MONITORING INTERNATIONAL TRENDS
posted January 2013
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The NBA monitors international developments that may influence the management of blood
and blood products in Australia. Our focus is on:
Potential new product developments and applications; and
Global regulatory and blood practice trends; and
Events that may have an impact on global supply, demand and pricing, such as changes in
company structure, capacity, organisation and ownership; and
Other emerging risks that could potentially put financial or other pressures on the Australian
sector.
A selection of recent matters of interest appears below:
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) The 54th Annual Meeting and Exposition of the American Society of Hematology
(ASH) was held in Atlanta, Georgia in December 2012. Amongst the presentations:
a. Baxter International announced Phase I/III study results evaluating the safety
and efficacy of BAX 326, an investigational recombinant factor IX (rFIX)
protein, for the treatment and prophylaxis of bleeding episodes for patients
with hemophilia B over 12 years of age. BAX 326 was recently granted
orphan-drug designation by the U.S. Food and Drug Administration (FDA), a
special status given to a product that when approved, will address an unmet
need for people with a rare disease or condition. Data supporting the
prophylaxis indication, which is the basis for the orphan drug designation,
was included in the biologics license application (BLA). The Phase I/III
prospective, controlled, multicentre study investigated the pharmacokinetics,
efficacy and safety of BAX 326 in 73 previously-treated patients with severe
or moderately severe hemophilia B. Results from the study showed that
twice-weekly prophylactic treatment with BAX 326 achieved a median
annualized bleed rate of 1.99 with 43 percent of patients experiencing no
bleeds1.
b. Inspiration Biopharmaceuticals announced interim clinical results for two
products- its intravenous recombinant porcine factor VIII (OBI-1) for treating
serious bleeds in acquired hemophilia A2; and rFIX (IB1001) for treating and
preventing bleeding in haemophilia B in children under 123.
1
No inhibitors were detected and no cases of anaphylaxis were reported in any patients. Mild and
transient treatment-related adverse events were reported in 2 of the 73 patients.
2
The poster Recombinant B-domain deleted porcine FVIII (OBI-1) safety and efficacy in acquired
hemophilia A: interim results referred to the prospective Phase II/III trial of OBI-1 in serious bleeds.
Sixteen acquired haemophilia A (AHA) subjects were all judged by the investigator to have had either
effective or partially effective control of serious haemorrhage 24 hours after the initial dose, and
subsequent resolution of their bleed. There were 11 serious adverse events to September 2012 and
5 deaths were reported, with none of the deaths being attributed by the investigator to OBI-1. One
serious adverse event (pneumonia and atrial fibrillation) was deemed by the investigator to be
probably not/remotely related to OBI-1. Antibodies to OBI-1 developed in 3 subjects. No specific
treatment was given for the anti-OBI-1 antibodies. These interim results were interpreted as
1
i. Inspiration will file a BLA for OBI-1 in the first half of 2013. OBI-1 has
orphan drug designation in the US and EU, has fast track designation
from the FDA. This designation is for a drug intended to treat a
serious disease and which has a potential to fill an unmet medical
need. It may receive priority review (eight months).
ii. Inspiration filed a marketing authorization application in Europe for
IB1001 late in 2011 and a BLA license application in the US for
IB1001 in the first half of 2012. Regulatory reviews are ongoing4.
iii. Ipsen and Inspiration made some changes in their partnership
arrangements in 2012. In January 2013, Baxter announced it will be
acquiring OBI-1 and related assets.
c. Alnylam Pharmaceuticals presented new pre-clinical data from its RNAi
therapeutic program for the treatment of haemophilia and other bleeding
disorders. Data showed that ALN-AT3, a subcutaneous RNAi therapeutic
targeting antithrombin (AT), delivers “potent, dose-dependent, and durable
knockdown of AT in non-human primates with an up to four-fold increase in
thrombin generation”. The company said the drug is expected to be subject
to an investigational new drug filing in mid-2013.
d. AesRx announced data from its Phase I study for its drug Aes-103 shows the
treatment is safe and well-tolerated for patients with sickle cell disease. The
drug has orphan drug status from the FDA.
e. Emmaus Medical discussed its sickle cell research. It had earlier announced
the completion of patient enrolment for its Phase III trial to study L-glutamine
as a treatment for sickle cell anemia and beta-thalassemia. L-glutamine
therapy for these conditions is a patent protected treatment, which has
orphan drug status in both he US and Europe. It has fast track designation
from the FDA.
f.
