3.3 Plasma Products
During 2008–09, the NBA closely monitored product developments, particularly alternative uses of plasma products and changes in plasma market structure. In particular, research on treatment regimes using IVIg have potential for a major impact on our blood sector.
3.3.1 New plasma-derived products
The rate of development of innovations based on both human plasma-derived and recombinant products continues apace. The developments have the potential to change clinical practice and improve patient safety, but at the same time they bring increased costs. Understanding these developments is central to Australia being well placed in the timing and design of tenders and in contract negotiations. The following are some of the most significant product developments that emerged in 2008–09:
- new immunoglobulin products—including those administered subcutaneously
- an intravenous fibrinogen concentrate produced by CSL Ltd
- an anthrax immunoglobulin produced by Talecris Biotherapeutics Inc
- a rabies human monoclonal antibody product by Dutch company Crucell with Sanofi Pasteur as its commercial partner and a synthetic anti-rabies immunoglobulin, which is being developed by US and South Korean interests
- plasmin (human) to treat acute peripheral arterial occlusion, being developed by Talecris Biotherapeutics
- the development of ‘follow-on biologics’
- Halozyme Therapeutics, along with Baxter Healthcare Corporation, starting a Phase III clinical trial of the latter’s Gammagard Liquid for the treatment of primary immunodeficiency. The key benefit of this product, if approved, is that patients could receive a full monthly dose in a single injection site in their home setting
- Baxter presenting data suggesting it can make antibody therapy more convenient for patients with primary immunodeficiency by subcutaneous delivery using an enzyme to disperse the antibodies in the appropriate phase
- French group LFB announcing the availability for humans of its first two therapeutic monoclonal antibodies. One is an anti-Rh(D) product. The company has also filed a biological licence application for a new-generation multivalent human immunoglobulin. LFB’s new nano-filtered fibrinogen is also likely to gain marketing authorisation later in 2009.
3.3.2 Substitutes for plasma products
Alternatives to plasma products are being developed for a number of conditions. These advances are crucial to a full and informed understanding of future likely demand trends and include the following:
- Two new drugs have become available to boost platelet production—electrombopag (trade name Promacta or Revolade) and romiplostim (trade name NPlate). In Australia around 7 per cent of current intravenous immunoglobulin use is in treating chronic immune thrombocytopenic purpura. In the United States this use accounts for around 15 per cent of IVIg use.
- Studies suggest that a new vaccine from Sanofi blocks about half of primary cytomegalovirus infection in young women, which could ultimately reduce the need for CMV immunoglobulin to prevent health problems in newborns.
- Work is also occurring overseas on anti-Rh(D) products. If this is successful, it could ultimately reduce the need for Rh(D) immunoglobulin. Danish company Symphogen, for instance, is interested in an anti-Rh(D) recombinant polyclonal antibody.
3.3.3 Developments in intravenous immunoglobulin
In 2008–09 IVIg accounted for 20 per cent of the total spend by governments in Australia on blood and blood products and used 380.5 tonnes of plasma collected by the Australian Red Cross Blood Service. This tonnage was supplemented by the importation of 27.5 per cent of total IVIg demand. Demand has grown by 10–14 per cent per annum in the past six years. Accordingly, any changes in the development and use of IVIg can potentially have a large impact on Australia’s blood budget and on the pressures in the system for collection of plasma.
There was initial concern during the reporting year that global demand for IVIg would outstrip supply and cause significant price increases. The possible global supply shortage has, however, been mitigated in the short term by the current economic downturn in the United States, which has increased the number of donors wanting to donate plasma and receive financial compensation. Meanwhile, the pressure on demand has been slightly eased by the development of alternative treatments for some conditions.
The recent comparative stability in IVIg prices could disappear if the current major trial of its use in treating Alzheimer’s disease produces a positive result. Baxter Healthcare Corporation announced a Phase III clinical trial following a US Food and Drug Administration review of its investigational new drug application to evaluate Gammagard Liquid3 (IVIg) for treatment of mild to moderate Alzheimer’s disease. It is a prospective, 18-month, randomised, double-blind, placebo-controlled, two dose-arm parallel study of 360 subjects, from both genders and aged 50 to 89 years, with dementia severity ranging from mild to moderate.
- Marketed as Kiovig in the European Union
There is concern that a successful outcome for this study could have major implications for IVIg demand, adequacy of supply and price. In Australia, for instance, between 1998 and 2007 the number of deaths from dementia and Alzheimer’s disease more than doubled—from 2.6 to 5.3 per cent of all deaths. There is therefore strong interest in Australia and internationally in other Alzheimer’s treatments, not based on plasma, which are being developed and trialled.
Amongst drugs of interest are Pfizer/ Medivation’s Dimebon, Elan/Wyeth’s bapineuzumab, and Eli Lilly’s solanezumab. The NBA is closely monitoring these developments and others to ensure potential impacts on the IVIg markets are fully understood.
An additional pressure may arise from the publication in April 2009 by Talecris Biotherapeutics, of health-related quality-of-life results from the largest clinical trial ever conducted in patients with chronic inflammatory demyelinating polyneuropathy. The data demonstrate that long-term treatment with Gamunex (immune globulin intravenous (human), 10 per cent caprylate/chromatography purified) improves and maintains health-related quality of life in patients with the condition, which affects two to seven individuals per 100 000 worldwide, and can occur at any age and in both genders, although it is more common in young adults and in men. It is the top user of IVIg in Australia (see Figure 2.21).
3.3.4 New recombinant products
Developments in recombinant products offer great scope for replacement of plasma-derived products and therefore for improving the sustainability of the sector. Many companies are working to develop products; the following paragraphs summarise a selection of developments.
