Monitoring International Trends
posted May 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………………………………………………………………2
Country- specific events………………………………………………….………………………….3
Safety and patient blood management…………………………………………………………….3
Research………………………………………………..……………………………………….…....4
Infectious Diseases…………………………………………………………………………………..5
Appendix: Alzheimer’s Research…………………………………………………………………...8
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.
Immunoglobulin
Results are expected during May from a trial of Baxter’s Gammagard liquid in Alzheimer’s disease. While trials of immunoglobulin in Alzheimer’s are ongoing, a positive result from this trial could put pressure on limited global supplies, in the first instance because of increased off- label use. Regulatory approval may follow results of this or ongoing trials, and would increase demand further. The NBA monitors global research findings on Alzheimer’s, and a short summary is provided in an appendix to each of these monitoring reports.
2. Regulatory
The NBA monitors overseas regulatory decisions on products, processes or procedures which are or may be of relevance to its responsibilities.
a) The US Food and Drug Administration (FDA) has approved Kcentra (Prothrombin Complex Concentrate, Human) for the urgent reversal of vitamin K antagonist (VKA) anticoagulation eg warfarin in adults with acute major bleeding[1]. Plasma is the only other product approved for this use in the US. Kcentra does not require blood group typing or thawing and can be administered quickly. It is given in a much lower volume than plasma at recommended doses, which assists those patients who may not tolerate the volume of plasma required to reverse VKA anticoagulation. Kcentra carries a boxed warning regarding the risk of blood clots. The FDA says patients receiving it should be monitored for signs and symptoms of thromboembolic events, as both arterial and venous thromboembolic complications have been reported in clinical trials and post marketing surveillance.
b) The FDA has granted orphan drug status to Pluristem Therapeutics for its PLacental eXpanded (PLX) cells for the treatment of aplastic anaemia.
c) The FDA has granted orphan drug status to ProMetic's plasma derived plasminogen for the treatment of hypoplasminogenemia, or type I plasminogen deficiency.
d) The FDA again rejected rivaroxaban (Xarelto) to treat patients with acute coronary syndromes. 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.
e) Affymax and Takeda Pharmaceutical, which jointly marketed 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.
f) The FDA sent a warning letter to Novo Nordisk concerning inadequacies it perceived during an inspection of a facility in Denmark.
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) Baxter’s first quarter results showed the company had exceeded its estimates for its haemophilia business, which analysts interpreted as arising from continuing growth in prophylaxis with recombinant factor VIII (rFVIII). Immunoglobulin sales were lower than expected, which was probably affected by supply constraints while the Los Angeles fractionation plant was shut down. Analysts reported the company has been focussing on supplying the US market, where margins are higher than in Europe.
b) Baxter is reported to have been in discussion with state and local authorities in Minnesota about possible tax incentives for it to commence manufacturing in a vacant facility it purchased in Brooklyn Park.
c) In the six months to December 2012, CSL’s earnings per share rose 30 per cent. CSL’s share price in the twelve months to April 24 2013 rose 66 per cent.
d) The retiring CEO of CSL has been questioned by class action lawyers for three American hospitals about an allegation that the company was involved in an international cartel that fixed the price of plasma. When the US Federal Trade Commission blocked CSL’s takeover of Talecris on competition grounds, it said the industry operated as a “tight oligopoly” but nowhere in its ruling did it identify wrongdoing by CSL executives.
e) Xencor Inc of California has agreed to provide CSL access to Xencor's Xtend (half- life extension) technology to optimize the performance of CSL's monoclonal antibodies.
f) Novo Nordisk opened its new US headquarters in Plainsboro, New Jersey.
g) Boehringer Ingelheim’s anti-clotting drug Pradaxa achieved blockbuster status in 2012 (ie reached over $US 1billion in sales).
h) LFB (Laboratoire français du Fractionnement et des Biotechnologies) reported its financial results for the year ended December 31st 2012. It returned to profitable growth during the year.
i) OPKO Health will buy Israel-based Prolor Biotech in a deal valued at $US 480 million. Phillip Frost, OPKO's chief executive said "Prolor's drug-product candidates for growth hormone deficiency, haemophilia, obesity and diabetes ... are highly valuable assets that will complement OPKO's strategy”.
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) The Haemophilia Federation (India) used World Haemophilia Day as the occasion to launch its “Close the Gap” campaign to accentuate the plight of haemophiliacs and push for “advanced treatment for all”.
b) Leukaemia & Blood Cancer New Zealand announced they have committed over $NZ 1 million of initial funding for a Leukaemia & Blood Cancer Research Unit at Auckland University.
c) Germany’s Federal Joint Committee is conducting a cost benefit analysis of a number of drugs with high volume sales, including blood thinners Xarelto (rivaroxaban from Bayer) and Pradaxa (dabigatran from Boehringer Ingelheim). These reviews may lead to price cuts.
5. Safety and patient blood management
We follow current issues and new developments.
a) Blaze Medical Devices of Michigan is developing a table-top device and disposable cartridges for evaluating red blood cells before transfusion by the strength of their membranes rather than by age alone.
i) To identify how storage changes have affected the quality of the cells Blaze is measuring mechanical fragility, which is assumed to be associated with lower cell viability and less ability to deliver oxygen to tissue.
ii) A preclinical study was conducted at the Mayo Clinic and an initial clinical study at Henry Ford Hospital. CEO David Weaver says the company will release a research-only version of the device late this year, and begin commercialization in Europe in 2014. It hopes it will have US FDA clearance in time to begin sales in the US in 2015.
b) Medgenics developed its Biopump for the sustained production and delivery of therapeutic proteins in patients using their own tissue.
