Monitoring International Trends

posted March 2013

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

  • Potential new product developments and applications;
  • Global regulatory and blood practice trends;
  • Events that may have an impact on global supply, demand and pricing, such as changes in company structure, capacity, organisation and ownership; and
  • Other emerging risks that could potentially put financial or other pressures on the Australian sector.

A selection of recent matters of interest appears below.

Table of Contents

Products...... 1

Regulatory matters...... 2

Market structure and company news...... 4

Country- specific events...... 5

Safety and Patient Blood Management...... 6

Infectious Diseases...... 7

Appendix: Alzheimer’s Research...... 9

1.Products

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

Clotting factors

a)Baxter in February submitted a biologics license application (BLA) supplement to the US Food and Drug Administration (FDA) for the approval of prophylaxis with FEIBA NF (anti-Inhibitor coagulant complex), nanofiltered and vapour heated, in patients with haemophilia A or B and inhibitors.

b)The FDA in March accepted Biogen Idec’s BLA for the marketing approval of its recombinant factor IX Fc fusion protein (rFIXFc) for treating haemophilia B. The application included results from the B-LONG phase III clinical trial. This demonstrated that rFIXFc provides longer-lasting protection from bleeding with fewer treatments than are required with the current standard of care.

c)Biogen also submitted to the FDA its BLA for its long- lasting recombinant factor VIII Fc fusion protein (rFVIIIFc) to treat haemophilia A. Biogen Idec stated, "In our phase III study, patients treated with rFVIIIFc were able to inject rFVIIIFc once-weekly to twice-weekly, which creates the potential for those currently on prophylactic treatment to reduce injections by 50 to 100 per year. Moreover, patients currently treating bleeding episodes could potentially dose prophylactically once per week and maintain significant protection from bleeding with about the same total number of injections each year they use to treat bleeding episodes today."

Other

d)The FDA has approved a 40g (400 ml) vial size forPrivigen,immune globulin intravenous (human), for treatment of primary immunodeficiency and chronic immune thrombocytopenic purpura.

e)At the 2013 annual meeting of the American Academy of Allergy, Asthma & Immunology (AAAAI), data were presented showing CSL Behring’s Berinert, C1 esterase inhibitor (human), provides significant relief from cutaneous attacks of hereditary angioedema (HAE). Also at the Academy meeting, CSL Behring announced the results of a cost-effectiveness analysis which they said showed that on-demand treatment of HAE attacks with Berinert provides cost savings to payers when compared with the use of two other therapies approved in the US for the acute treatment of HAE, Firazyr and Kalbitor

f)A team from the University of Michigan Medical School has found that an antidepressant drug used for decades - tranylcypromine, or TCP - may be useful in treating sickle cell disease[1].

g)Hydoxyurea is currently the only FDA-approved medication for sickle cell anemia. It reduces the pain and organ damage caused by sickled blood cells; it is inexpensive. Not all patients respond to it, but it now appears response may be able to be predicted through genetic analysis.

h)Targeted Medical Pharma unveiled new results from an open label study of its oral amino acid-based erythrocyte stimulating system (ESS) for the treatment of chronic anaemia. The system is designed to stimulate progenitor stem cells in the bone marrow.

i)The FDA has accepted for review AMAG’ssupplemental new drug application (sNDA) for iron deficiency anaemia therapy -- Feraheme (ferumoxytol) injection for intravenous (IV) use. Approval would expand the indication for ferumoxytol beyond the current indication for the treatment of iron deficiency anaemia (IDA) in adult patients with chronic kidney disease (CKD) to adult patients with IDA who have failed or could not take oral iron treatment.

2.Regulatory

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

a)In February, Europe’s Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion recommending a variation to the terms of the marketing authorisation for CSL Behring’s Privigen[2].

b)The FDA has expanded the indication for Corifact, fXIII concentrate (human). In 2011 Corifact was approved in the US for the routine prophylactic treatment of congenital f XIII deficiency. Its indications now include the peri-operative management of surgical bleeding in adult and paediatric patients with congenital fXIII deficiency.

c)The FDA has granted orphan drug status to Pluristem Therapeutics for its PLacental eXpanded (PLX) cells for the treatment of aplastic anemia.

d)Affymax and Takeda Pharmaceutical, which jointly market the drug, Omontys, or peginesatide, to treat anaemia in patients undergoing kidney dialysis, recalled all lots of the product after reports that it had caused severe allergic reactions, including some that were fatal. The FDA announced 19 reports of anaphylaxis. Three of the patients had died.

e)The FDA sent a warning letter to Novo Nordisk concerning inadequacies it perceived during an inspection of a facility in Denmark.

f)The FDA again rejected rivaroxaban (Xarelto) to treat patients with acute coronary syndromes (ACS). Janssen Pharmaceuticals in March received a second "complete response letter," which generally means the FDA requires more data. Bayer HealthCare partnered with Janssen to develop rivaroxaban.

