NBA - Highlights of Monitoring International Trends 2011- 2012

Highlights of Monitoring International Trends, 2011- 2012

MONITORING INTERNATIONAL TRENDS

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

Information that may have an impact on global supply, demand and pricing
Potential new product developments and applications
Trends in clinical practice, government regulation and legal decisions
Emerging risks that could put financial or other pressures on the Australian sector.

Matters of interest are posted on the NBA website provide in each section below a description of the types of information we seek, with selected highlights from the year under review.

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

a.Clotting factors. New products may lead to improved therapies for patients, and in some instances to more competitive pricing.

Competitiveness is of particular importance for recombinant factor VIIa (rFVIIa) where there is currently only one product commercially available.
In January Pfizer initiated a Phase I trial for a variant of rFVIIa for haemophilia A and B patients with inhibitors.
CSL Behring announced in March the first dosing of recombinant fusion protein linking FVIIa with albumin (rVIIa-FP). Albumin has long half-life, tolerability, known mechanism of clearance and low immunogenic reactions.
Prolor Biotech in February reported positive results in a comparative study of its longer-acting version of Factor VIIa (Factor VIIa-CTP) in mice.
Bayer continued clinical development of itsrFVIIa candidate.
In rFIX, used in haemophilia B, only one product is currently available. However:
Inspiration's IB1001 has completed Phase III clinical testing and the company submitted a Biologics License Application (BLA) to the FDA in April.
CSL Behring’s Phase I study evaluating recombinant fusion protein linking FIX with albumin (rIX-FP) in severe haemophilia B showed it was well tolerated, and lasted longer in the body than current FIX treatment options.
In rFVIII, used in haemophilia A, there are several products in the pipeline:
CSL Behring’s recombinant coagulation single-chain FVIII trial.[1].
BiogenIdec and Sobi’slonger-lasting FVIII Fcfusion protein (also rFIXFc).
Inspiration’s OBI-1,anintravenous(IV) porcineFVIII,for use in hemophiliaA withinhibitorsandinacquiredhaemophilia.
Baxter’s BAX 855,alonger-acting (pegylated) form ofafull-lengthrFVIII.
Baxter’s subcutaneous BAX 499totreat haemophiliaA andBby targetinganovel pathway responsiblefor regulating the clottingprocess. Baxter is also developing a recombinant vonWillebrandFactor (rVWF).
Pfizer Canada in May launched XYNTHA Solofuse, the first device in Canada preloaded with rFVIII and diluent.

b.Immunoglobulin

Immunoglobulinis used by patients with primary immunodeficiencies (PI). Self- administered injection is now an option as well as infusion. Researchers reported that subcutaneous Hizentra is safe and effective up to two years in treating PI. [2]
Intravenous immunoglobulin (IVIg) is an effective treatment for certain disorders of the nerve and muscles, including Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyneuropathy (CIDP), according to a guideline issued by the American Academy of Neurology[3]. CSL Behring announced the first patient has been enrolled in the PATH[4] study, atrial to evaluate the efficacy, safety, and tolerability of two different doses of subcutaneous immunoglobulin (SCIg), compared with placebo, in maintenance treatment of CIDP.
Baxter presented Phase III clinical data evaluating the safety and efficacy of Gammagard Liquid 10% [Immune Globulin Infusion (Human)] for the treatment of multifocal motor neuropathy (MMN). The data on 44 patients formed the basis for a regulatory filing. Gammagard demonstrated an increase in mean grip strength of the more affected hand during treatment, as compared with a decrease in mean grip strength with placebo. A greater proportion of patients who received placebo experienced progressive disability.
Baxter initiated a second Phase III trial evaluating the use of Gammagard Llquid in patients with mild to moderate Alzheimer's disease (AD). This complements Baxter’s first Phase III trial, which is fully enrolled and will conclude by the end of 2012.The company also announced an extensive study for some patients who completed 18 months of treatment in the first Alzheimer's Phase III trial. This will provide additional data related to the longer-term safety, efficacy and pharmacoeconomic impact of immunoglobulin treatment in these patients.
Other studies are also assessing the tolerability and efficacy of IVIG in AD. One hypothesizes that the slow release of immunoglobulins into the circulation and eventually into the brain for a protracted period of time may delay Alzheimer's disease dementia onset and eventually its progression[5].
If immunoglobulin were to become a recognised therapy for AD the increased demand would have a major impact on price, particularly in the short-term. Drugs not based on plasma products are therefore of interest, including
Bapineuzumab. (Pfizer, Johnson and Johnson and Elan).
Solanezumab. Eli Lilly’s anti-beta-amyloid therapyto launch in 2014.