Transgenic products
A significant development during the reporting year was the approval for use in both Europe and the United States of the first product from transgenic animals:
- GTC Biotherapeutics, in partnership with LFB Biotechnologies, developed ATryn(R), a recombinant human antithrombin produced from the milk of transgenic goats and used in patients with a hereditary deficiency.
- GTC Biotherapeutics has also entered into a collaboration with New Zealand-based AgResearch Ltd to develop transgenic founder animals that produce bio-similar monoclonal antibodies. AgResearch will establish transgenic founder production lines, mainly funded by a grant from the New Zealand Government.
- GTC Biotherapeutics, again in collaboration with LFB Biotechnologies and using its transgenic production platform, is also developing recombinant human coagulation Factors VIIa and IX.
Factors VIII, IX and VIIa
Other companies are working to develop a recombinant Factor IX to compete with Wyeth’s Benefix in what is currently a monopolistic market or to develop Factor VIIa products to compete with Novo Nordisk’s Novo Seven:
- In mid-2008 Bayer acquired Maxygen’s haemophilia program assets, including a next-generation recombinant Factor VIIa protein known as MAXY-VII. Bayer’s goal is to market this next-generation Factor VIIa product in 2012.
- Avid Bioservices has been developing its Factor VIIa candidate, CB 813.
- Inspiration Biopharmaceuticals announced the initiation of a Phase 1 clinical trial of IB1001, an intravenous (IV) recombinant Factor IX product for control and prevention of haemorrhagic episodes in patients with haemophilia B.
- Baxter Healthcare Corporation has acquired rights to Avigen’s early-stage blood coagulation compound, intended as an oral treatment for bleeding disorders such as haemophilia A. If the promise of pre-clinical studies is realised this could be a stand-alone treatment or an adjunct to treatment with Factor VIII or Factor IX concentrates.
Other products
- CSL Ltd, Talecris and GlaxoSmithKline have individually signed agreements with DSM Biologics and Crucell to develop protein therapeutics on their PER.C6(R) platform. This allows large-scale manufacture of recombinant proteins including monoclonal antibodies.
- ProFibrix BV has a commercial licence agreement with Crucell for PER.C6(R), its human protein production platform. The company’s lead product, Fibrocaps, is based on fibrinogen derived from human blood plasma and is a dry powder topical haemostat that stops acute and severe bleeding during surgery or after trauma injury. The company is planning to develop recombinant fibrinogen for systemic applications in haemostasis and later on for the development of tissue repair products.
- A recombinant human polyclonal antibody is being developed for future prevention of haemolytic disease of the newborn, which can occur in Rh(D) negative mothers carrying an Rh(D) positive foetus. Currently in Australia this is managed using Rh(D) immunoglobulin.
- Wyeth has produced an albumin-free version of its recombinant Factor VIII, ReFacto. It intends to phase out supply of the original ReFacto.
- Origen Therapeutics of California and Genavia Therapeutics of Auckland announced an agreement granting Genavia access to Origen’s transgenic technology for the production of therapeutic proteins in the whites of chicken eggs. Genavia will initially apply the avian transgenic technology to produce human Factor VIII.
- Stem Cell Innovations announced in Houston that its C3A human liver cell line is capable of producing bio-similar serum proteins for follow-on biologics and has stated that Factors VIII and IX are its first target indications.
- Amgen announced that the European Commission has granted marketing authorisation for Nplate(R) (romiplostim) for the treatment of splenectomised adult chronic immune (idiopathic) thrombocytopenic purpura patients who are refractory to other treatments (for example, corticosteroids and immunoglobulins).
3.3.5 Plasma market structure
Sales and profits in the plasma products industry have largely withstood the depressing effect of the global financial crisis. Growth and changes in the plasma market were intense during the reporting year. In summary:
- CSL Ltd bid $US3.1 billion for Talecris Biotherapeutics. The private equity companies that owned Talecris agreed with the bid, but it was opposed by the US Federal Trade Commission on the grounds that the combination of the second- and third-largest operators in the US plasma products business would reduce competition and adversely affect consumers. CSL withdrew its interest and in August 2008 decided to return $A1.59 billion of the $2 billion it raised from shareholders to fund the deal.
- Speculation continues as to who will purchase Talecris or whether in the strong market conditions for plasma products it will return to earlier plans for a public offering of shares.
- Biotest Pharmaceuticals (formerly the biologics unit at Nabi Parmaceuticals) has been expanding its plasma plant in Florida to increase production of its hepatitis treatment, Nabi HB.
- Biotest AG, headquartered in Germany, has expressed a desire to expand in the United States and might also be interested in acquiring some or all of Talecris’s assets. At present 73 per cent of group sales are outside Germany. Biotest has broadened its basis for future growth by signing a further cooperation agreement with the Belgian organisation CAF-DCF.
- Grifols, headquartered in Spain, has been expanding production capacity significantly in the United States and announced it expected a 50 per cent rise in its plasma production by 2013. Its new IVIg production facility in Los Angeles will represent $US135 million of the $US600 million long-range investment plans announced in October 2007. Grifols inducted its first class of students into the Grifols Academy of Plasmapheresis in Glendale, Arizona. Adjacent to a fully operational plasma donor facility, the site will serve as the company’s central location for employee education, training and development.
- Octapharma has been increasing its ownership of US collection facilities.
- China Biologic Products gained control of plasma products company Qianfeng Biological Products Co. Ltd. This makes China Biologic the country’s largest non-state owned enterprise in the plasma products sector. It now accounts for 14.3 per cent of the Chinese market.
To better understand how to deal with these market changes the NBA instigated the collaboration of National Plasma Product Supply Planners. The first meeting of the group was held in March 2009.
