques in the mice without causing damage to tiny vessels in the brain28. Lead researcher Ronald DeMattos said "We don't know how it translates in humans until we test human antibodies in clinical trials." Lilly may begin clinical trials using a human antibody within a year.

g) Luca Santarelli, head of neuroscience at Roche, said of Alzheimer’s disease: “The disease is possibly caused by amyloid and tau, which start depositing at least 15 or 20 years before you see symptoms. We’re going at this at an earlier stage when patients don’t have dementia …and the way we do that is to utilize a molecular

26 The amyloid hypothesis suggests that the formation of the particular amyloid peptide that leads to amyloid plaque deposits in the brain is the basic cause of Alzheimer's disease. BACE is regarded as a key enzyme in the production of this peptide. If inhibiting BACE decreases the production of the peptide it may reduce amyloid plaque formation and slow disease progression. Merck researchers have already presented findings of a multiple dose Phase I study which demonstrated that MK-8931 can reduce the target amyloid in cerebral spinal fluid by more than 90 percent in healthy volunteers. 27 The discovery appeared online in the American Chemical Society journal ACS Chemical Neuroscience and offers a new target for the design of anti-Alzheimer's and related drugs.28 Results were published in Neuron on 5 Decmber 2012.

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biomarker, which we measure in cerebral spinal fluid and through that aid, we are able to identify patients as early as 3 to 5 years before they develop dementia. This gives us a point of intervention possibly when function and structure of the brain is still better preserved….. the study involving RG-1450 (gantenerumab) was recently increased in scope and doubled in size enrolling 770 patients and that could give it potential to be randomized-controlled trial for use in registration. To our knowledge this is the only monoclonal antibody that is being tested at this stage of the disease.”…… DIAN (Dominantly Inherited Alzheimer’s Network at Washington University) is a prevention trial and (gantenerumab) will be tested in (160) people who carry the gene that makes them produce more amyloid in the brain….. We have four compounds in clinical development. There’s another monoclonal antibody that is in Phase II called crenezumab. We also have a monoamine oxidase B (MAO-B) inhibitor in a Phase IIb dose-ranging study. This targets the inflammatory aspect of age-related neurodegeneration. And we have an oral BACE1 inhibitor in Phase 1….. Our research right now is very focused on the proteins, because that’s where we think the disease is originating… We have to realize it’s a very difficult area of research. In spite of knowing for almost two decades these proteins cause damage to the brain, we still have a lot to learn… There’s better understanding of the disease and when to intervene, though. We’re trying to intervene earlier and using molecular diagnostics as opposed to waiting until dementia has already started and then rely on pure clinical diagnosis, which still leads to a large number of patients.”

h) Bionomics is moving an Alzheimer's drug candidate towards clinical trial. It will conduct formal toxicology studies and GMP manufacturing scale-up studies for BNC375, a positive allosteric modulator of the alpha-7 nicotinic acetylcholine receptor. It is claimed to improve memory and reduce learning defects in neurodegenerative diseases including Alzheimer's. Bionomics said that in pre- clinical testing its candidate performed better than alternatives including Donepezil. Its claimed characteristics include rapid action and compatibility with other medications such as acetylcholinesterase inhibitors.

i) Two new studies29 suggest that one of the standard tests used in Alzheimer’s, the Alzheimer’s Disease Assessment Scale—Cognitive Behavior section (ADAS-Cog), may be too insensitive to detect minor improvements in drug trials30. Other researchers do not accept that the ADAS-Cog was the reason recent drug trials were unsuccessful31, but many agree new tests are needed.

j) A recent study32 shows a new way to diagnose Alzheimer’s disease. Dr. Jeffrey R. Petrella, director of the Alzheimer’s disease Research Lab at Duke University Medical Center said “Our study looks at whether more sophisticated diagnostic tests such as magnetic resonance imaging (MRI), positron emission tomography (PET) and spinal fluid protein analysis might provide additional prognostic information, compared to more readily available cognitive and blood testing." The study observed 97 patients with MCI from the Alzheimer’s Disease Neuroimaging Initiative, where patients are followed to track disease progression. The Duke team analyzed MRI and FDG-PET results, along with cerebrospinal fluid proteins and compared