c.Treatment for hereditary angioedema (HAE)

CSL Behring showed that treatment with plasma- derived Berinert, C1 Esterase Inhibitor (Human) within six hours of the onset of an acute HAE attack provides faster relief than later treatment. A second study retrospectively analysed patient outcomes associated with intravenous self-administration of C1 Esterase Inhibitor (C1-INH). This was found to be a good option for patients.[6]
ViroPharma and Halozyme Therapeutics announced positive data from a Phase II subcutaneous trial of Cinryze (C1 esterase inhibitor [human]) in combination with Halozyme's Enhanze technology, in patients with HAE. Subcutaneous co-administration was easy, well tolerated and resulted in sustained physiologically relevant C1 INH functional concentrations. Cinryze is approved in the US for IV administration for routine prophylaxis against angioedema attacks in adolescent and adult patients with HAE, and in Europe for routine prevention, pre-procedure prevention, and acute treatment of attacks in adolescents and adults.
Treatment with the drug icatibant (Firazyr) was shown to lead to rapid resolution of all types of oedema attacks in patients with hereditary angioedema. Icatibant was approved by the US Food and Drug Administration (FDA) in August 2011. It is given subcutaneously, so patients can administer it themselves.

d.Promoting haemostasis (preventing blood loss)

CSL Behring announced in March that the first patient has been treated as part of the REPLACE Phase III clinical trial evaluating the efficacy and safety of fibrinogen concentrate (Human) (FCH) in controlling micro-vascular bleeding during aortic aneurysm surgery. The purpose of this study is to demonstrate that FCH can reduce intraoperative bleeding and the volume of blood products (fresh frozen plasma, platelets, and red blood cells) needed during complex cardiovascular surgical procedures. The study also aims to show that FCH is safe and well tolerated. The primary efficacy endpoint measurement will be the number of units of all allogeneic blood products transfused during the first 24 hours after administration of FCH or placebo.
A new biological dressing has been designed to achieve a rapid halt to bleeding, reducing military and civil casualties. The nanoscale spray coating of thrombin (a blood-clotting protein) and tannic acid (a component of black tea with antibacterial properties) was developed to coat sponges, which are convenient for soldiers and medical personnel to carry.
Twenty additional medical centres within the US have acquired the Rotem whole blood haemostasis analyser, which monitors the coagulation state of a blood sample in order to assist in the assessment of patient clinical haemostasis conditions. The Rotem results, within 10 minutes, and in conjunction with other tests, assist the clinician manage dangerous surgical and trauma bleeding[7].

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

a.Baxter International and Halozyme Therapeutics announced in April the FDA wanted more information about long-term use of its PI drug, HyQ. HyQ is a combination of immune globulin and recombinant human hyaluronidase to boost absorption so delivery can be by injection instead of an IV drip. An application in the European Union was also pending.

b.Biotest obtained marketing authorisation from the Paul Ehrlich Institute for Fovepta, a hepatitis B hyperimmunoglobulin. Fovepta can be administered subcutaneously to the newborn babies of mothers infected with hepatitis B.

c.Baxter in March recalled one lot of its GAMMAGARD LIQUID 10%, 20g because of incorrect labelling on manufacturing and expiry dates. A March report analysing biologics recalls issued or reported with the FDA and its agencies concluded that immunoglobulins and vaccines are involved in more recalls than other drug classes.

d.The FDA’s Blood Products Advisory Committee (BPAC) provided a unanimous positive recommendation for the company's OraQuick in-home HIV Test.

e.Gilead Sciences announced in May that the Antiviral Drugs Advisory Committee of the FDA voted to support approval of once-daily oral Truvada (emtricitabine and tenofovir disoproxil fumarate) to reduce risk of HIV-1 infection in uninfected adults,

f.The US National Institutes of Health (NIH) and the FDA are collaborating on a series of workshops on moving pluripotent stem cell therapies into the clinic.

