Download August 2012 Monitoring International Trends

MONITORING INTERNATIONAL TRENDS
posted August 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.
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.
a. Clotting factors
 Portola Pharmaceuticals in June announced enrolment of patients in the second
cohort of its Phase 1 study of PRT4445, the first universal Factor Xa inhibitor
antidote in clinical development. PRT4445 is a recombinant biologic.
 Bayer presented data on new treatments and modalities for haemophilia A at the
World Federation of Hemophilia (WFH) Congress in Paris in July.
 Bayer presented data from several clinical trials, including results from
Spinart, a phase III study assessing Kogenate. It demonstrated the success
of secondary prophylaxis with Kogenate on bleeding frequency and joint
damage, compared with on- demand treatment, in adults and adolescents.
 Bayer announced it has initiated enrolling patients in an international phase III
trial to evaluate its investigational compound BAY94-9027 for the treatment of
haemophilia A. The PROTECT VIII1 trial is investigating whether the
compound, a recombinant human factor VIII (rFVIII), can prolong the duration
of protection from bleeds and with less frequent infusions when used
prophylactically, while also being suitable to treat acute bleeding events.
 Inspiration Biopharmaceuticals reported positive interim results from a Phase II/
III study of its product OBI-1 In acquired haemophilia A at the WFH Congress.
OBI-1 is an investigational recombinant porcine factor VIII. A second Phase II/III
trial is underway to evaluate OBI-1's ability to control bleeding in people with
congenital haemophilia A with inhibitors, and its safety in that population.
 Prolor Biotech presented data on its long-acting clotting factors at the WFH
Congress -from preclinical studies of long-acting versions of Factor VIIa (Factor
Vlla-CTP) and Factor lX (Factor IX-CTP)2.
 Alnylam Pharmaceuticals in July presented new pre-clinical data for its RNAi
therapeutic for the treatment of haemophilia at the WFH Congress.
 Biogen Idec and Swedish Orphan Biovitrum announced in July the initiation of
two global paediatric clinical trials of their long-lasting recombinant Factor VIII
and Factor IX Fc fusion proteins (rFVIIIFc and rFIXFc) in haemophilia A and B.
The two products were developed using Biogen Idec's proprietary monomeric Fc-
1
PROphylaxis in haemophilia A patienTs via directly pEgylated long-aCTing rFVIII
In haemophiliac mice they demonstrated superior performance of clotting efficacy compared with
commercially available products, including survival following a bleeding challenge, thrombin
generation, duration of clotting activity and number of spontaneous re-occurring bleeding episodes.
The posters,"F VIIa-CTP and F IX-CTP are novel long-acting coagulation factors with prolonged
hemostatic activity in hemophilic animal models," Hart G, Monahan P, Seligsohn U, Zakar M,
Hershkovitz O, Bar-Ilan A, Fima E, were presented in Paris.
2
1
fusion technology, which makes use of a natural mechanism to recycle rFVIIIFc
and rFIXFc in the circulation in the body.
 An intensive study of postpartum women with von Willebrand Disease showed
potential risk of delayed haemorrhage, despite treatment, and recommended a
study of the benefits of prophylactic treatment.
 Recombinant factor VIII produced in hamster cells has been available since the
early 1990s for treatment of haemophilia A. This may cause immunogenic
reactions and the development of inhibitors against rFVIII. Now, say researchers
from Octapharma, rFVIII produced in a human cell line is available3.
b. Immunoglobulin
 Data presented4 from the PRIMA5 trial, suggested that treatment with CSL’s
Privigen, an intravenous immunoglobulin (IVIg), may lead to improved function in
patients with chronic inflammatory demyelinating polyneuropathy (CIDP).
 Expression of inflammatory cytokines in cerebrospinal fluid has led to the
hypothesis of intrathecal chronic inflammation to explain the denervation
observed in post-polio syndrome (PPS). It has been shown6 that therapy with
intravenous immunoglobulin (IVIG) improves physical performance and dampens
down the inflammatory process at 6 months in PPS patients.
c. Other
 Grifols published Phase I study results demonstrating safety and tolerability for
the investigational therapy plasmin in treating patients with blood clots in the
lower extremities, or acute peripheral arterial occlusion7. Plasmin is a stabilised
protein derived from human plasma.
 The US Defense Advanced Research Projects Agency (DARPA) has awarded
$US 1m to Spot On Sciences. to develop its blood-sampling device, HemaSpot.
This uses dried blood spot testing, based on a type of absorbent filter paper. It
improves sample quality, simplifies collection and allows sample storage at room
temperature—enabling home sampling and shipment by mail, and point-of-care
testing for the military.
 CSL Behring UK in June announced8 the launch of the Beriplex P/N Dosing
Calculator App. The mobile app, for use on smart phones, is designed to assist
healthcare professionals with dosage calculation when administering CSL’s
human prothrombin complex concentrate, Beriplex P/N.
 Emmaus Medical in July received Orphan Medicinal Product designation from the
European Commission for its investigational drug Levoglutamide (L-glutamine)
for the treatment of sickle cell disease. Emmaus said it was currently conducting
a Phase III clinical with the US Food and Drug Administration (FDA) to study Lglutamine as a treatment for sickle cell disease. The drug has both an orphan
drug designation and fast track status in the US.
 Grifols in July announced plans for a safety trial of a novel, inhaled formulation of
alpha1-proteinase inhibitor [Human] later this year. In April, the FDA granted
orphan drug designation for Grifols' inhaled alpha1 formulation as a treatment for
cystic fibrosis, an inherited disease that can cause life-threatening lung infections.
