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.
1
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 bleeding1. 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
1
The FDA approval follows a study of 216 patients who had been receiving VKA anticoagulation and
who had acute major bleeding. Kcentra proved similar to plasma in terms of the ability to stop acute
major bleeding.
2
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 (halflife 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
3
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.
4
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 believedi2.
c) A team from the Singapore-MIT Alliance for Research and Technology’s Infectious
Diseases Research Program reported3 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.
2
The T cell finding was published April 11th in a paper "Comprehensive analysis of dengue virusspecific responses supports an HLA-linked protective role for CD8+ T cells" in Proceedings of the
National Academy of Sciences. Dr. Sette was senior author on the paper and Dr Daniela Weiskopf
was first author. Dr Sujan Shresta and Dr Bjoern Peters were significant contributors.
3
Tharakaraman et al., (2013) “Redesign of a cross-reactive antibody to dengue virus with broadspectrum activity and increased in vivo potency”. Published online before print April 8, 2013, in
Proceedings of the National Academy of Sciences.
5
Influenza
f) At 16 April 2013, the World Health Organization (WHO) said there was so far no
evidence of ongoing human to human transmission of the H7N9 virus. At that stage
the exact source of infection was still unknown, though a number of people who had
been taken ill had had contact with poultry. Testing of contacts of affected people
had led to the discovery that the virus could be asymptomatic, so it could be more
widespread than had been reported. It was already known to be more dangerous to
humans than to birds.
g) At 26 April 119 cases and 23 deaths had been reported. Before then the US Centers
for Disease Control (CDC) had advised hospitals and clinics to be vigilant for people
with flu type symptoms who had been in China; and The Economist had published an
article on pandemic preparedness titled “Coming, ready or not”.
h) The WHO were also questioning why there was a preponderance of elderly men
amongst those who had contracted H7N9. Theories advanced were cultural -that
they were the family members attending live poultry markets, that they kept
songbirds and met in parks with other fanciers, or perhaps that they kept pigeons.
Later an immunological suggestion emerged that it was possible that if they had been
exposed to earlier avian flu this could increase susceptibility to H7N94.
i) On 24 April Taiwan reported its first case, a worker who had returned from China.
He was being treated in a negative pressure isolation room.
j) By then, Chinese scientists said they had identified the direct avian origin of H7N9 flu
as live poultry markets, although they were not certain about the ancestry of all the
genes. They observed that the isolates obtained from humans had acquired critical
mutations which made them more “human-like” and said it was therefore imperative
to take strong measures to control the virus in both birds and humans. H7N9 had
been found in chickens, pigeons and the environment at live poultry markets, whose
multiple species, high density setting was seen as an ideal environment for reassortment among avian influenza of different subtypes. Some genes are thought to
be from a duck virus. There have been suggestions that at the live poultry markets it
may be the feather removal machines that contribute to the spread of the virus by
distributing particulate matter as they spin.
k) By 25 April WHO was saying that H7N9 was more lethal than H5N1 as it could jump
more easily to humans, and it could infect birds without causing noticeable
symptoms.
l) Although the WHO did not suggest limitations on travel to China, or a requirement for
medical checks for those returning from China, some countries issued national
guidance. The Ministry of Health in Israel, for instance, decreed that any patient
presenting acute, severe respiratory disease signs who had been in China during the
10 days before the onset of symptoms will be regarded as a suspect case of the new
virus and be hospitalized under isolation in a biosafety facility (under negative
atmospheric pressure). The Ministry further prescribes medical monitoring of contact
persons and family members of such patients, during 10 days following
hospitalization.
m) NanoViricides said it expects that its oral and injectable FluCide drug candidates
would be effective against the novel H7N9 strain that has caused human fatalities in
China in recent months. The company says both injectable and oral FluCide bear a
virus-binding ligand that mimics sialic acid. This ligand is capable of substituting for
both the mammalian form (sialyl-alpha2,6-gal-) or the avian form
(sialyl-alpha2,3-gal-). The company says the dual biomimetic capability of the
FluCide ligand would be an advantage.