Acetylon Pharmaceuticals announced results from a preclinical study of a
selective histone deacetylase (HDAC) 1/2 inhibitor for the treatment of sickle
cell disease and beta-thalassemia. The study results suggest that selective
inhibition of the epigenetic regulators of gene expression, HDACs 1 and 2,
could represent a refined and targeted approach for the treatment of both
conditions through the induction of disease-corrective foetal hemoglobin in
human red blood cell progenitors.
g. Amgen presented data from several studies5. These included data evaluating
long-term use of Nplate (romiplostim) in paediatric chronic immune
thrombocytopenia (ITP).
suggesting that in this study OBI-1 was well-tolerated and effective in the treatment of serious
bleeding episodes in AHA.
3
The poster IB1001, an investigational recombinant factor IX, pharmacokinetics in pediatric patients
with hemophilia B reports preliminary pharmacokinetic data from 7 subjects. Compared with findings
previously reported by Martinowitz U, et al. in subjects 12 years of age and older, these pediatric
subjects demonstrated a more rapid metabolism of rFIX with a shorter terminal half-life and a lower in
vivo recovery. Results resemble those reported by Berntorp, et al (Haemophilia, 7, 2001) with
nonacog alfa.
4
The FDA placed a clinical hold on IB1001 in July 2012 when a number of study subjects developed
antibodies to the host cell protein, Chinese hamster ovary cell proteins (CHOP). No clinical sequelae
were associated with these antibodies and they were claimed not to limit the clinical effectiveness of
the product. Inspiration said it has made significant progress in addressing the situation, and intends
to submit data to the FDA in the first part of 2013.
5
Long-Term Use of Open-Label Romiplostim in Children with Chronic/Refractory Immune
Thrombocytopenia (ITP): Results from an Open-label Phase 1/2 Randomized Double-blind Placebo-
2
h. Noxxon Pharma presented Phase 1 results for its anti-hepcidin NOX-H94 to
treat anaemia associated with chronic disease. Excessive concentrations of
the peptide hepcidin occur in chronic diseases such as cancer, renal
disease, and inflammatory diseases. These concentrations lead to iron
restriction, or functional iron deficiency where iron is trapped in its cellular
stores and is unavailable for haemoglobin synthesis. NOX-H94 binds to and
inactivates hepcidin. The Phase I program consisted of a comprehensive
single and multiple ascending dose study in healthy volunteers and a
subsequent human pharmacodynamic study to assess the ability of NOXH94 to prevent endotoxin-induced hypoferraemia in healthy subjects. This
study delivered the first clinical evidence that NOX-H94 is capable of
neutralizing high levels of hepcidin in humans and maintaining higher serum
iron concentrations compared with subjects receiving placebo. Noxxon
Pharma has begun a Phase IIa clinical trial in Europe in anaemic patients
with cancer.
b) Arsenal Medical won a $US15.5 million contract from the US Defense Advanced
Research Projects Agency (DARPA) to develop a foam for battlefield use to stem
internal bleeding for at least an hour while a patient is transferred to a field hospital.
This is to support late-stage development as well as funding work to achieve FDA
approval. Arsenal’s long-term goal is to develop the product for civilian use for
severe trauma. Pre-clinical data was presented at the 2012 annual meeting of the
American Association for the Surgery of Trauma in Kauai. The data demonstrated
the foam can treat severe haemorrhage for up to three hours in a lethal model of liver
injury. The product could reduce blood loss six-fold and increase survival three
hours later from 8 percent to 72 percent.
c) Bayer's BAY 86-6150, a recombinant factor VIIa, is the subject of a Phase II/III study
called TRUST (TReatment with Unique recombinant rFVIIa STudy). This will
evaluate the safety and efficacy of the compound in patients with haemophilia A or
haemophilia B who have developed inhibitors (neutralizing antibodies to clotting
factor therapies). Part A of the trial involves sequential dose escalation and
assessment of dose response and the pharmacokinetics and pharmacodynamics
evaluation. Part B is to confirm efficacy and safety.
d) Kamada announced positive results of the Phase I/II clinical trial of its Alpha-1
Antitrypsin (AAT) protein, the active ingredient in its drug, Glassia, for the treatment
of type 1- juvenile onset- diabetes. Analysis of the results found that the AAT protein
may halt the progression of diabetes. It enables the pancreas beta cells to continue
excreting insulin, providing better glucose balance, thereby lowering or even
preventing serious future complications of the disease. In view of the success of the
trial and its results, Kamada is preparing further development of injectable AAT for
the treatment and curing of juvenile onset diabetes, and to move for regulatory
controlled Study. Lead Author: James B. Bussel, Department of Pediatrics, Division of Hematology,
Weill Medical College of Cornell University, New York, NY; Abstract No. 621
Integrated Analysis of Long Term Safety in Patients (pts) with Chronic Immune Thrombocytopenia
(ITP) Treated with Romiplostim: Results from a Safety Analysis of Pooled Data from ITP Romiplostim
Clinical Studies. Lead Author: Douglas B. Cines, Pathology and Laboratory Medicine, University of
Pennsylvania School of Medicine, Philadelphia, PA; Abstract No. 2185
A Systematic Literature Review and Meta-Analysis of the Risk of Thromboembolic Events in Patients
with Immune Thrombocytopenia (ITP) in Observational Studies: Results from a Systematic Review
and Meta-Analysis of Randomized Controlled Trials of Thrombopoietin-receptor Agonists (TPOr).