 Pharming Group has fully recruited to its US Phase III clinical study evaluating
Ruconest. (recombinant human C1 inhibitor) for the treatment of acute attacks of
3
Casademunt, E., Martinelle, K., Jernberg, M., Winge, S., Tiemeyer, M., Biesert, L., Knaub, S.,
Walter, O. and Schröder, C. (2012), The first recombinant human coagulation factor VIII of human
origin: human cell line and manufacturing characteristics. European Journal of Haematology. doi:
10.1111/j.1600-0609.2012.01804.x
4 at the Peripheral Nerve Society Inflammatory Neuropathy Consortium Meeting in Rotterdam, June
5
Privigen Impact on Mobility and Autonomy
6 Journal of Neuroinflammation 2012, 9:167
7 In the June issue of the Journal of Thrombosis and Haemostasis.
8 at The General Anaesthetists in Training Annual Scientific Meeting in Glasgow.
2
angioedema in patients with hereditary angioedema (HAE). Ruconest is
produced through Pharming's proprietary technology in milk of transgenic rabbits
and is approved in Europe for treatment of acute angioedema attacks in patients
with HAE. It is an investigational drug in the US with orphan drug designation9 for
the treatment of acute attacks of HAE10.
2. Regulatory Matters The NBA follows overseas regulatory decisions on products,
processes or procedures which are or may be of relevance to its responsibilities.
a. The FDA has granted CSL Behring orphan drug designation for its recombinant
fusion protein linking coagulation factor IX with recombinant albumin (rIX-FP).
The designation applies to both treatment and prophylaxis of bleeding episodes
in patients with haemophilia B. Genetic fusion with recombinant albumin in rIX-FP
extends the half-life of Factor IX. Albumin was selected as the partner because
of its long physiological half-life, good tolerability profile, low potential for
immunogenic reactions and a well-established mechanism of clearance.
b. The Committee for Orphan Medicinal Products of the European Medicines
Agency (EMA) adopted a positive opinion in June on Erytech Pharma’s
investigational product Enhoxy for sickle cell disease11.
c. The FDA approved Immunetics’ BacTx® test to test leukocyte-reduced whole
blood-derived platelets for relevant bacterial contamination. This test generates
results in less than one hour. Immunetics has already achieved FDA approval of
a C6 peptide ELISA for Lyme disease, and its Anthrax QuickELISA test. With
funding from the US National Institutes of Health (NIH) Immunetics is
collaborating with academic and medical institutions to develop a QuickELISA
test for SARS, a Chagas disease confirmatory test, and a test for detecting and
identifying drug-resistant bacteria including MRSA.
d. Nanosphere has received de novo clearance from the FDA for its gram-positive
blood culture nucleic acid test. This can identify genus and species for grampositive bacteria and some markers of antimicrobial resistance, and can give
results in two-and-a-half hours.
e. Osiris Therapeutics in June received approval for its stem-cell therapy Prochymal
drug in New Zealand, the second country to approve the drug. Canada approved
it in May. Prochymal uses healthy donor stem cells to treat children with acute
graft-vs-host disease, a deadly complication of bone marrow transplants. The
drug does not have FDA approval, but can be used in the US under the federal
9
Orphan drugs benefit a relatively small number of people (in the US, fewer than 200,000), and such
designations round the world usually carry economic advantages including market exclusivity for a
specified term.
10
a genetic disorder in which the patient experiences unpredictable and debilitating episodes of
intense swelling of the extremities, face, trunk, genitals, abdomen and upper airway. The frequency
and severity of HAE attacks vary and are most serious when they involve laryngeal oedema, which
can close the upper airway and cause death by asphyxiation. According to the U.S. Hereditary
Angioedema Association, epidemiological estimates for HAE range from one in 10,000 to one in
50,000 individuals.
11
Enhoxy, or human erythrocytes encapsulating inositol hexaphosphate, increases the oxygenation
capacity of red blood cells by reducing their oxygen-hemoglobin affinity and allowing them to release
more oxygen. Hypoxia, lack of oxygen in the blood, is associated with red cell sickling and severe cell
sickling crisis. Total blood exchanges are often used needed to reverse hypoxic conditions and
prevent crises, but the company expects Enhoxy will reduce the need for transfusion. Sickle Cell
disease is genetic, characterized by periods of painful vascular occlusive crises and often including
chronic haemolysis and increased susceptibility to infections. Its complications can be life threatening,
and it can lead to extensive organ damage reducing both quality of life and life expectancy. There are
about 80,000 patients in Europe and about 100,000 in US.
3
3.
4
Expanded Access Program, which allows promising drugs to be used as
treatment for serious diseases prior to FDA approval.
f. Takeda Pharmaceutical Company Limited and AMAG Pharmaceuticals in June
were granted marketing authorization by the European Commission for
ferumoxytol, an intravenous therapy to treat iron deficiency anemia in adult
patients with chronic kidney disease.
g. The FDA approved Baxter’s Gammagard Liquid to treat multifocal motor
neuropathy, characterized by progressive weakness in the limbs. Gammagard
Liquid is the first immunoglobulin treatment approved in the US for the condition.
h. Pfizer and Bristol-Myers Squibb in June failed to win approval of their blood
thinner Eliquis from the FDA, which sought more data.
i. The FDA issued in June, for comment purposes only, Draft Guidance for Industry
Recommendations for Donor Questioning, Deferral, Reentry and Product
Management to Reduce the Risk of Transfusion-Transmitted Malaria.’
j. After facing criticism for not releasing clinical trial data, the European Medicines
Agency said in July it would hold a conference in November to review how large
data sets could be released in a timely fashion for research use.
k. In July, the FDA approved a new 4000IU presentation of Baxter’s Advate. It will
be available in the US in August.
l. The FDA in July notified Inspiration Biopharmaceuticals that both adult and
paediatric studies evaluating IB1001 for the treatment and prevention of bleeding
episodes in people with haemophilia B have been placed on clinical hold. The
drug is an intravenous recombinant factor IX (rFIX) therapy. A trend was noted
towards a higher proportion of IB1001-treated individuals developing antibodies
to proteins from the Chinese hamster ovary (CHO) host cells used to
manufacture the therapy than was expected based on earlier study data.
