NBA - Monitoring Internation Trends - Prepared November 2012
MONITORING INTERNATIONAL TRENDS
posted November 2012
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. Amongst the highlights:
- A range of new clotting factors are in development.
- An overseas economic model suggests that when hospital costs are taken into account, higher dosing of subcutaneous immunoglobulin therapy in patients with primary immunodeficiencies is cost-effective compared with intravenous immunoglobulin.
- Two drugs which were thought to offer some hope for Alzheimer’s patients – bapineuzumab and solanezumab- did not meet their endpoints in clinical trials, although there is some suggestion they may have some positive effect early in the disease. The spotlight is focussed now on the trial of Baxter’s intravenous immunoglobulin in Alzheimer’s disease, due to report in 2013.
- A product made from human blood past its use- by date is claimed to boost the capacity of red cells to deliver oxygen to organs and tissues after trauma- induced bleeding.
- Blood salvage technology designed at the University of Strathclyde, Glasgow, has gained both European and Canadian approval.
Table of Contents
Products...... 1
Regulatory matters...... 3
Market structure and company news...... 4
Overseas events...... 6
Safety...... 7
Research...... 8
Legal actions and enquiries, Infectious Diseases……………………………………… 11
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)Biogen Idec and Sobi also announced positive results from their Phase III study of their long- lasting rFVIII fusion protein in haemophilia A. They said their A-LONG study showed their rFVIIIFc was effective in controlling and preventing bleeding, in routine prophylaxis, and in peri-operative management. A Biologic License Application (BLA) will be submitted to the FDA in the first half of 2013. The European Medicines Agency (EMA) requires a study in children less than 12 years of age prior to filing, so a Marketing Authorization Application cannot be submitted to the EMA until completion of the Kids A-LONG study.
b)Novo Nordisk in October announced the submission of the application for marketing authorisation for turoctocog alfa (NN7008) to the FDA and EMA. Turoctocog alfa is a third-generation rFVIII for prevention/ treatment of bleeding in haemophilia A. The application is based on the results from clinical trials Guardian1 and Guardian3, completed in 2011. More than 200 patients round the world were enrolled, making Guardian the largest clinical pre-registration trial programme conducted in haemophilia A. The phase III trials included previously treated adults and children with severe haemophilia A and demonstrated efficacy in preventing and treating bleeds with no development of inhibitors. Applications for regulatory approval in other countries will follow. Novo Nordisk’s rFXIII (NN1841) has already been submitted for approval, and the company has a long-acting rFIX derivative in development.
c)Prolor Biotech’s FVIIa differs from NovoNordisk’s experimental FVIIa therapy, vatreptacog alfa, on which work was recently discontinued. In the NovoNordisk compound, three amino acids had been substituted to enhance platelet enzyme activity, but this has not been done in the Prolor drug which uses Carboxyl Terminal Peptide technology (CTP) to extend half- life.
Immunoglobilin
d)At the 15th Biennial Meeting of the European Society for Immunodeficiencies, Elie Haddad(Professor, Department of Pediatrics, Microbiology and Immunology, University of Montreal) presented a new economic model to demonstrate that higher dosing of subcutaneous immunoglobulin therapy (SCIg) is cost-effective in patients with primary immunodeficiencies compared with intravenous immunoglobulin (IVIg). The higher doses of SCIg are cheaper than IVIg therapy because they mean lower costs for hospital care. The speaker said: “This new model shows that, in addition to the benefits of improved clinical outcomes and increased patient satisfaction, SCIg also provides true monetary value across a wide range of dosing scenarios.”
e)In children with acute Kawasaki disease, a randomized, double-blind, placebo-controlled trial showed that adding Remicade (infliximab, a tumor necrosis factor inhibitor) to standard treatment with IVIg plus aspirin did not affect treatment resistance or coronary artery outcomes[1].
f)Grifols announced in September that it had a robust inventory of rabies immune globulin (human) to overcome US supply constraints. The product immediately protects people exposed to rabies who have not been vaccinated. They are then given a series of rabies vaccinations to ensure permanent immunity.