i) The company has now provided an update on results from the first four patients treated in its ongoing Phase IIa clinical trial in Israel treating anaemia in patients on dialysis with end-stage renal disease. In this single treatment study, each patient received a single administration of EPODURE Biopumps, measured to produce between 19 to 51 IU erythropoietin (EPO) per kg per day, in place of the serial injections of EPO or erythropoiesis-stimulating agent (ESA) the patient had been receiving with each dialysis session.
ii) Following the administration, the haemoglobin in these patients remained in the desired 9-11 g/dl range for approximately 2-4 months, without needing any EPO or other ESA injections. At no point following the treatment did the concentration of EPO in the serum of the patients exceed the typical normal range and always remained under 100 mU/ml.
iii) A larger Phase II trial will be implemented in the US in the second half of 2013.
iv) President and CEO of Medgenics, Andrew L. Perlman, said: “When EPODURE reaches routine clinical use, we believe the ability to titrate the dose to reach the most effective dosing level based on the patient’s early hemoglobin response could further extend the duration of hemoglobin maintenance. ”
c) A new drug being developed by GlaxoSmithKline (GSK) aims to trick the body into boosting its production of red blood cells by making it behave as though it is at altitude.
d) Candida is a frequently fatal fungal bloodstream infection. Now a small, portable device can detect it rapidly and accurately, according to a study published in the April 24 issue of Science Translational Medicine.
6. Research
a) Research led by Johns Hopkins scientists on using partially matched bone marrow transplants to conquer sickle cell disease has been named as one of the Top 10 Clinical Research Achievements of 2012 by the Clinical Research Forum.
b) Scripps Research Institute scientists say they have found an antibody that transforms bone marrow stem cells directly into brain cells. Cell therapies derived from patients’ own cells are widely expected to be useful in treating spinal cord injuries, strokes and other conditions throughout the body, with little or no risk of immune rejection.
c) Scientists at the Rockefeller University, New York, and Astex Pharmaceuticals have developed a new antibiotic Epimerox, which kills a range of bacteria, including methicillin-resistant Staphylococcus aureus and the bacteria that causes anthrax.
d) Harvard Medical School is closing its primate research facility after fifty years, due to cost concerns. The facility has made many significant contributions to research, including helping to establish that AIDS is caused by a virus. The 2,000 monkeys in the facility will be transferred to other primate centres.
e) Manufactured blood vessels implanted in primates for six months survived regular needle punctures, were not rejected by the immune system, and remained free of blood clots; and they could be safely stored in a refrigerator for up to one year. Scientists reported their research online in the American Heart Association's Emerging Science series.
i) The researchers have started a clinical trial in Europe and have received FDA authorization for a clinical trial in the US.
ii) The “off the shelf” blood vessels are made by placing human aorta cells into a biodegradable mesh tube. After two months a new blood vessel has developed and the mesh has dissolved.
iii) "Eventually, off-the-shelf blood vessel grafts might be used in kidney dialysis patients and potentially in many vascular procedures, such as bypassing blocked arteries in the legs, repairing vessel damage after trauma, or in coronary bypass operations," said study lead author Shannon Dahl of Humacyte, Inc. of Research Triangle Park. North Carolina. Some commentators point out that not all studies in animals translate into success in humans.
f) In April the bioscience world paused briefly to reflect on sixty years of DNA. It was on 25 April 1953 that Nature published three papers describing the structure of DNA: one from James Watson and Francis Crick of Cambridge University proposing the now famous double helix, and papers from Rosalind Franklin and Maurice Wilkins of King’s College, London, who supported the helix hypothesis used X-ray diffraction images.
7. Infectious diseases
The NBA takes an interest in infectious diseases because: the presence of disease in individual donors (e.g. influenza), or potential disease resulting from travel (e.g. malaria) means a donor must be deferred; temporary disease burden within a community (e.g. dengue in North Queensland) may limit blood collection in the community for a time; and some people may not be permitted to donate at all (e.g. people who lived in the UK for a period critical in the history of vCJD). Blood donations are tested for a number of diseases (e.g. HIV and Hepatitis B), but there are also emerging infectious diseases for which it may become necessary to test in the future (e.g. Chagas disease, and the tick-borne babesiosis and Lyme disease).
Mosquito- borne diseases
a) In Queensland, forty-one cases of Barmah Forest virus were recorded in the Redlands district between January and mid- April compared with 94 cases for the entire year 2012. An outbreak of the virus had been reported on the Gold Coast, where 22 people were infected since mid-March, a rate of almost one person a day. The increased incidence of Barmah Forest virus coincided with high rainfall over summer. From January to mid-April, more than 702mm of rain was recorded in the Brisbane area, compared with the median rainfall for those three months of 397mm. Point Lookout had recorded 763mm since January.
b) Researchers at the La Jolla Institute for Allergy & Immunology in San Diego have found evidence which not only explains why the Sanofi dengue vaccine trial disappointed on the number of strains against which it protected, but suggests the need for a revised approach to the design of dengue vaccine. Dr Alessandro Sette, and his team found that T cells are significant in controlling dengue infection, rather than ultimately worsening the disease as has been widely believed[i][2].
c) A team from the Singapore-MIT Alliance for Research and Technology’s Infectious Diseases Research Program reported[3] it has engineered a potent antibody against the dengue virus. “That was the motivation for carrying out our study, to generate a fully neutralizing antibody that works for all four serotypes,” said team leader Professor Ram Sasisekharan, who hopes the antibodies can be tested in humans in the next two to three years.
d) Ingham has joined the towns in the northernmost part of Queensland where dengue has been detected.
e) Papua New Guinea’s Institute of Medical Research says chikungunya has now spread through about eight provinces, after first appearing a year ago in Vanimo near the Indonesian border. Chikungunya has also been diagnosed in Cairns.