MONITORING INTERNATIONAL TRENDS

posted 4 May 2012

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

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

A summary of recent matters of interest appears below. Highlights include:

  • Clinical trials are continuing on a number of new therapies for haemophilia.
  • At the annual meeting of the American Academy of Allergy, Asthma and Immunology, presentations reported on studies in treating primary immunodeficiency and hereditary angioedema.
  • A number of companies are interested in developing treatments for sickle cell disease.
  • Research continues on treating Alzheimer’s Disease with plasma products.
  • The impact of transfusion on outcomes in cardiac surgery remains a research interest, as does the relationship between age of red cells and surgical outcome.
  • Researchers have investigated subsets of blood ‘progenitor’ cells and the signals that cause them to expand and develop into mature blood cells.
  • The American Association of Blood Banks issued new guidelines on the level at which a patient's red blood cell count can be viewed as so low as to require a transfusion.
  • Scientists have developed a gene therapy strategy they say could feasibly treat both β-thalassemia and sickle cell disease.
  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. This update includes clinical trials on new therapies for haemophilia and studies on treating primary immunodeficiency and hereditary angioedema.

a.Coagulation factors

  • In January Pfizer initiated a Phase I clinical trial for PF-05280602, an investigational proprietary, engineered variant of recombinant human Factor VIIa developed by Catalyst Biosciences. PF-05280602 has been engineered to provide improved acute and prophylactic treatment for haemophilia A and B patients with inhibitors. Catalyst is also engineering next generation recombinant human Factor IX and Xa variants.
  • CSL Behring announced in February the results of a Phase I study evaluating recombinant fusion protein linking coagulation Factor IX with albumin (rIX-FP) in patients with severe hemophilia B. Results of the study, which were presented at a congress in Switzerland, showed that rIX-FP was well tolerated in all patients and lasted longer in the body due to its prolonged half-life, compared with current Factor IX treatment options. In this analysis, no serious adverse events (including no hypersensitivity reactions), presence of inhibitors to Factor IX, or antibodies to rIX-FP were reported. Terminal half-life (a measure of how long the drug lasts in the body) was more than five-times longer in comparison with values associated with current recombinant Factor IX therapy. Incremental recovery and area under the curve (a measure of total exposure to the drug) were also significantly improved in comparison with values associated with current recombinant Factor IX therapy. The drug received orphan drug status in the US[1] in February 2012, having received orphan drug status from European regulators in May 2011. The CSL Behring rVIIa-FP clinical program is being initiated with the intention of demonstrating that an extended half-life rVIIa-FP will result in a requirement for fewer doses, while providing adequate therapeutic response in patients who have haemophilia A and B with inhibitors.
  • CSL Behring announced in March the first in human dosing of recombinant fusion protein linking coagulation factor VIIa with albumin (rVIIa-FP). The Phase I study will investigate in healthy volunteers the safety and pharmacokinetics of rVIIa-FP in comparison with placebo. CSL Behring, in collaboration with its parent company, CSL Limited, is developing rVIIa-FP, to treat hemophilia A and hemophilia B patients who have inhibitors, as part of the PROLONG 7- FP clinical study program. CSL Behring's technology uses albumin as the ideal recombinant genetic fusion partner for coagulation factor proteins due to its inherently long half-life, high potential for tolerability, known mechanism of clearance and low potential for immunogenic reactions. CSL Behring's rVIIa albumin fusion protein is expected to exhibit a good tolerability profile and improved pharmacokinetics that may enable prophylaxis. CSL Behring's rVIIa-FP was previously granted Orphan Drug Designation by the European Commission and the United States Food and Drug Administration (FDA).
  • Prolor Biotech in February reported positive results in a comparative study of its longer-acting version of Factor VIIa (Factor VIIa-CTP) in a preclinical trial in mice. The study found that the mice which received Factor VIIa-CTP showed a superior survival rate over a longer time period following a bleeding challenge, superior and longer-lasting generation of thrombin (a key pro-clotting enzyme) and significantly higher in vivo recovery. Prolor had previously reported that Factor VIIa-CTP had increased half-life and clotting activity compared with Factor VIIa.
  • CSL Behring announced in February that the first patient has been screened in its recombinant coagulation single-chain factor VIII trial, part of the AFFINITY clinical trial program. The Phase I/III study is an open-label, multicentre trial that examines the crossover safety, efficacy and pharmacokinetics of recombinant coagulation single-chain factor VIII compared with recombinant human anti-haemophilic factor VIII (octocog alpha)[2]. The underlying research is the result of collaboration across CSL research sites in Germany, the US and Melbourne.
  • Inspiration's recombinant factor IX (IB1001) has completed pivotal Phase III clinical testing in the US, Europe, Israel and India. To date, IB1001 has been well-tolerated by patients and pharmacokinetic results have demonstrated non-inferiority to the one approved recombinant Factor IX product currently marketed for treating haemophilia B. Inspiration says the data demonstrated effective surgical haemostasis in people with haemophilia B undergoing major surgical procedures. The data were highlighted in a poster presentation at the 5th Annual Congress of the European Association for Haemophilia and Allied Disorders (EAHAD) in Rome. Inspiration submitted a Biologics License Application (BLA) to the FDA in April for the approval of IB1001.