4
Skowronski DM, Janjua NZ, Kwindt TL, De Serres G : “Virus-Host Interactions and the Unusual Age
and Sex Distribution of Human Cases of Influenza A(H7N9) in China, April 2013”, in Eurosurveillance,
Volume 18, Issue 17, 25 April 2013.
6
n) The Infectious Diseases Research Institute (IDRI) in Seattle and Canadian company
Medicago announced positive results for their Phase I trial of an H5N1 vaccine.
Other
o) Japanese researchers say they have created a cell capable of producing
erythropoietin (and helping to increase red blood cell count) using induced pluripotent
stem, or iPS, cells. The team from Kagawa University and Kyoto University’s Center
for iPS Cell Research and Application, is headed by Professor Shinya Yamanaka,
whose iPS cell experiments won him a Nobel Prize in 2012.
p) US government scientists announced5 that two drugs currently used to treat hepatitis
C in laboratory tests stopped the novel coronavirus virus from replicating. While
results suggest that the combination of of two antivirals- ribavirin and interferon-alpha
2b- could be used to treat novel coronavirus, more research is needed to confirm
these early findings.
q) Dr Leo Joosten from the Department of Medicine at the Radboud University in the
Netherlands, has been involved in Lyme disease research for several years. He
believes there is a persistent Lyme disease and that patients continue to have clinical
symptoms because of an active immune system. He is unsure what proportion of
Lyme disease patients are in this category. He says it may be continued exposure
to to live Borrelia or Borrelia antigens that keeps the immune system activated. He
says "If chronic or persistent Lyme disease exists, we will need more than antibiotics
for treatment. Anti-inflammatory components or anti-cytokine treatment will be
option.”6
r) At the US National Foundation for Infectious Diseases 16th Annual Conference on
Vaccine Research in Baltimore, Baxter announced Phase I/II data evaluating the
safety and immunogenicity of its investigational Lyme disease candidate vaccine.
The vaccine was shown to induce substantial antibody titres against all targeted
species of Borrelia, the causative agent of Lyme disease, transmitted by ticks.
s) Chimerix announced the final study design for the Phase III SUPPRESS trial of
CMX001 in the prevention of cytomegalovirus (CMV) infection following an allogeneic
hematopoietic stem cell transplant.
Appendix: Alzheimer’s Disease Research
With intravenous immunoglobulin (IVIg) being trialled as a treatment for Alzheimer’s disease,
the NBA – concerned about market pressure if the trial result is positive- takes an interest in
research on other possible treatments for Alzheimer’s, on the identification of genetic
predisposition, and on improvements in diagnostic tools.
a) Sanofi’s CEO says the company will not invest in the search for a treatment for
Alzheimer’s disease because of the difficulty of finding suitable targets.
b) Eli Lilly has acquired two investigational positron emission tomography (PET) tracers
from Siemens Medical Solutions USA. The tracers are designed to image tau (or
neurofibrillary) tangles in the brain.
c) Researchers at Duke University found that many people who had a parent or sibling
with Alzheimer’s disease showed silent brain changes7.
d) In the US, the Alzheimer's Drug Discovery Foundation and BrightFocus Foundation
will jointly fund a Phase I human clinical trial to evaluate the cancer drug bexarotene
as a treatment for Alzheimer's disease.
5
in the April 18 issue of the journal Scientific Reports.
6
http://www.huffingtonpost.com/c-m-rubin/lyme-disease_b_3113544.html
7
7
Reported online April 17 in the journal PLoS ONE.
e) Scientists funded by the US National Institutes of Health have identified a possible
strategy for stemming the disease process in Alzheimer’s by facilitating the
removal of toxic debris accumulating in the brain, by blocking activity of a
regulator protein called CD338.
8
“Alzheimer’s disease risk gene CD33 inhibits microglial uptake of amyoid beta”. Griciuc A, SerranoPozo A, Parrado AR, Lesinski AN, Asselin CN, Mullin K, Hooli B, Choi SH, Hyman BT, Tanzi RE.
Neuron, April 25, 2013.
8