Lead Author: Wendy Langeberg, Amgen, Thousand Oaks, CA; Abstract No. 2187
Romiplostim for the Treatment of Adults with Primary Immune Thrombocytopenia (ITP) in Routine
Clinical Practice – Interim Results From a Large, European, Observational Study. Lead Author:
Dominik Selleslag, Department of Hematology, AZ St-Jan, Brugge, Belgium; Abstract No. 3316.
Abstracts were made available on the ASH website at www.hematology.org
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approval. Most patients in the trial reported reduced use of insulin, and there was a
corresponding reduction in the level of specific diabetes antibodies, which may
indicate a reduction in the autoimmune response in the pancreas.
e) Novo Nordisk in November introduced HemaGo, a mobile application for people with
haemophilia and their carers to monitor medications and dosing, details of their
bleeds, their pain, and the impact of haemophilia on the rest of their lives.
b) FibroGen and Astellas Pharma in December announced the commencement of a
Phase III trial of FG-4592/ASP1517 for treatment of anaemia in chronic kidney
disease (CKD) patients. The inhibitor of hypoxia-inducible factor prolyl hydroxylase
demonstrated the potential to maintain haemoglobin levels, without any intravenous
iron supplementation, in CKD patients who are not on dialysis, and in end-stage renal
disease patients on dialysis.
f)
Halozyme Biotherapeutics works with human enzymes to modify biotechnology
medicines for administration by injection rather than intravenously. Its recent
agreement with Pfizer includes a licence to develop two specific treatments, and the
right for Pfizer to select up to four other targets.
g) CSL, which markets Beriplex, a four-factor prothrombin complex concentrate (PCC),
sponsored a study which found Beriplex superior to plasma for urgent reversal of
warfarin and other vitamin K antagonists in patients experiencing major bleeding. Dr.
Joshua N. Goldstein of the University of Rochester, NY, told the annual meeting of
the American College of Emergency Physicians that Beriplex had a higher rate of
INR6 reversal than did plasma at 30 minutes after the start of infusion, based on the
Phase IIIb prospective, multicentre, randomized clinical trial. Beriplex was also
shown to be superior to plasma at early replacement of depleted coagulation factors
and was noninferior to plasma in terms of blinded investigator–rated haemostatic
efficacy in the first 24 hours7.
Regulatory Matters
The NBA monitors overseas regulatory decisions on products, processes or procedures
which are or may be of relevance to its responsibilities.
a) In a Safety Communication on 13 November 2012 the FDA updated information on
the risks of thrombosis and haemolysis potentially related to administration of
intravenous, subcutaneous and intramuscular human immune globulin products.
This follows the FDA Interim Statement Regarding Immune Globulin Intravenous
(IGIV), of August 22, 2002, regarding thrombotic events following infusion. The FDA
6
International normalized ratio, a laboratory test measure of blood coagulation.
7The
study included 202 adults on warfarin or another vitamin K antagonist who presented with acute
major bleeding. The objectives were to correct their INR as quickly as possible and thereby reduce
their blood loss. Participants were randomized to INR- and weight-based dosing of the PCC or to
plasma on top of background vitamin K given by slow intravenous infusion in all cases. Thirty minutes
after the start of the infusion, the mean INR was significantly lower in patients on the PCC than in
those given plasma. The higher the baseline INR, the greater was the benefit of the PCC. One hour
after the start of infusion, roughly 70 percent of PCC recipients had corrected their INR as defined by
an INR of 1.3 or less, compared with less than 5 percent of plasma recipients. Median factor levels
were below 50 percent at baseline. Levels increased significantly more within 30 minutes of starting
PCC infusion than with plasma. Dr Goldstein observed this wasn’t particularly surprising, since the
PCC contains factors II, VII, IX, and X, along with proteins C and S. Blinded investigators rated
haemostatic efficacy in the first 24 hours as good or excellent in 72 percent of the PCC group and in
65 percent of patients on plasma, a nonsignificant difference. Thromboembolic event rates through 51
days of follow-up were 7.8 percent with the PCC and 5.5percent with plasma. Dr. Goldstein serves as
a consultant to and advisory board member for CSL Behring.