b.Treatment of primary immunodeficiencies

  • At the annual meeting of the American Academy of Allergy, Asthma, and Immunology (AAAAI) in Orlando in March, researchers reported that subcutaneous immune globulin (Hizentra) remains safe and effective up to two years in the treatment of patients with primary immunodeficiency diseases. The overall rate of infections was 2.4 per patient-year among patients receiving once-weekly infusions, according to Robert P. Nelson Jr., of Indiana University in Indianapolis. The study[3] was funded by CSL Behring.
  • At the same meeting, Baxter presented additional long-term data supporting the clinical profile of HyQ, its investigational combination product for use in patients with primary immunodeficiencies (PI). The company also introduced HyQvia [Immune Globulin Infusion 10% (Human) with Recombinant Human Hyaluronidase], as the submitted brand name for the investigational product, previously referred to as HyQ.
  • Also at the AAAAI meeting CSL Behring suggested that the bioavailability of immunoglobulin G (IgG) therapies is consistent when patients with primary immunodeficiencies switch from one IgG product to another by the subcutaneous route. The analysis was a joint effort between CSL Behring and physicians at the University Hospital of Wales and the University of South Florida. Based on an analysis of published data, the study found that bioavailability – the percentage of unchanged drug that reaches the circulation – was similar among four subcutaneous IgG (SCIg) preparations and all fell within the range of 66.7+2.7% as compared with intravenous IgG[4]. "Maintaining a consistent level of IgG in the blood is important for patients with primary immunodeficiencies in order to prevent infections," said John W. Sleasman of the University of South Florida. "This analysis provides reassurance that regardless of current treatment – intravenous or subcutaneous – patients can switch IgG products without undue concern about dosing or therapeutic IgG levels."

c.Treatment of hereditary angioedema (HAE)

  • At the AAAAI meeting CSL Behring presented data showing that treatment with Berinert®, C1 Esterase Inhibitor (Human) within six hours of the onset of an acute HAE attack provides faster relief than later treatment. A second study retrospectively analysed patient outcomes associated with intravenous self-administration of C1 Esterase Inhibitor (C1-INH), which enables patients to treat themselves earlier, at home. The study, conducted over a period of more than 18 months, enrolled a total of 13 HAE patients who were shown how to self-administer. The study found that self-administration of intravenous C1-INH concentrate can be a good option for patients with HAE. Adverse events were rare in the study, and no complications related to home administration were reported. Berinert is derived from human plasma[5].
  • ViroPharma and Halozyme Therapeutics announced positive data from ViroPharma’s Phase II subcutaneous trial of Cinryze (C1 esterase inhibitor [human]) in combination with Halozyme's Enhanze technology, a proprietary drug delivery platform using Halozyme's recombinant human hyaluronidase enzyme (rHuPH20), in patients with HAE. The data demonstrated that subcutaneous co-administration of Cinryze with rHuPH20 was easy, well tolerated and resulted in sustained physiologically relevant C1 INH functional concentrations. The combination administered subcutaneously as a single injection will be further evaluated for the prevention of HAE attacks. Cinryze is approved in the US for intravenous (IV) administration for routine prophylaxis against angioedema attacks in adolescent and adult patients with HAE, and in Europe for routine prevention, pre-procedure prevention, and acute treatment of angioedema attacks in adolescents and adults.
  • The AAAAI meeting was told that treatment with the bradykinin receptor blocker icatibant (Firazyr) led to rapid resolution of all types of oedema attacks in patients with hereditary angioedema, even the most severe. By four hours after a subcutaneous injection of icatibant, the percentage of patients reporting severe or very severe cutaneous involvement had fallen from 40.4% at baseline to 2%, compared with only 19.7% of those receiving placebo. Among patients with potentially life-threatening laryngeal attacks, the percentage reporting severe or very severe difficulty swallowing had decreased from 28.6% to 10.6% after two hours and to 1.9% by four hours[6]. The data were from the FAST-1, -2, and -3 (For Angioedema Subcutaneous Treatment) trials[7]. Icatibant was approved by the FDA in August 2011. It is given subcutaneously, so patients can administer it themselves, and will know within minutes if it is working.

