MONITORING INTERNATIONAL TRENDS

posted December2012

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.

Table of Contents

Products...... 1

Regulatory matters...... 3

Market structure and company news...... 3

Country- specific events...... 5

Safety...... 6

Research...... 7

Legal actions and enquiries, Infectious Diseases.....……………………………………… 9

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.

Clotting factors.

a)In the US, Octapharma presented five clinical posters[1] at the National Hemophilia Foundation’s64th Annual Meeting in Florida in November.

Immunoglobulin

b)At the 15th Biennial Meeting of the European Society for Immunodeficiencies data was presented from a new study in Japan which supports the previously demonstrated safety and efficacy of Hizentra (Immune Globulin Subcutaneous [Human]) for the treatment of primary immunodeficiency (PID)[2]. Hizentra is the first and so far the only 20 percent subcutaneous immunoglobulin (SCIg) therapy in the world for the treatment of PID. CSL Behring submitted the new drug application for Hizentra to the Pharmaceutical and Medicines Devices Agency in Japan in September

c)A recent assessment[3]confirmed that a high level of health-related quality of life can be achieved for patients managing hereditary angioedema, when treatment such as C1-inhibitor concentrate is available.

Patient Blood Management

d)At the 2012 Annual Meeting of the American Society of Hematology (ASH) in December in Atlanta, AMAG Pharmaceuticals presented four abstracts [4]. They contained new data on Feraheme (ferumoxytol) injections for intravenous (IV) use in patients with iron deficiency anaemia and a history of unsuccessful oral iron therapy

e)A team at Johns Hopkins University has created HemoGlobe, a small device that allows health workers in the field to use the computing power of a cellphone to screen for anaemia. The HemoGlobe is an inexpensive sensor connected to the cell phone. The sensor resembles those used to measure blood oxygen levels, and attaches to tip of a finger. A light shines through the finger and the sensor detects the colour of the blood through the skin along various wavelengths. The specific colour indicates the specific level of haemoglobin. The cell phone displays the result- a color-coded readout indicating whether the patient is anaemic, and the degree of severity. HemoGlobe can automatically send the output as a text message to a server set up to produce an epidemiological map of anaemia cases in the area.

Other

f)Adventrix Isomark, based in Madison, Wisconsin, hopes to launch a sepsis detection device in late 2014. In contrast with conventional methods of detection (which measure heart rate, blood pressure and temperature), this new device measures two isotopes of carbon found in a patient’s breath. By measuring both carbon 12 and carbon 13, and detecting changes in their ratio, scientists can see when the body is metabolizing in a way specifically associated with an infection. The clinical trial with 33 patients showed that the device detected sepsis, in one case 48 hours before and in another case 12 hours earlier than conventional methods.

g)Norwegian company SpinChip has developed a device claimed to draw a blood sample directly from a fingertip into small analytical chips that are placed in a microcentrifuge. The analysis can be read optically within a few minutes. This portable instrument can move from laboratory to bedside to surgery. Development work on SpinChip will continue to 2015.

h)Kamada’s drug Glassia, used in alpha-1 atrypsin deficiency, is now claimed to have other therapeutic indications. Kamada says it shows promise in treating bacterial lung infection, as an anti inflammatory agent in chronic obstructive pulmonary disease, and in the prevention of transplant rejection. A Phase II study has also been conducted in Type 1 diabetes. Kamada says its AAT protein is modulating the activity of type B lymphocytes and thus enabling the avoidance of organ transplant rejection. The company says that in the presence of its AAT protein in serum, pro-inflammatory proteins are inhibited.

i)CSL is studying CSL 112 to reduce the risk of recurrent heart attacks. Data from pilot studies of this formulation of apolipoprotein A-I were presented in Los Angeles at the American Heart Association 2012 Scientific Sessions. Apolipoprotein A-I is the main component of high-density lipoprotein (HDL), which plays a role in the removal of cholesterol from arteries.

j)Oxygen Biotherapeuticsis developing its proprietary perfluorocarbon-based intravenous emulsion, Oxycyte as a treatment for a variety ofischemic conditions. ItsUS Army-funded preclinical program is addressing safety questions raised by the US Food and Drug Administration (FDA). Meanwhile, clinical studies of Oxycyte in patients with traumatic brain injury are being conducted outside the US.