Patient Blood Management
g)Sandoz, the generic arm of Novartis, has marketed biosimilar epoetin alfa[2] in the European Union for five years under the brand name Binocrit, but is now conducting a Phase III trial in the US.
h)The American Society of Nephrology’s Kidney Week 2012 meeting began on October 30 in San Diego[3]. FibroGen presented data on FG-4592- its oral hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) clinical candidate for the treatment of anaemia in chronic kidney disease. Medgenics presented on its Epodure Biopumps[4].
i)Sangart’s MP4OX is made from human blood stocks past their use-by date. It is claimed to carry no infection risk and be safe for all patients after a traumatic bleeding event. It is not a substitute for transfusion of red cells, but is said to increase the ability of red cells to do their job, delivering an oxygen boost to organs and tissues. It is currently in a Phase IIb trial in 56 locations round the world.
Other
j)Adventrix Pharmaceuticals is initiating a Phase III clinical study of ANX-188, or purified poloxamer 188, in sickle cell disease at around 40 sites in the US. The primary objective will be to show that ANX-188 reduces the duration of vaso-occlusive crisis in patients with sickle cell disease.
k)HemoSonics has partnered with Cambridge Consultants to complete development of its point-of-care analyzer to to test the four treatable systems that control clotting: platelets, coagulation factors, fibrinogen and fibrinolytic proteins.
l)The Pharming Group has completed a Phase III trial of Ruconest (recombinant human C1 inhibitor) to treat acute attacks in hereditary angioedema.
Regulatory Matters
The NBA monitors overseas regulatory decisions on products, processes or procedures which are or may be of relevance to its responsibilities.
a)Terumo BCT's Mirasol(R) Pathogen Reduction Technology System has been authorized for use in Austria The first customer, Europlasma GmbH, which supplies hospitals in the Vienna region, will use the Mirasol System for platelets.
b)Terumo BCT has been cleared by the FDA to prepare plasma held at 1° to 6° C within 8 hours and frozen within 24 hours after phlebotomy, and plasma held at room temperature for up to 24 hours and frozen within 24 hours after phlebotomy, from apheresis plasma collected on the company’s Trima Accel Automated Blood Collection System. These extended handling permissions facilitate the use of satellite collection centres and mobile blood drives. Fenwal has received FDA clearance for plasma products collected on the Fenwal Alyx® and Amicus® systems to be held up to 24 hours before freezing. These systems are already cleared to collect fresh frozen plasma, which is frozen within eight hours.
c)Kamada has FDA approval for a Phase II/ III clinical trial of the inhalable version of its treatment of Alpha-1 antitrypsin deficiency, to manage congenital emphysema. Kamada hopes that if its Phase II/III clinical trial currently underway in Europe is successful, this may suffice. Data will be available late in 2013.
d)Duke University’s School of Medicine has FDA approval to sell Ducord, a stem cell product derived from cord blood, for use in transplants between unrelated donors and patients whose diseases or treatments damage bone marrow cells.
e)Thomson Reuters reported the “orphan drug” market is worth over $US50 billion annually: “The high cost of therapy and attractive developmental drivers, such as government incentives (including tax credits), smaller and shorter clinical trials, extended exclusivity and high rates of regulatory success, have made top orphan drugs as equally viable as their non-orphan peers.” Of the 86 drugs considered, 25 generated sales in excess of $US1 billion. Some were approved for use in more than one rare illness.
f)The FDA’s Blood Products Advisory Committee discussed bacterial contamination of platelets[5], and Hepatitis E in relation to transfusion safety[6]. The FDA provided final guidance on pre- storage leukocyte reduction of whole blood and blood components intended for transfusion[7]. The FDA’s Center for Biologics Evaluation and Research (CBER), in response to the recent severe storm on the US east coast, issued guidance on the Impact of Severe Weather Conditions on Biological Products[8]. Repeated appeals for blood donors and platelet donors were issued by blood banks after the storm.
g)The EMA has started an infringement procedure against Roche Registration Ltd[9]. The European Commission requested an investigation of allegations that the company has failed to comply with pharmacovigilance obligations in relation to its 19 centrally authorised medicines. Starting this procedure means that the Agency will further investigate within the legal framework of Regulation (EC) No 658/2007. It does not prejudge the outcome of the investigation.