g)The FDA has granted orphan drug status[3] to ProMetic's plasma derived plasminogen for the treatment of hypoplasminogenemia, or type I plasminogen deficiency (T1PD)[4].

h)With intravenous immunoglobulin (IVIg) being trialled as a treatment for Alzheimer’s disease, there is concern that a positive result could put pressure on limited supply of the product. The FDA is now proposing to lower the hurdle drug developers will face in gaining approval for Alzheimer’s drugs. So far, the FDA has expected developers to demonstrate improvements in both cognition and function. Patients have had to demonstrate improved memory and acuity compared with a placebo group and also do better at tasks like dressing. The FDA is now planning guidances on trial designs that can focus on cognitive improvements alone or on preventive measures proved with biomarkers[5]. A short summary of some recent Alzheimer’s research is provided in an Appendix.

i)Tenaxis Medical has received FDA approval to market its ArterX surgical sealant for prophylactic use and for treating bleeding after clamp release. ArterX is designed for use in vasculature reconstruction in a range of surgical procedures. It is a two-part liquid system that when mixed and applied to the vasculature will transform into a flexible gel in under 15 seconds. Results of the clinical trial appeared in the Annals of Vascular Surgery.

3.Market structure and company news

The NBA’s business intelligence follows company profitability, business forecasts, capital raisings or returns, mergers and takeovers, arrangements for joint research and/or development, contracts for supply of manufacturing inputs, and marketing agreements. Companies considered include suppliers, potential suppliers and developers of products which may be of interest.

a)Cangene has purchased commercialization rights from bankrupt Inspiration and its partner Ipsen to IB1001, a recombinant factor IX (rFIX) currently under review by US and European regulators for treatment and prevention of bleeding in patients with haemophilia B. Cangene also acquired Inspiration’s rights to two preclinical drug candidates IB1007 (recombinant FVIIa) and IB1008 (recombinant FVIII).

b)Cangene reported its results for the second quarter of 2013, ending January 31, 2013. Total revenues for the quarter were $C 25.9 million, less than the $C 33.6 million in the same quarterof 2012. The decrease included a $C 9.7-million reduction in revenue from US government stockpiling and lower revenue for WinRho SDF. Partially offsetting these declines was a $C 4.0-million increase in vaccinia immune globulin (intravenous) revenue. Net loss for the current quarter was $C 3.3 million, an improvement from a net loss of $C 3.9 million in the same quarter of 2012.

c)A technology targeting Alzheimer's disease has been developed at The University of British Columbia (UBC) and licensed to Cangene Corporation. Dr.Neil Cashman's discovery will allow Cangene to advance an immune therapeutic treatment approach to Alzheimer's by targeting the toxic form of Amyloid-beta with the potential to directly impact the disease mechanism of action. Dr. Cashman is an expert in misfolded protein diseases. Dr. Laura Saward, Cangene's Chief Scientific Officer, says "While this work is in its early stages, it is showing promise for the development of a novel immunotherapy to address this devastating disease and fits Cangene's refocused strategy".

d)Grifols reported a 46 per cent increase in sales in 2012 over 2011, following its acquisition of Talecris. Profits rose some 500 percent.

e)Cerus Corporation announced financial results for the fourth quarter and year ended December 31, 2012. The company had year-on -year product revenue growth of 20 per cent. INTERCEPT Blood System disposable kit demand was up 28 per cent from 2011.

f)Kamada in 2012 posted its first profit from operations. Revenue rose 22 per cent to $US 72.7 million in 2012 and the company posted a net profit of $US 260,000 compared with a net loss of $US 3.7 million in 2011. Kamada's lead product is Glassia, an intravenous treatment for alpha-1 antitrypsin deficiency (AAT deficiency) in congenital emphysema. A milestone in 2013 will be obtaining the results of a Phase II/III clinical trial in Europe for inhalable AAT, due in December. Kamada will commence a Phase II clinical trial of inhalable AAT in the US in mid-2013.

g)Kamada is planning to trial its AAT in Type 1 diabetes. The company hopes ".. that the product can go directly to a Phase III clinical trial, because it is already registered for treating AAT deficiency in the US, Brazil, Argentina, and Israel, and we believe that at least in some of these markets, we can go directly to advanced studies " The AAT protein already has FDA orphan drug status. Kamada's distribution agreement with Baxter for Glassia can be expanded to the AAT protein for diabetes. If Baxter exercises this option, it will accept most of the cost of a US clinical trial.