Inspiration chief executive John Butler said "we have already made progress in
identifying potential options to reduce antibody formation and will continue to
work with the FDA on plans to move the IB1001 programme forward".
m. In July, the FDA approved Gilead Sciences’ HIV combination pill Truvada for preexposure prophylaxis. This is the first time the FDA has endorsed a medication
to combat HIV among uninfected but high- risk individuals.
n. Israel-based Pluristem Therapeutics, which develops therapies from placental
cells, expects to file an FDA application before the end of August for orphan drug
status and accelerated review, to treat anemia caused by abnormal (or aplastic)
bone marrow.
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. Grifols in July confirmed the winners of the 2012 Martin Villar Awards for
research in haemostasis. A group led by Rodney Camire won first prize for a
paper indicating that the zymogen-like FXa variant corrects the coagulation
defect in haemophilic mice. Second prize went to Rezan Kadir for a publication
entitled Noninvasive prenatal diagnosis of haemophilia by microfluidics digital
PCR analysis of maternal plasma DNA, which developed a methodology for
determining whether a foetus has inherited a causative mutation for haemophilia
from its mother. Katherine High was awarded third prize for a paper entitled In
vivo genome editing restores haemostasis in a mouse model of haemophilia.
 Biotest says it has 300 million euros to spend on acquisitions, perhaps of makers
of clotting agents.
 ProMetic Life Sciences in June received a $US 4.6m purchase order under its
ongoing supply agreement with Octapharma, for PrioClear, its prion capture

resin incorporated into Octapharma's manufacturing process for its
solvent/detergent treated plasma product.
Bristol-Myers Squibb in July began a tender offer to acquire Amylin
Pharmaceuticals, the offer to expire on 7 August.
4. 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.
a. US
 Puget Sound Blood Center and Auburn Regional Medical Center have
implemented a Remote Allocation system to provide point of use access to blood
components. The system consists of automated and refrigerated dispensing units
(HemoSafes) in hospitals– controlled by inventory management software,
BloodTrack. When patients need transfusions, their blood is electronically crossmatched with components in the HemoSafes. Waiting times for transfusion have
been significantly reduced.
 The rate of perioperative blood transfusion after nephrectomy appears to be
higher in practice than the rates commonly cited in published urologic reports,
researchers reported at the American Urological Association 2012 Annual
Scientific Meeting in June. The transfusion rate was strongly associated with
patient factors such as age and comorbidity, and with procedure type, surgeon
and hospital volume. Year of surgery, gender, and income quintile had no impact
on the transfusion rate.
 Drugstore chain Walgreen and several other pharmacies are offering free, rapid
HIV tests in a small number of stores under a two-year pilot program to make
diagnosing the AIDS virus more convenient and accessible to Americans.
Announcing the pilot program the Centers for Disease Control and Prevention
(CDC) said information gathered will help to develop a nationwide model for
pharmacists and nurse practitioners to detect the virus.
 In 2012, more serious cases of West Nile virus have been reported in the US
than in any year since 2004. Ninety per cent of people infected with the virus do
not feel ill with it, and are detected only if they donate blood, or their blood is
tested for another reason. About 10 per cent of people infected will develop a flulike fever and some will have dangerous infections of the nervous system. The
mortality rate is about 6 per cent for West Nile in the US.
 In the US summer, babesiosis -- spread by ticks -- is endemic in the Northeast
and upper Midwest, according to the CDC12. Babesiosis can also be transmitted
through blood transfusions or from mother to child during pregnancy13.
Babesiosis can be life-threatening, especially for people without a spleen and for
the elderly, though most healthy people remain asymptomatic; or at worst
develop headache, fever, or chills. The same ticks carry Lyme disease. Both
diseases can be treated with antibiotics.
 The Immunoglobulin Nursing Society’s first national conference was held in
Orlando in August. Presentation topics included an update on clinical trials.
b. UK
 NHS medical director Sir Bruce Keogh in June called on clinicians to prescribe
blood transfusions only when necessary, in a bid to prevent demand outstripping
12
Stephanie J. Yendell, D.V.M., Dana Woodhall, M.D., both at U.S. Centers for Disease Control and
Prevention; Marc Siegel, M.D., associate professor, medicine, NYU Langone Medical Center, New
York City; July 13, 2012, Morbidity and Mortality Weekly Report
13 In the US, Westchester County researchers confirmed in July for the first time a case of a pregnant
woman passing on babesiosis to her unborn baby. See Emerging Infectious Diseases, a journal
published by the US Centers for Disease Control.
5
supply. He told the NHS Blood and Transplant’s patient blood management
conference that one in five blood transfusions was not clinically necessary.
 AstraZeneca’s Fluenz, a needle-free flu vaccine for children, has been launched
in the UK for the 2012/13 flu season. The live attenuated vaccine was approved
in Europe in 2011 for children aged from 24 months to less than 18 years, but it
has been sold in the US as FluMist - since 2003.