d.Treating anaemia

  • On 7 March Amag Pharmaceuticals reported preliminary results from the first of two Phase III studies in its global registrational program for Feraheme (ferumoxytol) in patients with iron-deficiency anaemia regardless of the underlying cause. The study compared treatment with Feraheme to treatment with IV iron sucrose, and enrolled 605 patients at 74 sites in Europe, Asia Pacific and Australia[8]. The other study in the US, Canada, Europe and India is evaluating Feraheme compared with placebo in 800 patients. This study is now fully enrolled with results expected in mid-2012.
  • A once-daily oral anaemia drug from Akebia Therapeutics met its primary endpoint in a phase IIa trial of chronic kidney disease patients. Akebia expects to file a new drug application for the oral anaemia drug in 2015.

e.Treating sickle cell disease

  • Adventrix Pharmaceuticals’ lead candidate is ANX-188, a rheologic, antithrombotic and cytoprotective agent that improves microvascular blood flow and has potential application in treating a range of conditions, such as complications arising from sickle cell disease. Adventrix began 2012 with a cash position of $US50 million, which will be used to fund its planned Phase III study of ANX-188 in patients with sickle cell disease.
  • San Diego-based HemaQuest Pharmaceuticals has raised an additional $US13 million to support a mid-stage trial of the company’s lead drug candidate for sickle cell disease. The company expects to complete a planned Phase IIb trial of its lead drug by early 2014. HQK-1001, belongs to a class of compounds known as Short Chain Fatty Acid Derivatives that have been shown to stimulate foetal hemoglobin expression and red blood cell production in the laboratory.

f.Treating Alzheimer’s Disease (AD)

  • One major study yet to report is testing the use of IVIg for AD, and if this trial has a positive result there would be major implications for demand and price. Thus the NBA is also interested in the development of drugs not based on plasma products.
  • Pfizer research chief Mikael Dolsten told an Investor Conference in New York in February that the experimental treatment for Alzheimer’s, bapineuzumab, was the drug industry’s “best chance” to delay progression of the illness. His comments come months before critical Phase III trial data for the drug is due to be published. The development of bapineuzumab was originally a joint venture between Elan and Wyeth. Johnson and Johnson has an 18.4% stake in Elan.
  • Eli Lilly’s anti-beta-amyloid therapy solanezumab for the treatment of mild to moderate Alzheimer’s disease is expected to launch in 2014.

g.Promoting haemostasis (preventing blood loss)

  • CSL Behring announced on 16 March that the first patient has been treated as part of the REPLACE Phase III clinical trial evaluating the efficacy and safety of fibrinogen concentrate (Human) (FCH) in controlling micro-vascular bleeding during aortic aneurysm surgery. The purpose of this study is to demonstrate that FCH can reduce intraoperative bleeding and the volume of blood products (fresh frozen plasma, platelets, and red blood cells) needed during complex cardiovascular surgical procedures. The study also aims to show that FCH is safe and well tolerated. The primary efficacy endpoint measurement will be the number of units of all allogeneic blood products transfused during the first 24 hours after administration of FCH or placebo. "Potentially life-threatening bleeding events can occur during cardiovascular surgery because the patient's fibrinogen levels are depleted, which delays clotting" said Dr. Niels Rahe-Meyer, Department of Anesthesiology and Intensive Care, Franziskus Hospital, Bielefeld, Germany and coordinating investigator of the study. Of the 12 million units of blood used in the US each year, 15% are used in cardiovascular surgery. Some studies have suggested that blood transfusion during or after adult cardiac surgery is associated with increased long-term mortality.
  • A new biological dressing has been designed to achieve a rapid halt to bleeding, reducing military and civil casualties. The nanoscale spray coating of thrombin (a blood-clotting protein) and tannic acid (a component of black tea with antibacterial properties) was developed by a team of researchers from the Massachusetts Institute of Technology to coat sponges, which are convenient for soldiers and medical personnel to carry. These dressings overcome the disadvantages of some other haemostatic materials. A tourniquet cannot be used on the neck. Chitosan bandages, adopted by the US Department of Defense, can be used only on simple wounds. Ferrosan sponges, which are used in some hospitals, require soaking in thrombin solution prior to application on the wound, thus proving impractical on battlefields.
  • Rotem Systems announced in February that 20 additional medical centres within the US have acquired the ROTEM® whole blood haemostasis analyser, which monitors the coagulation state of a blood sample in order to assist in the assessment of patient clinical haemostasis conditions. The ROTEM results, within 10 minutes, and in conjunction with other tests, are designed to assist the clinician manage dangerous surgical and trauma bleeding, while reducing the need -and inherent risks- of blood transfusions and assisting with the selection of the most appropriate blood product required[9].