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says it continues to investigate whether or not specific characteristics of immune
globulin products such as excipients, concentration, or trace procoagulant activity
account for an increased risk of thrombosis.
b) Biotest received FDA approval for its polyspecific intravenous immunoglobulin
Bivigam for the treatment of patients with primary humoral immunodeficiency. The
approval was based on a Phase III study in 63 patients. Participants received 300–
800mg/kg of IVIg every three or four weeks for a year. The primary efficacy endpoint
was demonstration that the rate of acute serious bacterial infections was <1.0 per
person-year. The study achieved its primary endpoints for safety, efficacy, and
tolerability. Bivigam will be available in a 10% liquid in 50mL and 100mL vials.
c) The FDA approved Cangene’s Varizig for reducing the severity of chicken pox in high
risk individuals when given within four days of exposure. Varizig is a varicella zoster
immune globulin preparation.
d) The FDA approved GlaxoSmithKline’s Promacta (electrombopag) for the treatment of
thrombocytopenia (low blood platelet counts) in patients with chronic hepatitis C to
permit them to initiate and maintain interferon-based therapy.
e) Novartis received approval from the European Commission for Exjade, its oral drug
used to reduce iron overload in patients undergoing chelation therapy for nontransfusion-dependent thalassemia, or NTDT, syndrome. The pivotal study,
THALASSA, showed a significant dose-dependent decrease in concentration of ironburden in the body as well as liver in patients on Exjade, compared with placebo.
The overall adverse event rate for Exjade was similar to the placebo arm.
f)
Medgenics, the developer of the Biopump, which sustains production and delivery of
therapeutic proteins using a patient's own tissue, announced a patent from the US
Patent and Trademark Office for the use of Medgenics’ EPODURE technology for
delivery of erythropoietin (EPO). The USPTO also recognised claims for a similar
method for delivery of FVIII, underpinning Medgenics’ HEMODURE Biopump
technology for sustained prophylaxis in haemophilia. Claims covering EPODURE
and HEMODURE were recently recognised in Australia, Japan, China, and Korea.
g) The European Medicines Agency (EMA) held its promised workshop on access to
clinical-trial data and transparency. Participants included representatives of the
European Federation of Pharmaceutical Industries and Associations, and the
Cochrane Collaboration, which has campaigned for Roche to publish the complete
raw dataset on its antiviral Tamiflu (oseltamivir). The EMA said it "is committed to
proactive publication of clinical-trial data, once the marketing-authorisation process
has ended. We are not here to decide if we publish clinical-trial data, but how". The
EMA wants r "to build trust and confidence in the system by allowing re-analysis of
clinical-trial data by stakeholders". The commitment to publication will apply only to
drugs that receive marketing authorisation process from a set date, probably 1
January 2014.
h) In December the European Parliament voted in favour of introducing a unified patent
system in 2014. If ratified, the new system is expected to reduce application costs
and make Europe more competitive.
i)
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Ethicon Biosurgery received FDA approval for its EVARREST fibrin sealant patch.
This is an adjunct to haemostasis for soft tissue bleeding during open retroperitoneal,
intra-abdominal, pelvic and non-cardiac thoracic surgery, when control of bleeding by
standard surgical methods (e.g., suture, ligature, or cauterization) is ineffective or
impractical. EVARREST is placed upon the bleeding wound surface and manually
compressed for three minutes. The human thrombin and fibrinogen initiate a fibrin
clot, which integrates into the patch. EVARREST remains in the patient's body
supporting the wound site as it is bio-absorbable. The patch is not for use in babies
under one month of age, and is not for use in place of sutures or other forms of
mechanical ligation in the treatment of major arterial or venous bleeding.
j)
Amag has submitted a supplemental new drug application to the FDA for its
intravenous Feraheme. The company has asked the FDA to extend the indication for
the drug to all iron-deficiency anaemia patients who have failed on, or could not
tolerate, oral anaemia drugs, not just to iron-deficiency anaemia patients with CKD.
The application is based on data from two Phase III trials (1,400 patients).
k) Anti- coagulant Eliquis has been approved for use in the 27 European Union (EU)
countries in patients who have an irregular heartbeat (atrial fibrillation) and are at risk
for strokes or systemic embolisms. Eliquis, developed by Bristol-Myers Squibb and
Pfizer, had already been approved in the EU in May 2011 for preventing dangerous
clots from forming in deep veins after hip or knee replacement surgery. The FDA in
December approved Eliquis after earlier rejections and requests for more trial data.