 The UK Department of Health in July appointed Lazard, the investment bank, to
explore a privatisation of Plasma Resources UK ,a principal supplier to the NHS.
PRUK owns a US-based plasma supply company and operates a production
facility in the UK (Bio Products Laboratory Limited).
c. Other
 The Rwandan government announced in June the release of five new iron-rich
bean varieties that could provide more iron in the diets of millions of Rwandese
who eat beans every day, and will thus aid in the fight against anaemia.
 China Biologic Products announced that its indirectly owned subsidiary,
Shandong Taibang Biological Products Co., has received a manufacturing
approval certificate from the China State Food and Drug Administration (SFDA)
for Human Coagulation Factor VIII.
 In Pakistan the World Health Organization (WHO) is spending $US 7.8m to buy
blood screening kits for HIV, hepatitis B and C to provide free screening services
in transfusion centres.
 The Nigerian Export- Import Bank has signed a financing agreement with the
National Institute for Pharmaceutical Research and Development for the
production of a sickle cell anaemia drug. Niprisan is to be made from four
botanical species indigenous to Nigeria.
 The health ministry in Bahrain in July convened a meeting to come up with a plan
to tackle the increasing incidence of sickle cell disease, after seven deaths
occurred in one week. Currentlyy18,000 patients are being treated at
government hospitals and the concern is that this will increase.
 The Khaleej Times (Dubai) reported that the Sharjah Blood Transfusion and
Research Center at the Ministry of Health is testing all donations for West Nile
Virus.
 An EU funded researcher has reported that blood bags made of polyvinyl chloride
(PVC) that contain diethylhexyl phthalate (DEHP) area are a significant risk to
human health.
5. Safety Issues We follow current issues in patient safety.
a. Appropriate transfusion
 Jehovah's Witnesses, whose religious beliefs don't allow for blood transfusions,
seem to do as well or better than other patients after heart surgery, according to
new research14. Surgeons typically take extra pre-operative precautions - such as
giving patients B vitamins and iron - to ensure their red blood cell counts don't get
too low during surgery. Jehovah's Witnesses also spent less time in the hospital
and the intensive care unit, on average, and are less likely to need an extra
operation because of bleeding problems.
 At Auckland Hospital a blood- saving measure focussed on single-unit
transfusions at higher haemoglobin levels and emphasised the added safety of
providing fewer transfusions. The number of red blood cell units transfused over
a ten month period fell by 11%.
b. Reversing the newer anticoagulants
 For the long- time standard anti- coagulant, vitamin K antagonist warfarin,
methods of reversal (in the event of trauma or surgery) are well understood. For
14
6
Published in the Archives of Internal Medicine, online on July 2 2012
newer blood thinners this may not be the case. However, a new study suggests
there are three different approaches to reverse the action of one new blood
thinner, the factor Xa inhibitor, apixaban (Eliquis) currently under review by the
FDA.
 “…..there is little information on how best to reverse the effects of newer
anticoagulants, which can take 10 to 18 hours," study author Dr. Gines
Escolar, an associate professor of hematology at the University of Barcelona,
explained in an American Heart Association news release. The study,
presented in the Emerging Science Series, was partially funded by BristolMyers Squibb, which is developing apixaban.
 In conducting the study, the researchers added a high dose of apixaban to
blood from healthy donors to test the effects of various methods of reversing
blood thinners on the new drug. They found that two blood-clotting agents -prothrombin complex concentrates15 and activated prothrombin complex
concentrates -- were more efficient than recombinant factor VII in reversing
apixaban. Recombinant factor VII, however, was the first to produce a blood
clot and was also most effective in studies with blood circulating through a
damaged blood vessel. Escolar said a clinical trial is essential to resolve
resolving dosing, efficacy and safety issues.
 "Apixaban, which is being considered for use in the prevention of stroke and
systemic embolism in patients with atrial fibrillation, can be an attractive
alternative to warfarin and heparin also used in similar patients," said Dr.
David Friedman, chief of Heart Failure Services at North Shore-LIJ's
Plainview Hospital, N.Y. "The hope would be for these researchers to next
show a safe, effective and quick way to clinically reverse the anticoagulant
effects of apixaban on patients with atrial fibrillation who come to the ER with
a new bleeding event," he said. If such a method of reversal is confirmed,
"clinicians may start to feel more comfortable with the advantages of these
newer medicines," he said.
 Apixaban has already been approved in Europe for preventing blood clots in
adults after knee or hip replacement surgery. The drug is currently under review
by the FDA to prevent stroke in people with atrial fibrillation.
 Escolar and his colleagues are now trialling recombinant factor VIIa and
prothrombin complex concentrate (PCC)—to reverse anticoagulation with another
factor Xa inhibitor, rivaroxaban (Xarelto, Bayer/Johnson & Johnson), and the
direct thrombin inhibitor dabigatran (Pradaxa, Boehringer Ingelheim).
c. Donor Deferrals
 A New Zealand report on World Blood Donor Day said that In the past five years,
the Human Rights Commission has received nine complaints from men denied
the opportunity to donate blood because of their sexual orientation. The report
suggested gay men are over forty times more likely than others to have HIV and
that testing does not always pick up the virus. "At this time we do not have robust
systems available to do that, and hence pending their development we need to
continue with this exclusion of all men who have had sex with other men," NZ
Blood Service medical director Dr Peter Flanagan said. The Aids Foundation
executive director Shaun Robinson told ONE News "We don't consider it
discrimination because the most important thing around the blood supply is that
it's 100% safe". Speaking on World Blood Donor Day in France Health Minister
Marisol Touraine said she would put forward proposals to allow homosexuals to
give blood, with risk assessed on multiplicity of partners. The ban was lifted in
15
The PCC products available in Europe (and Canada) contain all four of the vitamin-K-dependent
factors (II, VII, IX and X), whereas the PCCs available in the US have low levels of factor VII, so are
often considered only a three-factor concentrate.