h.Other

  • A mobile device tool has been created for easy access to the US Centers for Disease Control and Prevention's adverse reaction definitions used in the Hemovigilance Module of the National Healthcare Safety Network[10]. The tool, which can be shared with clinicians for categorising adverse reactions, is designed to work on iPhones, iPads and other mobile Internet-access devices.
  • Flinders University researchers have developed a device to warm blood for emergency transfusions in the field. The device is now in its first stage of commercialisation. The Intraheat device will not need a power source. The ambulance officer or combat medic "pulls the rip cord" on the portable, disposable unit to trigger a chemical reaction which heats the blood and other intravenous fluids as it flows from the bag to the patient.
  • University of Tasmania Professor Emily Hilder's new MilliSpot paper means a spot of blood can be used in place of vials of blood to provide accurate test results. Blood spots, which dry quickly, become non-hazardous and do not need refrigeration; but storing on paper, though useful for newborns since the 1940s, has not been reliable for drug testing. This new paper is a porous polymer-based material.
  • After three tours in Afghanistan as a trauma surgeon, and inspired by a simple hair clip, Canadian Dr Dennis Filips designed a clamp which stops bleeding from wounds within seconds. His Innovative Trauma Care (ITC) firm based at the Edmonton Research Park aims to launch the device later this year to hospitals, ambulances and the military in Canada, the US, Australia and New Zealand.
  • CSL Behring in March announced that the first patient has been enrolled in the PATH[11] study, an international clinical trial designed to evaluate the efficacy, safety, and tolerability of two different doses of subcutaneous immunoglobulin (SCIg), compared with placebo, in maintenance treatment of chronic inflammatory demyelinating polyneuropathy(CIDP).
  • Biotest announced in April the publication of clinical data[12] reporting on the efficacy of the company’s new investigational IVIg product, a 10% liquid product, which does not contain any sugar.
  • On 21 February CSL Behring announced that thought leaders from the medical community in Europe and the US examined the pros and cons of using albumin in treating liver disease and sepsis, in cardiac surgery and in burns patients, during CSL Behring’sKey Issues Dialogue – “Albumin in Clinical Fluid Management.”
  • German company AiCuris announced trial results for Letermovir (AIC246). It met primary efficacy endpoints in Phase II for human cytomegalovirus (HCMV) prophylaxis in human blood precursor cell recipients. The company said the trial showeddose-dependent effect on the prevention of HCMV re-activation/re-infection and an excellent tolerability.
  • Vical announced in April that the company and Astellas Pharma had finalised the general design of a pivotal, multinational Phase 3 trial of TransVax, the companies' therapeutic cytomegalovirus, or CMV, vaccine for transplant recipients. The companies expect to begin the Phase 3 trial of TransVax for hematopoietic stem cell transplant recipients in the second half of 2012, and initiate a Phase 2 efficacy trial of TransVax for solid organ transplant recipients shortly thereafter. If such a vaccine proves successful, there would be implications for the demand for cmv immunoglobulin for transplant patients.
  • On 17 April, Medgenics filed a new drug application to FDA so that it can start a Phase II trial for the Biopump. The multi-centre trial comprising 100 patients is designed to evaluate the safety and efficacy of sustained erythropoietin (EPO) therapy, which is delivered by Medgenic’s EPODURE Biopump, for the treatment of anaemia in dialysis patients with end-stage renal disease. EPODURE is a small tissue implant made from the patient's own skin tissue. The company says a previous study provided positive data which demonstrated that a single administration of EPODURE can raise and maintain haemoglobin levels for many months without any injections of EPO or other stimulating agents.
  1. Regulatory Matters. Here the NBA follows overseas regulatory decisions on products, processes or procedures which are or may be of relevance to its responsibilities.

a.In January the FDA approved Baxter’s fibrin sealant Tisseel to include general haemostasis in surgery when control of bleeding by standard surgical techniques is ineffective or impractical. Tisseel is approved by Australia’s Therapeutic Goods Administration (TGA). The NBA notes that fibrin sealants are one of the most commonly requested products for addition to the supply plan with strong interest from clinicians.