The FDA approved the oral treatment for atrial fibrillation, in patients at risk for
strokes or dangerous clots, but warned that patients with artificial heart valves should
not take the drug as it had not been studied in that population.
l)
Boehringer Ingelheim’s anti- coagulant Pradaxa (dabigatran) continues to attract
discussion.
a. In November 2012, the FDA issued a Drug Safety Communication informing
the public that the Agency has evaluated new information about the risk of
serious bleeding associated with use of the anticoagulants Pradaxa and
warfarin. Following the approval of Pradaxa, the FDA had received a large
number of post-marketing reports of bleeding among Pradaxa users. As a
result, the FDA had investigated the actual rates of gastrointestinal bleeding
and intracranial hemorrhage for new users of Pradaxa compared with new
users of warfarin. The indications were that bleeding rates associated with
new use of Pradaxa did not appear to be higher than bleeding rates
associated with new use of warfarin, consistent with observations from the
RE-LY trial used to approve Pradaxa. The FDA is continuing to evaluate
multiple sources of data in the ongoing safety review of this issue.
b. In December Boehringer Ingelheim said it would inform physicians that
Pradaxa is contraindicated in patients with mechanical heart valves. This
followed advice from regulators.
c. Australia's Pharmaceutical Benefits Advisory Committee (PBAC) advised the
government that, because of new information about Pradaxa,"it is of a mind to
rescind its March 2011 recommendation" that the drug be available on the
Pharmaceutical Benefits Scheme (PBS). A report on the use of anticoagulant
therapy was prepared for the government by Emeritus Professor Lloyd
Samson. The report says more work is needed before new oral
anticoagulants (NOACs) such as Pradaxa can be listed on the PBS. He
found actual use of Pradaxa had not matched the clinical trial evidence
presented to the PBAC in March 2011, including the average age of patients,
the dosage, and the treatment they would otherwise be receiving. In light of
this clinical information, the review concluded that the net benefit of NOACs in
clinical practice and the subsequent impact on cost-effectiveness "is
uncertain." Boehringer Ingelheim and the sponsors of other NOACs will be
able to make submissions to the March meeting.
m) Cerus Corporation said the FDA had accepted its proposed modular pre market
approval application for the INTERCEPT Blood System for plasma. A PMA shell
outlines the structure, content and timing of each module, and will allow Cerus to
leverage its existing regulatory dossier from European approvals. It will begin the
INTERCEPT plasma submission early in 2013. Carol Moore, Cerus' Vice President,
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Regulatory Affairs, Quality and Clinical, said: "FDA's agreement with our proposal
means that we can target completing all four modules in 2013, putting us in a position
to receive US approval as early as 2014.”
n) Australia’s Therapeutic Goods Administration(TGA) has approved a 30-minute test
for HIV for use in sexual health clinics.
o) The EMA’s Committee for Medicinal Products for Human Use (CHMP) recommended
new instructions for fibrin sealants such as Tisseel, Tissucol, Artiss and Beriplast P to
ensure their safe use when applied as spray during surgery. This follows reports of
gas embolism with Evicel and Quixil in association with the use of spray devices that
use a pressure regulator. Amongst the recommendations were that product
information advise recommended pressure and distance for spray use.
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) The first of CSL’s new buildings from a $A250 million investment at Broadmeadows
will begin production of biopharmaceuticals early this year. rF IX is scheduled for
2013, with the immunoglobin Privigen scheduled to be produced in 2015. CSL’s
Australian plasma business, previously within CSL Biotherapies, is now part of
CSL’s global plasma business, CSL Behring, creating a globally-integrated supply
chain for the complete portfolio of plasma and recombinant protein products. Other
areas of CSL Biotherapies’ business - vaccines, pharmaceuticals and in-vitro
diagnostics – are now operating as bioCSL. CSL Behring in Australia will be led by
Dr Simon Green and bioCSL by Dr John Anderson.
b) Sanguine, an innovator in perfluorocarbon (PFC) based therapies, in December
announced its intention to acquire New Alliance Pharmaceuticals. New Alliance
holds an exclusive license for Oxygent, a PFC product with 20 clinical studies and
around 250 preclinical studies already completed.
c) Grifols’ shareholders in December approved a bonus share issue.
d) Cerus signed a two-year agreement with two Swiss Red Cross Blood Services Lausanne and Zurich- for deployment of the INTERCEPT Blood System for plasma.