7
November 2011 in England, Scotland and Wales for homosexual and bisexual
men who had not had sex with another man in the previous 12 months.
d. Testing the blood supply and blood products
 The Wall Street Journal reported on 30 July that about 150 US hospitals have
adopted a bacterial contamination test, made by Verax Biomedical, that can be
used for platelets immediately before patients are transfused. The test was
approved in 2007 by the FDA and adds around $US 25 to $US 30 to the average
$US 540 cost of a unit of platelets. Nevertheless, the WSJ says, “hundreds of
non- fatal sepsis cases and other adverse reactions are still linked to
contaminated platelets. Experts say the rate may be much higher than reported
because infections might have been attributed to other causes. In a study of over
four million platelet units the American Red Cross collected and distributed to
hospitals from January 2007 to December 2011, it found 381 suspected septic
reactions in platelets it distributed, 38 definite or probable cases and four deaths”.
6. Research A wide range of scientific research has some potential to affect the use of
blood and blood products. However, research projects have time horizons which vary
from “useful tomorrow” to “at least ten years away”. Likelihood of success of particular
projects varies, and even research which achieves its desired scientific outcomes may
not lead to scaled- up production, clinical trials, regulatory approval and market
development.
a. Swedish doctors paired a vein from a dead donor with stem cells from a young
girl and implanted the healthy vein into the girl, improving blood flow in her lower
body and hence her quality of life16.
b. Pfizer has ended its attempt to save money by using social media to recruit
patients for clinical trials. There was substantial traffic to the information website
but this did not convert into people willing to participate in the study.
c. A professor of biochemistry and molecular biology at Saint Louis University
School of Medicine, has received a four-year, $US 1.52m grant from the US
National Heart Lung and Blood Institute to study how the blood clotting inhibitor
antithrombin might be used to prevent premature death from heart disease.
d. ScienceDaily reported (July 11, 2012) that a new Cochrane systematic review
had found that taking iron supplements one to three times a week instead of
every day is just as effective at preventing anaemia in pregnant women.
e. With conventional antibiotics losing their potency against new strains of
multidrug-resistant bacteria, the US National Institutes of Health (NIH) has
allocated $US 4.48m to a collaboration between the Monash Institute of
Pharmaceutical Sciences and Californian biotech Rempex Pharmaceuticals to
develop new antibiotics. The bacteria to be targeted have been identified by the
Infectious Diseases Society of America as being the most difficult to treat.
f. The genetic mutation responsible for haemophilia B is among embryonic stem
cell lines created by the University of Michigan and believed to be the first in the
world to carry the disease. They have been added to the US national registry
and are available for federally funded research.
g. Harvard researchers have developed a biomimetic strategy to deliver
nanotherapeutics directly to obstructed blood vessels to dissolve blood clots.
This requires only a fraction of the drug dose normally used.
h. Terumo BCT has received a $US 3.5m grant from the US Department of Defense
grant for two collaborative, clinical trials being conducted in the US and Europe.
The Mirasol System for Whole Blood is being evaluated for its capacity to reduce
disease transmission and leukocyte-related transfusion reactions. Pre-clinical
16
8
Reported online in June in The Lancet.
work will evaluate platelet and plasma function in vitro and in vivo, and study
parasite reduction (eg babesia). Total Department of Defense sponsorship of the
Mirasol program to date is now $US 14m.
i. In stem cell transplants for sickle cell anaemia doctors at the University of Illinois
are preparing patients following a regimen used by NIH researchers that relies on
immunosuppressants and low-dose radiation rather than chemotherapy.
j. Scientists have discovered how to administer oxygen to circulating blood, which
could eliminate the need to keep patients breathing throughout surgery. Oxygen
molecules enclosed in fatty molecules are injected directly into the bloodstream.
This is regarded as a short- term oxygen substitute, giving maybe an extra 30
minutes of life in surgery and trauma.
k. Alzheimer’s Disease
 A major clinical trial, expected to report in 2013, is assessing Baxter’s
immunoglobulin, Gammagard, as a treatment for Alzheimer’s disease. Interim
comments have been suggesting a positive outcome is likely. If the results lead
across a number of jurisdictions to approval of immunoglobulin as a treatment for
Alzheimer’s disease, then we can expect supply constraints and rising prices at
least in the short term. Accordingly, the NBA takes an interest in research
concerning Alzheimer’s disease: its prevention, its diagnosis and its treatment.
 At the Alzheimer’s Association’s International Conference in Vancouver in July
Dr. Norman Relkin of New York-Presbyterian Hospital/ Weill Cornell Medical
Center and leader of the late-stage, 390-patient study of Gammagard, gave a
three-year progress report on 16 patients out of the original 24 enrolled in an
earlier study17. He said Gammagard halted the progression of Alzheimer’s
disease for as long as three years. Four patients given 0.4 g/kg every 2 weeks
from the start of the trial showed no decline in test scores. Five patients initially
given a placebo, and seven others on varying amounts of Gammagard,
experienced no benefit until they were switched to 0.4 g/kg. Results of the larger
trial are expected by mid-2013.
 The rationale for trialling intravenous immunoglobulin in Alzheimer's disease is
that it contains antibodies against beta amyloid proteins and it also modulates
immune function to reduce inflammation. Also targeting amyloid are two
labpratory- made treatments whose trials are about to report.