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 of interest include suppliers, potential suppliers and developers of products which may be of interest.
a)At CSL’s annual meeting, the Chairman said growing healthcare systems in emerging markets would also provide growth for CSL. The company already has 20 per cent of the Chinese market for albumin. The company is to improve its capital strength and earnings per share by buying back another $A900 million in shares before November 2013. It initiated a similar buyback a year ago.
b)In its five-year, long-range financial outlook Baxter International is looking for compound annual sales increases of 5%. Baxter’s profits have increased for more than a year on strong demand from haemophilia and immunodeficiency markets. Its $US1 billion investment in new plant will alleviate capacity constraint in plasma therapies, although if the trial of Gammagard in Alzheimer’s Disease gives positive results[10] severe pressure can still be expected in the IVIg market. The company’s new plant in Georgia is expected to be operational by 2018. Baxter has also taken a financial interest in development of a recombinant version of IVIg.
c)Gliknik researchers have generated GL-2045, a recombinant Fc fusion protein designed to mimic the efficacy and safety of IVIg in patients with autoimmune diseases. Clinical studies are scheduled to begin in late 2013. In October Gliknik announced that it raised $US 4.9 million in Series B Financing. Baxter Ventures, an initiative created in 2011 by Baxter International, led the Series B raising, and was joined by existing investors.
d)On October 31 Grifols announced that its nine- month net profit had increased fourfold over the same period last year.
e)Novo Nordisk increased operating profit by 34 per cent in the first nine months of 2012. The company was the leading Danish contributor to US election funding, but the Copenhagen Post reported that the company has been criticised for backing opponents of President Obama’s healthcare reform, since its own ethical standards say it is “firmly committed to improving access to health”.
f)Swedish Orphan Biovitrum announced a third-quarter 2012 loss of 45.4 million Swedish Krona, compared with last year's 38.4 million Swedish Krona loss. Quarterly total revenues went up 4 per cent to 463.8 million Swedish Krona, from 447.1 million Swedish Krona in the prior-year quarter.
g)In Heidelberg Octapharma opened a €25 million research facility dedicated to recombinant protein drug development.
h)France’s Ipsen and Massachusetts company Inspiration Biopharmaceuticals in August renegotiated their strategic partnership agreement for the development and commercialization of Inspiration’s recombinant product portfolio: OBI-1, a recombinant porcine factor VIII (rpFVIII) for the treatment of patients with acquired haemophilia A and congenital haemophilia A with inhibitors, and IB1001, a rFIX for the treatment and prevention of bleeding in patients with haemophilia B. Ipsen made an upfront payment to Inspiration and gained commercial rights in key territories. Inspiration remained responsible for the world-wide development of OBI-1 and IB1001 and could receive further investment from Ipsen. Ipsen then controlled 40 per cent of Inspiration and held $US 200 million in convertible bonds. However, in July the FDA had placed a clinical hold on a trial of IB1OO1 after patients developed antibodies to the Chinese hamster ovary protein in it; and it was not long before Ipsen faced a $US153 million write-off when Inspiration filed for Chapter 11 bankruptcy protection and prepared for asset sales.
i)Italian plasma products producer Kedrionbought Grigols’ factory in Melville, NY. It is to receive a subsidy of $US3.3 million from New York State for preserving and creating jobs. It has also arranged tax breaks with Suffolk County.
j)Cangene Corporation reported financial results for the year to 31 July. Net loss was $C28.3 million compared with net income of $C1.5 million the year before. This included $C32.8 million less in revenue on its US government deliveries.