These two centres supply around 15,000 plasma units annually.
e) Cangene Corporation in December reported financial results for the quarter which
ended on October 31, 2012. Revenues for the quarter were $C36.5 million,
compared with $C21.5 million in the same quarter of the previous year. The increase
was largely attributable to revenue from US government stockpiling contracts. There
were lower research and development expenses because of the cancellation of
intravenous immunoglobulin development.
f)
Johnson & Johnson has invested in biological sealant developer Lifebond as part of
the company's $US 20 million third financing round. Lifebond’s co- chairman is
Robert Taub, who founded Omrix Biopharmaceuticals which Johnson and Johnson
acquired for $US425 million in 2006. Lifebond's flagship product is a surgical sealant
for tissue after surgery to shorten the bowel. It partly competes with Omrix.
g) Amgen agreed to buy the genetic-research company DeCode Genetics for $US415
million to help it develop new medicines that target defective DNA. The all-cash deal
will give Amgen access to Iceland-based DeCode’s technology used to sequence
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human genomes. DeCode’s research enables it to identify genetic variants that may
be linked to a disease or disorders such as cancers or heart disease.
h) The Medicines Company and Bristol-Myers Squibb have signed a global licence and
two year collaboration for Recothrom. Recothrom is a recombinant thrombin
approved by the FDA for use as a topical haemostat to control non-arterial bleeding
during surgical procedures. As part of the agreement, The Medicines Company will
make Bristol-Myers Squibb an upfront collaboration payment, an upfront option fee
and a tiered royalty on annual net revenues from Recothrom during the two-year
collaboration period. Bristol-Myers Squibb will manufacture Recothrom and act as
exclusive supplier to The Medicines Company during the agreement term.
i)
Eisai is collaborating with University College, London in drug discovery and
development, focussing on neurological diseases such as Alzheimer’s, Parkinson’s
and other related disorders. Meanwhile, Biogen Idec has leased some of Eisai's
facility in Research Triangle Park in North Carolina to manufacture oral solid dose
products for both companies The 10-year lease agreement gives Biogen the option
to purchase the plant. Some 50 Eisai personnel are expected to become Biogen
employees in early 2013.
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 Australian Competition and Consumer Commission (ACCC) decided to
authorise Medicines Australia’s latest Code of Conduct for two years - rather than
the five years sought. Under the Code’s new edition member companies will, for the
first time, disclose aggregate payments made to doctors and consumer groups.
b) The Scottish Government has approved the business case for a £36.4 million centre
for the Scottish National Blood Transfusion Service, to be constructed at Heriot Watt
Research Park near Edinburgh, and to be completed in 2017. It will centralise the
testing and processing of blood and tissue donations.
c) Victor Grifols has said that he is not willing to invest any more in Spain “if things
don’t change.” In media comments, Sr Grifols said that unless there is change, he
envisages moving to the US.
d) In the US, a meningitis outbreak arising from tainted steroid injections prepared by a
compounding pharmacy had reached 620 cases by 17 December with 39 fatalities.
e) Fewer black women in the US are being infected with HIV, but the number of young
gay and bisexual men infected is rising, the Centers for Disease Control and
Prevention announced in December.
f)
The US PreventiveServices Task Force in November said everyone aged 15 to 65
should be tested for the virus that causes AIDS. Previously it recommended
screening only those at high risk, but percent of people with HIV don't know, and
early treatment can prolong lives and greatly reduce spread of HIV.
g) In November Canadian Blood Services revealed that it expected to replace the
lifetime ban on gay men donating blood with a deferral system. The plan submitted
to Health Canada proposed that men who had not had sex with other men for
somewhere between five to ten years would be eligible.
h) Mexico has implemented new blood donation regulations screening donors based
on sexual history rather than sexual orientation. HIV- and hepatitis- negative gay or
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bisexual men who have histories of safe sex and are not sex workers or injecting
drug users may become donors.
Safety Issues
We follow current issues in patient safety.
a) In a study reported in the December issue of Anesthesiology8, researchers found
that inhaled nitric oxide decreased tissue injury and improved short-term survival in
mice who suffered haemorrhagic shock and were then resuscitated with a
transfusion of stored blood.
b) Dr Michael Stark, from the University of Adelaide's Robinson Institute, has told the
media that premature babies given blood transfusions have elevated levels of
chemicals which can cause bowel and lung problems. "We believe that the
bioactive components of packed red blood cell transfusions are initiating or
amplifying these inflammatory processes in the body," he said. Researchers in
January began a two-year trial at the Women's and Children's Hospital to "wash"
blood in a solution just before being administered to the baby to reduce the risk of
complications because their immune systems are still not fully developed.
c) Officials from the World Health Organisation (WHO), International Haemovigilance
Network (IHN) and International Society of Blood Transfusion met at the Global
Consultation on Haemovigilance in Dubai in November. IHN will hold a seminar in
Brussels in February 2013. It will highlight achievements of countries with welldeveloped haemovigilance systems and will give the opportunity for others to
present their challenges.
d) The British Heart Foundation is funding University of Hull researchers to investigate
part of the process of blood clotting. Although clotting is normal after injury, the
clumping together of platelets is also the last stage in the process that leads to a clot
blocking a blood vessel in the heart or brain, leading to a heart attack or stroke. Hull
researchers have found a protein called thrombospondin-1 can disrupt the action of
prostacyclin, which is released by the cells lining blood vessels and helps prevent
platelets from becoming too sticky. Using mice they will test whether tackling
thrombospondin-1 offers prospects as an anti- clotting treatment.