Osiris Therapeutics won approval in Canada for its stem-cell drug, Prochymal, for a disease that can attack patients who received bone-marrow transplants. Prochymal was approved for the treatment of acute graft versus host disease in children for whom steroids haven’t worked.
Market structure and company news. In general terms, the industry is currently in growth mode.

a.Baxter. In April, the US State of Georgia announced it is giving Baxter a $US78m incentive package to build an integrated plasma processing facility in Georgia, with greater capacity than its Los Angeles plant.. Construction in Georgia will begin in 2012 and commercial production in 2018.

b.CSL. In February CSL announced that first-half net profit fell 3.4% as the high Australian dollar put pressure on its earnings. Without the impact of exchange-rate movements, net profit would have grown 16%. However, the company also upgraded its full-year profit guidance, citing vigorous demand for its products. North America was CSL’s biggest market, accounting for 42% of revenue, followed by Europe with 32% and Australia with 10%. CSL said it plans to begin reporting in US dollars in the year starting 1 July, in line with industry practices and to reflect the predominance of the company’s global sales. The company made a provision of about €11 million ($A15 million) in the first half in case of delays or defaults in payments by southern European customers.

c.Grifols.has acquired 51% of Araclon Biotech, which specialises in development of therapies and diagnostic methods for neurodegenerative diseases. It currently focusses on AD[8]. Grifols recently launched a second trial for the treatment of AD with plasma derivatives, combining haemapheresis with the administration of albumin and IVIg. Grifols is opening its largest and most advanced plasma testing facility in San Marcos, Texas. The facility will analyse up to 5 million human samples annually.

d.NovoNordisk reported Increased earnings were reported in the fourth quarter 2011 compared with prior-year earnings. Total revenues were up 12% (in local currencies), including a significant increase in NovoSeven (rFVIIa) sales where it is currently the sole supplier. Novo Nordisk increased its sales growth guidance for 2012 to 7%–11% in local currencies, with operating profit growth around 10%.

d.Octapharmain 2011 had net sales 2% above 2010. Gross profit in 2011 was €205 million, or 28% of net sales and an increase of €31 million compared with 2010.

e.Other

The Pharming Group signed an agreement with Renova Life for the development and supply of founder transgenic rabbits to enable Pharming to start the commercial breeding process. The first protein to be expressed in the rabbits will be recombinant human Factor VIII (rhFVIII) for the treatment of haemophilia A. Pharming said the European approval of its rh C1 inhibitor (Ruconest) has demonstrated its ability to produce industrial volumes of high quality recombinant human protein through a method which requires significantly lower capital investment and manufacturing costs than current cell based technologies.
Shire and Sangamo BioScienceshave agreed to develop therapeutics for haemophilia and other monogenic diseases. Products will be based on Sangamo’s zinc finger DNA-binding protein technology. Shire has also signed an agreement to acquire FerroKin BioSciences. This adds a product in development (iron chelator FBS0701) to iron overload following numerous transfusions.
Axerion Therapeuticsand MedImmune have a sublicense arrangement to develop and commercialize a biologic approach for the treatment of AD.

Overseas events. The NBA follows safety issues and instances of good practice. It monitors health issues in countries from which its visitors and immigrants come.