29 published in Alzheimer's & Dementia December 18. 30 Jeremy Hobart, a neurologist at the Plymouth University”s Peninsula Schools of Medicine and Dentistry, and his team found that the test could not distinguish small changes in early- stage patients. It bunched patients into groups of test scores, rather than along a continuous spectrum. 31 “The negative results are due to the small effect size of the drug being tested and not the measurement instrument,” Stephen Salloway, director of neurology and the Memory and Aging Program at Butler Hospital in Providence, Rhode Island, told Nature. “I wish I could blame it on the test.” He added: “These papers are very timely because we need new tests . . . that are more sensitive.” 32 Journal of Radiology, December 2012

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these to cognitive outcomes at two to three years. They found that by combining this data with routine clinical tests, the accuracy of predicting conversion to Alzheimer’s over clinical testing alone increased significantly. The combined testing reduced false classifications, dropping the rates from 41.3 percent to 28.4 percent. "In an ideal world, you'd obtain all information available—regardless of cost or number of tests—for the best prediction of cognitive decline. However, there's a trade-off between adding testing—some of which may add little new information—with the inconvenience, cost and risk to the patient. Though all the tests added some unique information, FDG-PET appeared to strike the best balance, adding the most prognostic information for patients with mild cognitive impairment,” Dr. Pretella said.

k) Researchers at the University of Pennsylvania, led by Virginia Lee, director of the Center for Neurodegenerative Disease Research, injected a synthetic version of the toxic protein associated with Parkinson's disease into the brains of healthy mice. In a paper in Science in November, they reported how the toxic protein spread from cell to cell in a prion-like fashion, causing the death of l dopamine-making neurons. The mice displayed impaired motor coordination and balance. The team is now testing an antibody therapy to stop the toxic misfolded proteins from spreading in the mice. If it works, it could provide a possible therapy to test in people with Parkinson's disease, and the concept may translate to AD.

l) Todd Sherer, chief executive of the Michael J. Fox Foundation for Parkinson's Research, spoke with scientists researching protein misfolding across a number of neurodegenerative conditions, exploring ways to prevent cell- to – cell spread.

m) Kurt Giles, of the Institute for Neurodegenerative Diseases at the University of California, San Francisco, co- authored a paper in the Proceedings of the National Academy of Sciences, showing that the amyloid-beta protein associated with Alzheimer's shares prion-like characteristics. The research team included the institute's director Stanley Prusiner, whose discovery of prions won a 1997 Nobel Prize. Researchers injected amyloid beta protein into one side of mice brains. They followed the spread of the disease using a light-generating molecule. The toxic protein set off a chain reaction of misfolding throughout the brain, as it does in AD.

n) These findings may have implications in cardiac disease too, says Avijit Chakrabartty, of the University of Toronto. His lab has been working on amyloid cardiomyopathy, caused by misfolding of a particular protein. Clot busters and other heart-disease drugs don't work in these patients because it is not cholesterol but misfolded protein clogging their arteries. One version of this disease runs in families, and treatment is available. But so far there is no way distinguishing cases that do not involve a genetic mutation. The Toronto team is looking for a test for the misfolded protein in the blood.

o) Elan Corporation announced in November that it had enrolled the first patient in a Phase II clinical trial of ELND005 (Study AG201) for the treatment of agitation/aggression in patients with moderate to severe Alzheimer’s disease.

p) An FDA-approved treatment for insulin resistance in diabetics shows promise as a way to improve cognitive performance in some people with Alzheimer's. Using genetically engineered mice, University of Texas Galveston researchers found that the anti-insulin-resistance drug rosiglitazone improved learning and memory while normalizing insulin resistance. The researchers believe that the drug reduced the negative influence of Alzheimer's on the behaviour of a key brain-signaling molecule. The molecule, called extracellular signal-regulated kinase (ERK), becomes hyperactive in the brains of Alzheimer's patients as well as in the mice at a disease stage corresponding with mild cognitive impairment in human Alzheimer's. This excessive activity leads to improper synaptic transmission between neurons, interfering with learning and memory.

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