 Bapineuzumab belongs to Pfizer, Johnson and Johnson, and Elan. Over 4,000
patients have taken part in four studies - two in people with a gene that raises the
risk of Alzheimer's and two in people who don't carry that gene. Patients have
had regular brain scans to track progress. Pfizer announced at the end of July
that its treatment had failed in one of the four trials, failing to improve cognition or
physical function in patients with the gene variation ApoE4 known to be a major
risk factor for the disease. They said results from the two North American
bapineuzumab studies would be presented on September 11 at a meeting of the
European Federation of Neurological Societies in Stockholm; and that results for
bapineuzumab would also be discussed at the American Neurological
Association meeting in Boston on October 8. The session will be devoted to
immune-based treatments for neurological disorders. Also at that meeting Eli
Lilly will present key data on solanezumab, which targets the same protein. Data
for both bapineuzumab and solanezumab were also to be discussed at a meeting
of the Clinical Trials Conference on Alzheimer's Disease in Monte Carlo in
October. Then early in August, another bapineuzamab study had disappointing
results for the companies, and they discontinued most other studies, including all
Pjase III studies, although they will complete follow- up evaluations and final data
analyses.
17
Alzheimer's Association International Conference. Relkin N, et al "Three-year follow-up on the IVIG
for Alzheimer's phase II study" AAIC 2012; Abstract P3-381.
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At the Vancouver conference EnVivo Pharmaceuticals announced positive
results from its Phase IIb trial of EVP-6124, a novel alpha-7 agonist and Eisai
presented the first data from clinical studies of E2609, a BACE (beta-site amyloid
precursor protein-cleaving enzyme) inhibitor.
Grifols’ AMBAR (Alzheimer Management By Amyloid Removal) study, will
investigate combining albumin plasmapheresis and intravenous immunoglobulin
at different doses. The researchers are looking for synergies between the two
treatments to reduce the frequency and volume of plasmapheresis. AMBAR is
expected to last two years.
Humanetics Corporation has its NIC5-15 in a Phase IIb clinical test. NIC5-15 has
been shown in preclinical studies and animal models to be effective in preventing
the formation of beta-amyloid plaques.
Araclon Biotech, in which Grifols has a majority shareholding, has found it
possible to quantify the protein Aß-17 in the blood for the first time. Its levels
change as Alzheimer’s disease progresses. Araclon says its patented “ABtest”
allows patients with Alzheimer’s disease to be distinguished from those without.
Furthermore, together with the proteins Aß-40 and Aß-42, it is possible to identify
the patients with mild cognitive impairment who might develop Alzheimer’s.
Earlier detection and treatment may be a key to preventing brain damage.
CAD106, a vaccine developed by Novartis and Cytos to slow the development of
Alzheimer’s, targets the amyloid β peptide. It has shown promise of immune
responses in a clinical trial in people with Alzheimer's disease18.
An alternative approach to Alzheimer’s treatment targets the tau protein. In the
1990s some evidence suggested that tau deposits were a better indicator of
mental state than beta amyloid plaques. Normally, tau assists the supply of
nutrients to brain cells. Tangled tau cuts off the supply lines. Singapore
company TauRx is developing tau aggregation inhibitors.
Roche has entered into an agreement with AC Immune to gain access to anti-tau
antibodies for the treatment of Alzheimer’s disease and other neurodegenerative
diseases. Roche (through Genentech) is already working with crenezumab which
it in-licensed from AC Immune in 2006. That is an anti-amyloid antibody currently
being trialled in a Phase II study in Alzheimer’s patients with mild to moderate
symptoms. In May 2012, crenezumab was selected to be tested in a prophylactic
trial in healthy individuals genetically destined to develop Alzheimer’s disease.
Planned trials to evaluate whether earlier intervention will help people who are at
risk for Alzheimer’s- due to family history or because they carry certain
biomarkers for the disease- were discussed at the Vancouver meeting. Brain
changes that presage Alzheimer’s begin about 15 years to 20 years before
patients become symptomatic.
AstraZeneca and four academic research laboratories together will study a major
risk factor for Alzheimer's disease, the apolipoprotein E4 genotype (ApoE). ApoE
is regarded as second only to age as a risk factor. Members of the new A5
alliance have expertise in ApoE biology and will focus on identification, validation,
and risk reduction of drug targets for treatment of Alzheimer's disease.
Japanese company ReproCELL announced in June it is commercializing human
iPS-derived neurons in which an Alzheimer's disease related gene has been
incorporated. In these cells, it has been confirmed that amyloid beta 42 is
accumulated at higher levels compared with normal neurons. This is similar to
what is observed in neurons of Alzheimer's patients. Accordingly, ReproCELL's
The Lancet Neurology, Volume 11, Issue 7, Pages 597 - 604, July 2012
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7.
8.
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scientists believe the newly developed iPS cells can be useful for drug screening
to identify new therapeutic molecules to treat Alzheimer's disease patients19.
 StemCells, Inc. introduced preclinical data at the Vancouver conference
suggesting that its human neural stem cells restored memory and enhanced
synaptic function in two animal models relevant to Alzheimer's disease.
 Takeda finalized in June a contract to transfer TAK-070, which it developed as a
potential treatment of Alzheimer-type dementia, to the National University
Corporation, The University of Tokyo. TAK-070 suppresses the production of
amyloid-β protein by inhibiting β-secretase. The University of Tokyo Hospital is
designated by Japan’s Ministry of Health, Labour and Welfare as the base for
“the national early/exploratory clinical trial project” which aims to overcome
dementia and intractable neurological and psychiatric diseases. TAK-070 will be
its first new drug candidate in clinical research.