a.United Kingdom

Experts advising the Department of Health believe patients who have received more than 80 blood transfusions are most at risk of developing variant Creutzfeldt-Jakob disease (vCJD). They would expect to see 150 cases among the group of around 30,000.
Since August 2002, as one of a range of measures to minimise the risk of potential vCJD transmission through blood transfusion, imported fresh frozen plasma (FFP) hasbeen used to treat those born on or after 1 January 1996, and therefore unlikely to have been exposed to bovine spongiform encephalopathy (BSE) through their diet. The Advisory Committee on the Safety of Blood, Tissue and Organs (SaBTO) reviewed this measure at their meeting on 9 March 2012, and concluded that it should continue, even when those recipients become 16 years old or more. Adult patients with thrombotic thrombocytopenic purpura (TTP) should also continue to receive imported solvent detergent treated FFP.
SaBTO also published advice on the provision of blood components for transfusion that have been tested for cytomegalovirus (CMV) as well as being leucodepleted. CMV is a common virus, which causes chronic symptom-free infection for most adults, but may have more serious outcomes in some. SaBTO considered the potential risk to specific patient groups, and concluded the range of patients receiving CMV-tested blood should be reduced.
In a report to shareholders in March, ProMetic said it would continue to assist Macopharma, with the adoption of the P-Capt filter in the UK, in line with SaBTO's recommendation, in November 2009, for adoption of the P-Capt filter for red cells transfused to children born after January 1, 1996, depending on the results of the PRISM study. The PRISM (Prion-filtered vs. standard Red cells in Surgical and Multi-transfused patients) study by SaBTO showed that following administration of P-Capt filtered red cells to patients:
No antibodies found in study patients were attributable to use of the filter;
There was no significant difference in the number of definite and probable adverse events in patients receiving P-Capt filtered red cells and control patients who received standard red cells;
Use of the P-Capt filter did not reduce the overall safety of transfusion;
If implemented, the use of P-Capt filters would require post-marketing surveillance to assess continued safety in large populations of transfusees.

b.Canada

In February, Canadian Blood Services marked Black History Month by urging Canadians of African and Caribbean heritage to celebrate their unique culture through blood and stem cell donation. Individuals with African heritage possess certain minor blood groups that may make it difficult to find compatible blood when repeated transfusions are needed as in sickle cell disease treatment said Dr Isaac Odame, Medical Director of the Global Sickle Cell Disease Network at Sick Kids Hospital in Toronto.

c.Israel

Pluristem Therapeuticsannounced in May that a seven year-old girl suffering from an aplastic bone marrow whose condition was rapidly deteriorating had seen a reversal of her condition. The improvement came due to a significant increase in her red cells, white cells and platelets following the intramuscular injection of Pluristem's PLacental eXpanded (PLX) cells. In aplastic bone marrow the patient has no blood-forming hematopoietic stem cells in bone marrow.

d.United States

In May, the Obama administration presented its national plan to fight AD. The proposed 2013 budget provides $US 80m for additional research on AD.
The Vermont House voted in May to ask the FDA to lift its lifetime ban on blood donations by gay and bisexual men. The resolution called for a one-year period when blood should not be given after sexual contact with a man. The U.S. Department of Health & Human Services (HHS)had said that it would re-examine the ban. The Washington Times reported in May that the US government has one study in a planning stage and three studies under way.

Safety Issues. The impact of transfusion on outcomes in cardiac surgery remains an interest, as does the relationship between age of red cells and surgical outcome.

a.Patients given packed red blood cells had an increased risk for major infection after cardiac surgery, according to study results presented at The Society of Thoracic Surgeons 48th Annual Meeting[9].

b.At a professional update on paediatric and congenital cardiovascular disease in February, researchers reported that in paediatric heart transplantation, increasing amounts of blood transfused appears to be associated with worsening outcomes[10].

c.The duration of red blood cell storage did not adversely affect outcomes in ventilated patients receiving transfusions, according to a small randomized trial. There was no difference in short-term pulmonary, immunologic, or coagulation status between 50 patients who received fresh red blood cells (median storage of four days) and 50 who received standard-issue red blood cells (median storage duration of 26.5 days), reported Daryl Kor, from the Mayo Clinic in Rochester, Minnesota[11]. The study was done at a single centre, tertiary-care facility in a small patient population. The follow-up period was short, so delayed responses to the transfused red blood cell units were not identified. The investigators noted that their results differed from earlier study results that have found storage duration and adverse clinical outcomes. One possible reason is that patients in this study received a similar red blood cell dose, while earlier researchers did not adjust for dose, they suggested. Also, pre-storage leukocyte reduction was used for all red blood cell units transfused – including fresh ones – in this study, and this has been shown to lessen the accumulation of bioactive substances. The authors concluded that larger clinical trials randomising patients to fresh red blood cell units or prolonged storage units are ethical and possible.