4.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’s visitors and immigrants come.

a)In the US, the Obama administration called for open access to the results of federally funded research. John Holdren, chief of the White House Office of Science and Technology Policy, directed federal agencies that spend more than $US100 million annually on research and development to devise a plan to implement public access. The National Institutes of Health already has an open-access policy in place. The Holdren memo directed agencies are to ensure that papers stemming from research they fund should be freely available to the public within a year of publication.

d)The UK’s new Diamond Light Source in Oxfordshire is to analyse viruses requiring Containment Level 3 – including AIDS, hepatitis and some types of flu. They will be analysed at atomic and molecular level using the synchrotron light facility, which they hope will help develop new treatments and vaccines.

e)In Canada, a private company- Canadian Plasma Resources- announced that it plans to establish plasma collection operations in Toronto and Hamilton and that it will buy plasma. Currently, Canadian Blood Services and Héma-Québec buy immunoglobulin in the US and Europe. Cangene in Winnipeg has paid specialty plasma donors for decades, to provide antibodies used to create Rh immune globulin. A number of groups, including Canadian Doctors for Medicare, have called on the federal government to deny approval to Canadian Plasma Resources. Provincial health ministers are reportedly concerned about the impact on the voluntary donation system.

f)Taiwan is making publicly funded H5N1 vaccine available for high-risk people such as coastguardsmen, disease control medical personnel, airport security agents and individuals who are going to epidemic areas.

g)The Swiss Red Cross announced in February that it is reducing its supply of donor blood to Greece because bills have not been paid on time.

h)The French senate in December 2012 passed a law unilaterally banning the use of tubes containing di (2-ethyhexyl) phthalate (DEHP) from paediatric, neonatal and maternity wards. The ban will take effect from July, 2015, unless the European Commission takes action against France if the European Food and Safety Authority (EFSA)’s investigation into DEHP finds the ban is not scientifically justified. That report is expected in May.

i)Ireland’s Health Minister announced in March that the country’s blood service will continue permanent donor deferral for men who have sex with men (MSM).

j)The annual Royal College of Surgeons in Ireland Research Day was told how cancer cells 'hijack' platelets, enabling cancer to spread around the body and promote the growth of new tumours.

k)In New Zealand, Christchurch recorded a fourfold increase in infectious syphilis from 2011 to 2012. Most men who caught syphilis in 2011 were in their mid-40s and contracted the disease at sex-on-site venues, such as brothels. In 2012 the median age dropped to 26, with some sufferers as young as 19. Canterbury District Health Board Sexual Health Centre physician Dr Heather Young said: "The highest number of people contracting infectious syphilis is men having sex with men and many are using social media sites or smartphones to search for sexual partners." The applications enabled men to meet "anywhere safe and convenient" for casual sex. One of the big concerns was syphilis' potential to spread into the heterosexual community where it can be transferred from mother to baby during pregnancy. Congenital syphilis could result in miscarriages, stillbirths and abnormalities in babies, she said. Dr Ed Coughlan, clinical director of the Sexual Health Centre, said doctors around the city had been alerted and an advertising campaign was being published on Facebook and in homosexual magazines, he said.

5.Safety and patient blood management

We follow current issues in patient safety.

a)In a report published online in Anesthesia & Analgesia, Johns Hopkins investigators led by Steven M. Frank, M.D. say red cells in blood stored longer than three weeks lose the flexibility necessary to squeeze through the body’s smallest capillaries to deliver oxygen to tissue[6]. They found these changes are “not readily reversible after transfusion”.

b)At the American College of Cardiology meeting in San Francisco, results were presented from a new study that found transfusing donated blood more than three weeks old results in impaired blood vessel function . The authors[7] suggest why older blood might be detrimental to patient health: a deficiency in nitric oxide which is short lived but when present relaxes blood vessels.

c)Also at the American College of Cardiology meeting in March, researchers from the Cleveland Clinic and Sahlgrenska University Hospital (Sweden) reported that darbepoetin alfa - commonly used to treat anaemia in heart failure patients - does not improve patients' health does not reduce their risk of death from heart failure. Results were published simultaneously online by the New England Journal of Medicine.

d)Patients with major bleeding after procedures to open blocked heart arteries are at significantly increased risk of death, according to a new study published in the March 13 issue of the Journal of the American Medical Association. The researchers also said there are ways to predict a patient's risk of bleeding after percutaneous coronary intervention and the risk should be reduced through the use of drugs or other methods.

e)A meta-analysis[8] suggested that using hydroxyethyl starch for critically ill patients who required volume resuscitation was associated with higher mortality compared with using other fluids.

f)In the US, the proportion of hysterectomies conducted with robotic assistance increased from one in 200 procedures in 2007 to almost one in 10 in 2010, according to a new study led by. Dr. Jason Wright from Columbia University[9]. They found this did not reduce post- surgery complications. There was also no difference in patients’ chances of receiving a blood transfusion.

g)Dr. Sam Schulman of McMaster University in Ontario led studies of more than 2,800 patients who had venous thromboembolism[10]. In one, Pradaxa was compared with warfarin, and in the other Pradaxa was compared with placebo. Researchers found that 1.8 per cent of patients taking Pradaxa had recurrent clots, compared with 1.3 per cent of patients taking warfarin. Fewer patients taking Pradaxa had major bleeding compared with those taking warfarin (13 against 25). Three patients taking Pradaxa developed clots, compared with 37 patients taking placebo. The study was funded by the manufacturer of Pradaxa, Boehringer Ingelheim.