Legal actions and enquiries The NBA is interested in the implications for
Australia of any proceedings against companies, governments and professional
practitioners in relation to blood and blood products; or of relevant public enquiries
a. With three noninvasive tests for analyzing the DNA of a foetus, with a fourth
available soon, there is a legal issue over who can patent the technique, which
involves scanning maternal blood for foetal DNA. The tests can detect genetic
abnormalities as early as 10 weeks from conception. Mildred Cho, a bioethicist
at the Stanford University School of Medicine told Nature. “The bigger policy
issue is whether society should allow monopolies on medical practice, especially
for medical technologies that benefited from public funding.”
b. In July, the New Zealand High Court assumed guardianship of an Auckland girl
suffering a rare kidney disease because her Jehovah's Witness parents would
not consent to a kidney and liver transplant, because of the blood transfusions
that would accompany the surgery. She had had her kidneys removed and was
being kept alive by dialysis.
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)
a. Mosquito- borne diseases
 The CDC has developed a new test for the dengue virus in people with
symptoms of dengue fever or dengue haemorrhagic fever. The test, CDC DENV1-4 Real Time RT PCR Assay, has been authorized by the FDA for use in the
US. The test can, as its name suggests, identify all four dengue virus types.
Because it identifies the presence of the dengue virus itself, not antibodies the
patient has developed to it, this test allows confirmation of dengue earlier in a
patient’s illness.
 National University of Singapore (NUS) researchers studied over two years a
group of cell lines from 200 patients who recovered from dengue. They identified
an antibody that attaches itself strongly to a particular part of the dengue virus
and prevents it attacking other cells. This newly discovered antibody specifically
treats DENV1, only one of four dengue serotypes, but it is the serotype
responsible for up to 50 percent of the dengue cases in Singapore and other
Details of data of the cells announced at the 10th annual meeting of ISSCR (International Society
for Stem Cell Research) at Yokohama, Japan (June 13th-16th, 2012).
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countries in Southeast Asia. A clinical trial is planned for the DENV1 serotype
antibody and the team is working to find antibodies that target the other three
dengue serotypes.
 Two Colorado researchers are developing a drug to prevent replication of West
Nile, dengue and yellow fever viruses 20.
 In Florida, a significant number of Key West residents have objected to a plan to
release genetically modified mosquitoes as a way of controlling dengue.
 Sanofi’s dengue vaccine, trialled in Thailand, generated antibody responses
against all four strains of dengue but protected against only three.
 Queensland Institute of Medical Research (QIMR) tests show the Beauveria
bassiana fungus kills the Aedes aegypti mosquito, which carries dengue.
 Townsville has continued to see dengue cases during the winter.
b. Influenza
 A new study21 suggests the swine flu pandemic of 2009 killed an estimated
284,500 people, some 15 times the number confirmed by laboratory tests at the
time. It said the toll might have actually been twice as high. The original count,
compiled by WHO, put the number at 18 500, but these were only the deaths
confirmed by lab testing. It does not therefore include people outside a wellresourced health system. Also, the virus is not always identified at post mortem.
 Two University of Cambridge researchers have found that it might be possible for
human-to-human airborne transmissible avian H5N1 influenza viruses to evolve
in nature22. Two recent papers (in Science and in Nature) revealed that with as
few as five mutations (amino acid substitutions), or four mutations plus
reassortment, avian H5N1 can become airborne transmissible between
mammals. The Cambridge researchers found that two of the five mutations seen
in recently developed experimental viruses had occurred in numerous existing
avian flu strains; and that a number of the viruses had both of the mutations.
 The H3N8 virus was known as a bird flu but has crossed species and has been
killing seals on the north- east US coast. The virus targets the respiratory system.
There is serious concern about this new mammalian- transmissible virus to which
humans have not yet been exposed.
 At a meeting of influenza researchers in New York at the end of July, Anthony
Fauci, the director of the US National Institute of Allergy and Infectious Disease
(NIAID) recommended researchers continue their moratorium on creating highly
infectious strains of the avian influenza H5N1 virus. Flu researchers round the
world were divided in their opinions.
 The WHO recommended that the northern hemisphere's 2012-2013 seasonal
influenza vaccine be made from the following 3 vaccine viruses: an
A/California/7/2009 (H1N1)pdm09-like virus; an A/Victoria/361/2011 (H3N2)-like
virus; and a B/Wisconsin/1/2010-like virus (from the B/Yamagata lineage of
viruses). While the H1N1 virus used to make the 2012-2013 flu vaccine is the
same virus that was included in the 2011-2012 vaccine, the recommended
influenza H3N2 and B vaccine viruses are different from those in the 2011-2012
influenza vaccine for the northern hemisphere.
 Since the early 1980s, the seasonal flu vaccine has been trivalent with each
component selected to protect against one of the 3 main groups of influenza
viruses circulating in humans. In February 2012, quadrivalent flu vaccine
manufactured by MedImmune was licensed by the FDA for use in the US.
20
Brian Geiss and Susan Keenan online in June 2012 in the peer-reviewed Journal of Virology.
Published in Lancet Infectious Diseaes June 19 2012. Fatimah S Dawood, et al: “Estimated global
mortality associated with the first 12 months of 2009 pandemic influenza A H1N1 virus circulation: a
modelling study”.
22
Derek Smith and Colin Russell ,June 22 in the journal Science.
21
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Sanofi and University of Pittsburgh scientists have agreed to deveop a vaccine to
cover all strains of seasonal flu and have a production cycle of four months.