e) Amongst six research proposals funded by the US National Blood Foundation in
October was Identifying Innate Immune System Pathways Critical for RBC
Alloimmunization from Stephanie Eisenbarth, of Yale University. Every unit of
allogeneic red blood cells contains antigens foreign to the transfusion recipient. Why
do only some patients become alloimmunized after transfusion? Eisenbarth and her
colleagues will examine the initial stages after transfusion of allogeneic red blood
cells, seeking to "nail down the critical antigen-presenting cell that dictates when you
get an alloimmune T-cell response to RBCs", as she put it.
f)
A meta-analysis of 10 studies concluded that receiving a blood transfusion among
patients with myocardial infarction (heart attack) was associated with increased allcause mortality compared compared with not being transfused during a heart
attack9. If the transfusion was large, the risk increased by 12 percent.
8
Chong Lei, Binglan Yu, Mohd Shahid, Arkadi Beloiartsev, Kenneth D. Bloch, Warren M. Zapol.
“Inhaled Nitric Oxide Attenuates the Adverse Effects of Transfusing Stored Syngeneic Erythrocytes in
Mice with Endothelial Dysfunction after Hemorrhagic Shock”. Anesthesiology, 2012; 117 (6): 1190
DOI: 10.1097/ALN.0b013e318272d866
9
9
Arch Intern Med. Published online December 24, 2012. Includes comment by
g) The Journal of the American Medical Association (JAMA) published a summary of
the systematic review of the 19 clinical trials that compare higher versus lower
haemoglobin thresholds in red blood cell transfusion. “Our systematic review of
these clinical trials resolves that the use of a restrictive approach to blood
transfusions is safe for most patients,” said Jeffrey L. Carson, lead author. “The
evidence provided in the synopsis can be used to treat anaemic patients in both
critical and acute care settings without concern of causing undue harm.” The 19
studies included more than 6,000 patients with a mean age of 63 years. The
systematic review not only showed that death did not increase in patients given a
lower threshold blood transfusion, but showed there was not a significant difference
in major complications like pneumonia, pulmonary oedema, stroke, or infection10.
h) Debate continues on red blood cells (RBC) and the storage lesion11, and whether
patient outcomes are better when transfused RBC are fresher.
Anti- coagulants and antiplatelet drugs have improved how acute coronary syndrome is treated, but
may increase the risk for bleeding, anaemia and transfusion. A team led by Dr Saurav Chatterjee of
Brown University reviewed ten studies published between January 1966 and March 2012. They
included 203,665 participants. One study was a randomised trial, the rest were observational studies.
“Analyses of blood transfusion in myocardial infarction revealed increased all-cause mortality
associated with a strategy of blood transfusion vs. no blood transfusion during myocardial infarction,
the researchers said. Other statistical analyses suggest that blood transfusion was associated with a
higher risk for mortality independent of baseline haemoglobin level, nadir haemoglobin level and
change in haemoglobin level during the hospital stay. It appeared blood transfusion was alo
associated with a higher risk for subsequent heart attack. “Additional outcomes data are needed from
randomised clinical trials that investigate important outcomes with adequate sample size and with low
risk for bias," the researchers concluded. In a related commentary Jeffrey L. Carson and Paul C.
Hébert said of the meta- analysis “because of its many limitations, as physicians, we should not use
the results of this review to justify or limit the use of red blood cells…..…..For researchers and
decision makers, we can now appreciate how little reliable information is available to inform clinical
and policy decisions involving red blood cell transfusions in patients with acute coronary syndrome.
Given that real risks and potential benefits exist as to how we choose to use the valuable resource of
blood transfusion, we believe that high-quality research is long overdue."
10
Jeffrey L. Carson, Paul A. Carless, MMedSc; Paul C. Hébert, “Outcomes Using Lower vs Higher
Hemoglobin Thresholds for Red Blood Cell Transfusion”, JAMA. 2013;309(1):83-84.
doi:10.1001/jama.2012.50429. See http://jama.jamanetwork.com/article.aspx?articleid=1555108
Dr. Carson developed the blood transfusion guidelines along with specialists in cardiology,
paediatrics, critical care medicine, trauma and anesthesia that were issued last March by the AABB
(formerly the American Association of Blood Banks). He was lead author on two of the clinical trials
included in this Clinical Evidence Synopsis.
11
Heddle et al. (INFORM-P study) report on a single-site random controlled trial (RCT) iwith more than
900 patients. Mortality was slightly higher in patients receiving "fresh" RBC units. Similarly, the ABLE
Study showed a slight increase in mortality in the "fresh" group, but confidence intervals were high.