Regulatory Matters

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

a)Cytomedix has been given FDA clearance for its Angel Concentrated Platelet Rich Plasma (cPRP) System to process small samples of blood or mixtures of blood and bone marrow aspirate. This is mixed with bone graft material for use in orthopaedic procedures including spinal fusion. The automated system is designed to produce high platelet yields.

b)The FDA investigated a significant number of post-marketing reports of gastrointestinal bleeding in patients who were treated with the Pradaxa blood-thinner, approved two years ago. It concluded that the bleeding rates are no higher than with warfarin. However, there is no agreed antidote to reverse the effects of Pradaxa, and the FDA report did not address this issue.

c)The FDA has agreedCerus maysubmit a premarket application for approval of its plasma safety system. "Based on recent positive discussions with the FDA, Cerus now plans to move forward with a modular premarket approval application for the Intercept blood system for plasma in the United States," President and CEO William Greenman said in a press release. Cerus lost $US14.2 million on revenue of $US26.3 million in the nine months ended 30 September. That compares with a loss of $US9.2 million on revenue of $US22.6 million in the same period of 2011.

d)The FDA has approved Bayer’s oral anticoagulant Xarelto (rivaroxaban) for the treatment of deep vein thrombosis (DVT), pulmonary embolism (PE), and to reduce the risk of recurrent DVT and PE.

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 considered include suppliers, potential suppliers and developers of products which may be of interest.

a)Cerus Corporation in November compared the first nine months of 2012 with the same period in 2011. Although its product revenue increased by 26 per cent its operating expenses were higher and there was much less government grant revenue to recognize in 2012. The company is planning a modular[5] Premarket Approval Application for the INTERCEPT Blood System for plasma in the US. It believes its existing clinical data will be enough to begin the submission process.

b)Grifols announced the results of the fifth round of the Martín Villar Research Awards on Hemostasis. The projects receiving awards were:

  • Reduction in bleeding episodes associated with hemophilia with laboratory engineered proteins using mutagenesis techniques[6]
  • New progress in non-invasive prenatal diagnosis for female carriers of the hemophilia gene[7]
  • Targeting of impaired genes in the DNA of hemophilic mice and subsequent restoration of hemostasis[8].

c)Baxter International has announced an exclusive 20-year partnership with Hemobrás (Empresa Brasileira de Hemoderivados e Biotechnologia) to provide haemophilia A patients in Brazil with more access to recombinant factor VIII (rFVIII). The majority of Brazilian patients currently receive plasma-derived FVIII (pdFVIII). Baxter will have exclusive access to Brazil's rFVIII market over the next 10 years while the companies engage in technology transfer to develop manufacturing capacity by Hemobrás. Baxter will be paid in cash for product it supplies to Hemobrás and then royalties on rFVIII produced by Hemobrás.

d)Geoffrey McDonough, CEO of Swedish Orphan Biovitrum (SOBI) reported: "The third quarter continued to demonstrate solid underlying growth in product sales and an improvement of the gross margin in line with our expectations. In September we reported positive top-line results from our factor IX phase III program with Biogen Idec for the development of a long-lasting recombinant coagulation factor for haemophilia B."

e)Santarus' CEO spoke to Lazard Capital Markets’Ninth Annual Healthcare Conference in November about Ruconest, the company’s recombinant human c1 esterase inhibitor, being studied for acute hereditary angioedema attack. The product is currently approved in Europe and sold by Swedish Orphan Biovitrum. Results from a third Phase III study showed a very good safety profile. There are two plasma derived esterase c1 inhibitors on the market: Cinryze for prophylactic treatment of hereditary angioedema (HAE) and Berinert for acute treatment. Santaurus believes its recombinant product has a safety advantage.

f)ProMetic Life Sciences reversed last year’s loss, reporting it had a $C2.5 million net profit in the third quarter, when its revenue was $C7.7 million The financial report came six weeks after ProMetic announced that China’s Shenzhen Hepalink Pharmaceutical Co. Ltd. would take a 10 per cent stake in the Canadian company and its protein technology.

g)Pfizer, a major supplier of drugs to the NHS, avoided paying any corporation tax in the UK last year. The UK Government is cracking down on companies thatreduce their tax bills by recognising profits in countries with lower tax regimes. Pfizer has already faced questions over its tax arrangements in the US and Germany.

h)NuSep, a company listed on the Australian Stock Exchange, has received Australian Therapeutic Goods Administration (TGA) accreditation to manufacture in-vitro diagnostics medical devices (IVDs) used in the field of coagulation. The TGA certification will help NuSepto supply PrIME Biologics with cartridges to manufacture therapeutic plasma products. NuSep is currently in the process of spinning out its therapeutic plasma fractionation business, PrIME Biologics. The latter is concentrating on opening up the Asian therapeutic plasma market, particularly the untapped Currently Unprocessable Plasma (CUP) market.

Country- specific Events

The 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’svisitors and immigrants come.