 Joseph Kim, president and CEO of Inovio Pharmaceuticals, said in July the
company may be five to seven years from releasing a universal flu vaccine, if a
series of trials is successful. The company has developed a synthetic DNA
vaccine using computer code DNA of all the flu strains in the past 100 years. Kim
said the company has seen positive initial results in testing of its SynCon vaccine
against six representative strains of the deadly H5N1 (avian flu) virus.
 Biomedical engineers at Brown University and at Memorial Hospital, Rhode
Island, have designed a biochip that can detect the presence of a flu pathogen. It
pinpoints the specific RNA sequences and then uses small magnets to isolate the
sequence that contains the flu from the remaining RNA strand. The fast and
reliable test can also be used for on-site detection of HIV and TB23.
 Medline’s BioMask, the first-ever Food and Drug Administration cleared antiviral,
antimicrobial medical face mask, is shown to inactivate 99.99 percent of
laboratory tested flu viruses, according Medline.The BioMask works by using a
combination of citric acid, zinc and copper — all natural and safe ingredients, the
company said. A hydrophilic coating on the outside quickly wicks droplets away
from the surface while the low pH in citric acid begins to inactivate viruses on
contact. The droplet then lands on the mask’s inner blue layer where any
remaining viruses are inactivated by copper and zinc, which are toxic to
pathogens.
c. By mid- July, Mexican authorities had killed nearly 4 million chickens in an
attempt to stop the spread of bird flu.
 Egypt tops the list of human deaths due to infection with the H5N1avian flu virus,
followed by Indonesia and then Vietnam. Since the virus hit Egypt in February
2006, 60 million birds have been officially culled to date and the costs of poultry
production have continuously risen. In June, the National Research Centre (NRC)
in Cairo announced the first vaccine to be produced by Egyptian scientists
against ‘bird flu’ in birds. The Government had been importing vaccine at high
prices, but this will be manufactured locally.
d. Other
 Sanofi in June suspended production of its BCG tuberculosis vaccine at its plant
in Canada after regulators found problems with sterility. The company agreed
that “the level of sterility was not at an acceptable level. There is currently no
stock available in Australia and a return to supply is not expected in the short
term." The vaccine was also recalled in Canada and New Zealand. While the
vaccine is not given as part of Australia's routine infant vaccinations, it is
generally given to newborns in areas where tuberculosis is prevalent, or to
children under 5 years of age who will be in those areas for more than three
months.
 Mid-stage data on Otsuka Pharmaceutica’s drug delamanid suggests it might
become the first new tuberculosis treatment to be approved in decades24.
 Vaccines used against a respiratory disease in chickens caused outbreaks of the
same disease across Australia, according to a July 12 report in Science25.
Different attenuated versions of a live virus used in the local and foreign vaccines
exchanged portions of their genomes, resulting in virulent, disease-causing
strains. This in-the-field genetic reassortment has implications for both animal
and human health. Jim MacLachlan, professor of veterinary medicine at the
University of California, Davis, said “Concerns have previously been raised about
23
Described in a paper released 11 June 2012 in the Journal of Molecular Diagnostics
Data from a Phase IIb study was published in the New England Journal of Medicine
25
S-W. Lee et al., “Attenuated Vaccines Can Recombine to Form Virulent Field Viruses,” Science, doi:
10.1126/science.1217134, 2012.
24
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the genetic roulette associated with live attenuated virus vaccines. In particular,
extensive use of such vaccines in intensively housed livestock creates an
environment where novel virus strains rapidly can emerge.” The findings
highlight precautions to consider for human and animal vaccination strategies—
particularly, that the use of a single version of weakened virus might be safest.
Prions responsible for bovine spongiform encephalopathy are detectable in the
autonomic nervous system before the central nervous system, according to a
study published online July 11 in The American Journal of Pathology.
University of Alberta researchers have discovered a class of compounds that
inhibit the spread of malfunctioning proteins in the brain26.
July saw a new case of variant Creutzfeld-Jakob disease (vCJD) in France.
Researchers at the Scripps Research Institute in La Jolla and at Duke University
in North Carolina have been awarded up to $US 186m from the US National
Institute of Allergy and Infectious Diseases to develop an AIDS vaccine.
In the US, the CDC offers free drugs to treat Chagas, but they receive just 50 or
60 requests a year for the medications, although there are probably around
300,000 people in the US with Chagas. Most initial carriers in the US probably
acquired the disease in Bolivia, Mexico or Central America. The disease lingers
for years, then for about 30% of those infected serious illness emerges- often the
result of heart damage. Now the disease is being contracted locally by people
who have never been south of the US border and are not of Latin American
descent. They show up as positive when they donate blood.
An Australian study found the old whooping cough vaccine provided more
protection than the current vaccine, although it did cause bad reactions.
Biosecurity Queensland has been managing a further Hendra virus case near
Mackay after a positive test result was received at the end of July. This followed
incidents in Townsville in January, and in Ingham and Rockhampton in May.
A new strain of cholera bacteria is circulating in India It is resistant to third
generation antibiotics27.
Charles E. Mays, Shaon Joy, Lei Li, Linghui Yu, Sacha Genovesi, Frederick G. West, David
Westaway. “Prion inhibition with multivalent PrPSc binding compounds”. Biomaterials, 2012; 33 (28):
6808 DOI: 10.1016/j.biomaterials.2012.06.004
27
Mandal J, Sangeetha V, Ganesan V, et al. Third-Generation Cephalosporin-Resistant _Vibrio
cholerae_, India. Emerg Infect Dis 2012;18, (8), 1326-28. Available at
<http://wwwnc.cdc.gov/eid/article/18/8/pdfs/11-1686.pdf
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