k)Haemonetics delayed completing its acquisition of Hemerus Medical, when the FDA delayed approval of a Hemerus product, the SOLX whole blood collection system The acquisition is contingent on the FDA approval. The FDA requested additional information from Hemerus. Approval is now expected by mid-2013.
l)Irish company Elan announced in August it would spin off its Neotope drug discovery business platform as a separate public company. This makes Elan immediately profitable despite the failure in trials of its experimental Alzheimer's drug bapineuzumab developed with Pfizer and Johnson & Johnson.
m)The Board of NuSep resolved in mid- October, subject to shareholder approval, to spin out its therapeutic plasma fractionation business, called PrIME Biologics. PrIME Biologics intends to open up the Asian therapeutic plasma market particularly by tapping into the market for currently unprocessable plasma (CUP). Over the last six months PrIME has signed a Heads of Agreement to supply CUP products to India and completed the purchase of a cGMP1 facility in Singapore. It is drawing down a Singapore Government loan and installing the pilot scale PrIME production unit into the Singapore facility.
n)Merck and AiCuris have entered into an exclusive worldwide licensing agreement for AiCuris' portfolio of investigational medicines directed at human cytomegalovirus, including letermovir (AIC246), an oral, late-stage antiviral being developed to treat/ prevent infection in transplant recipients.
o)Pharmacyclics has made an agreement with Novo Nordisk under which the latter will acquire the world-wide rights to PCI-27483 for specific non-cancer-related uses[11]. The Danish company plans to use it as an excipient, usually an inactive ingredient used to carry or to add a certain consistency to a drug.
Overseas 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.
United States
a)By 5 November 2012, thirty people are known to have diedand 419 have become ill from an outbreak of fungal meningitis linked to contaminated steroid injections from a compounding pharmacy.
b)The possible need for donor screening for babesiosis continues to be a matter for discussion, along with ways this might be achieved[12].
c)In the US, the Securities and Exchange Commission is reported to have asked Pfizer to explain why its pre- tax earnings in 2011 were $US15 billion outside the US, while within the US it made a loss of $US2.2 billion. Forty per cent of its sales are generated outside the US.
d)Research released at the American Public Health Association's 140th Annual Meeting in San Francisco, demonstrated that the variation in size of red blood cells known as "red cell distribution width," (RDW) most recently used as a predictor of hospitalization outcomes and mortality, is linked to socioeconomic factors, with higher RDW found at lower socio- economic levels- and also among African Americans.
e)A study of 464 hospitals by Premier[13] suggested they could save over 800,000 units of blood annually (reducing their costs by $US165 million) if they followed thepractices of the top 25 per cent of hospitals. Recommendations included following evidence- based transfusion guidelines, establishing multidisciplinary blood stewardship teams, and developing processes to monitor adherence to guidelines and provide feedback to clinicians
Other
a)A recent study[14]in the Netherlands examinedthe impact of donor psychology on blood donation, along with the influence of needle reactions on the risk of donors not returning. Vasovagal or needle reactions are reflexes of the involuntary nervous system characterized by arteriolar dilation. They may lead to nausea, vomiting, weakness, hypotension, bradycardia, or syncope. The study showed female donors were more likely to have vasovagal reactions than males, although male donors were more likely to cease donating after a reaction. Dr. Wim de Kort, the Director of Donor Services at Sanquin Blood Bank in the Netherlands, was the senior author of the study. He is also the project leader of the European Union funded DOMAINE project evaluating donor management.
b)The Bahrain Society for Sickle Cell Anaemia Patient Care plans legal action against the Health Ministry, after the 33rd sickle cell patient death for the year.
c)In Pakistan, research at the National Institute of Blood Diseases found that in aplastic anemia was 5.8 times more common in the country than in the Westerncountries. It identified possible links with the use of painkillers or exposure to pesticides and benzene.