United States

a)By 9 November 2012, 32 people are known to have diedand 438 have become ill from an outbreak of fungal meningitis linked to contaminated steroid injections from a compounding pharmacy.

b)Biogen Idec, two patient advocacy groups, and a medical centre have combined to offer no- cost or low-cost genetic testing in the US to people with haemophilia and their families. This will identify ways to personalize patient care, generate new genetic information, and help create a database for use in research. The National Hemophilia Foundation said that the project - My Life, Our Future: Genotyping for Progress in Hemophilia- will provide genetic and clinical information to clinicians, researchers, and patients by overcoming the main constraint on genetic testing — cost and insurance coverage[9].

c)At the annual scientific sessions of the American Association of Blood Banks (AABB), in Boston in October initial results were presented for Imugen’s new investigational blood tests to screen blood donors for babesiosis. By then around 20,000 blood donors had been tested by nucleic acid tests and also by a new serologic test method. Babesiosis is currently the most common infectious disease transmitted by blood in the US. As a result of this testing, 69 blood units that were potentially infectious for Babesia were removed from the blood supply. These studies will finish early in 2013, and will be the basis of an application to the FDA to approve the test.

Australia

d)The Australian Bureau of Statistics (ABS) in November released the highest life expectancy estimates ever recorded in Australia[10] . Director of ABS Demography, Bjorn Jarvis, said that life expectancy figures continued to increase over the ten year period ending 2011."Under current estimates, a boy born today could expect to live 79.7 years while a girl could expect to live 84.2. A male currently aged 65 could expect to live a further 19 years and female a further 22 years," Mr Jarvis said." According to United Nations estimates, Australia’s male and female combined life expectancy figure of 81.4 years is higher than the rates in the UK, Canada, New Zealand and the USA.

e)A report has been released by the Advisory Council on Intellectual Property, which was appointed in 2010 by the former Minister for Innovation, Industry, Science and Research, Senator the Hon Kim Carr, to review how intellectual property acts as an enabler or disabler for research collaborations.The report has offered recommendations to improve research collaborations, including reforming the incentive structures that discourages researchers from working with the private sector[11]. The full review can be found on the Advisory Council on Intellectual Propertywebsite.

Other

f)The complete implementation of an EU Blood Directive was postponed in Ireland after it made the blood supply “very difficult” in July and August.The Irish Blood Transfusion Service had, in line with the Directive, implemented a policy to defer donations from people with low haemoglobin. The deferral rate in clinics had increased from an average of 15 per cent to 22 per cent. Chief Executive of the IBTS Andrew Kelly announced it would for the next year need to accept blood from women with a haemoglobin count of between 12 and 12.4gm/dl and men of 13 and 13.4gm/dl.

Safety Issues

We follow current issues in patient safety.

a)Early in-hospital mortality in adult trauma patients is predicted by transfusion proctocol employed, according to an article[12] in the Archives of Surgery. Where haemorrhage was the primary cause of death, the chance of death within six hours of admission was significantly and negatively associated with increased transfusion rates of plasma to red blood cells and with platelets to red blood cells. The authors suggested a randomized trial to examine the potential net survival benefit of early and higher plasma and platelet ratios.

b)A recent article[13]reported that data from the Australian Better Safer Transfusion programme show that about one-third of patients undergoing hip or knee arthroplasty receive perioperative blood transfusions, placing them at increased risk for adverse clinical outcomes. The authors described challenges associated with the provision of allogenic blood transfusions including the quality of stored red cells, cost of blood, and limited donors and suggested a new approach to transfusion management. This included pre-operative optimization of haemoglobin and iron levels, and intraoperative management of blood loss.

c)A new study reports that three- quarters of patients on blood thinners clopidogrel and prasugrelare on the incorrect dose and could be at risk for either uncontrolled bleeding or blood clots[14]. They found that age, gender, cholesterol levels and history of heart problems were not good predictors for how a patient would react to the blood thinners. They recommended a simple blood test to personalize dosing.

d)A pilot study[15]showed an optical scanner for Apple’s iPad tablet computer reliably estimated blood loss during surgery in both experimental and clinical settings. Precise measurement facilitates haemodtnamic stability of the patient and assists anaesthetists in deciding if and when to transfuse.

e)A Canadian study[16] found no difference in outcomes for premature babies between the transfusion of blood stored for a week or less and blood stored for a mean of two weeks.

f)Following the death of a Hong Kong woman from septic shock after receiving platelet rich plasma injections as a beauty treatment, two cosmetology hospitals in Shanghai were investigated. Platelet rich plasma injections (PRP) are not approved by Chinese health authorities.

g)Sumeet Goswami (College of Physicians and Surgeons of Columbia University, New York, USA) and team reported in Anesthesiologythat patients who receive intraoperative blood transfusion are at increased risk of intraoperative cardiac arrest (ICA); and that as the number of transfused units of blood rises, so does a patient's risk for ICA. In the study, ICA occurred at an approximate rate of seven cases per 10,000 noncardiac surgeries and carried a 30-day postoperative death risk of 63 per cent. The authors suggested primary prevention might be the key to reducing mortality from ICA[17].