Both these studies were intended to be pilot studies.
The ARIPI Study found no significant adverse outcomes in stable pediatric ICU patients when "older"
RBCs were transfused. But the meta-analysis by Wang and colleagues found the relative risk of
death associated with older blood to be as high assixteen percent.
Data from the RECESS Study and the NIH study of RBC units used in CVS are yet to come.
The INFORM-P study defined fresh vs. old as 12 days vs. 26 days on average. The ABLE Study
defined <8d as fresh. Aubron et al. comment that three studies imply a 14-day "rule" yet their two-site
RCT defined 12 days vs. 23 days, plus or minus several days. The studies also differed in terms of
storage solutions for red cells and in leucodepletion.
See Heddle N et al. Transf 2012; 52:1203 ;LaCroix J et al. Transfus Med Rev 2011; 25:197;
Fergusson D et al. JAMA 2012; 308:1443; Wang D et al. Transf 2012; 52:1184; Assmann S 2010;
http//clinicaltrials .gov/ ; Koch C 2011; http//clinicaltrials.gov/ ;Aubron C et al. Transf 2012; 52:1196
10
Patient Blood Management
The NBA is committed to appropriate use of blood and blood products and improved
outcomes for patients.
a) In Ontario, Canada, the Peterborough Regional Health Centre’s is one of 25
hospitals with a Blood Conservation Management Program. In 2011-2012, 4.8
percent of patients who underwent knee surgery received a blood transfusion,
compared with 10.1 percent across the province; the comparison in hip surgery was
4.8 percent against 12.8 percent; and in prostate cancer surgery 1.6 percent against
7.7 percent. The conservation program targets surgeries where typically more than
10 percent of blood is lost. Weeks before the surgery, a nurse will check a patient’s
iron level, and if it’s low, they’ll prescribe iron pills or have the patient undergo iron
transfusions to get levels up. A cell saver is mostly used during cardiovascular
surgeries. Patients who avoid transfusion usually leave the hospital 1.5 days earlier,
and have a decreased chance of contracting an infection.
b) Orthopaedic surgeons and anaesthetists with Jewish Orthopaedic Care, a part of
KentuckyOne Health, have reduced the number of total joint replacement patients
who require a blood transfusion. They now use transexamic acid for patients
undergoing total hip and knee surgeries. This reduces the number of patients who
need blood transfusions from 14 percent to 2 percent.
c) Robotic-assisted laparoscopic surgery for invasive bladder cancer was associated
with 50 precent less blood loss and allowed patients to return home sooner with no
difference in oncologic outcomes compared with conventional surgery (open radical
cystectomy), investigators reported in a small pilot study12.
d) The EMA has initiated a review of hydroxyethyl starch (HES) used to manage
hypovolaemia13 and hypovolaemic shock14 in critically ill patients. The review will
look particularly at its use in patients with sepsis15. Safety concerns follow the
publication of recent studies comparing HES with other volume expanders in
critically ill patients with severe sepsis.
e) In a small randomized controlled study of patients undergoing elective thoracic or
thoracoabdominal aortic replacement surgery with cardiopulmonary bypass (CPB),
nearly half those receiving fibrinogen avoided the need for blood transfusion,
whereas all patients on placebo required a transfusion. In an editorial
accompanying the report in Anesthesiology, Nauder Faraday (Johns Hopkins
University School of Medicine) cautions: "Enthusiasm for the administration of
fibrinogen as a clinical therapy for bleeding in surgical patients must remain
tempered at this time…..The administration of fibrinogen concentrates demonstrates
clear potential to improve hemostasis more rapidly and at lower risk of immunologic
reactions, infection, and volume overload than conventional allogeneic blood
products……(but) future studies should develop more clinically relevant treatment
algorithms and use modern randomization strategies that adhere to intention-to-treat
principles.‘’
f)
12
Biotest has begun a clinical development programme of human fibrinogen
concentrate to treat serious, life-threatening bleeding. It has approval to conduct a
Phase I/II clinical trial.
Dipen Parekh, of the University of Miami, and colleagues in the Journal of Urology online
low blood volume caused by dehydration or blood loss
14 a steep fall in blood pressure caused by drop in blood volume
15
damage to organs caused by bacteria and their toxins in the blood following an infection
13
11
g) At the 2012 American Society of Hematology (ASH) Annual Meeting and Exposition
in Atlanta in December Dr Tiziano Barbui reported on a large-scale randomized trial
to examine the efficacy and safety of efforts to maintain hematocrit levels among
patients with polycythemia vera16. The standard approach of maintaining hematocrit
levels less than 45 percent was associated with a lower risk of thrombosis than the
less aggressive strategy of maintaining levels between 45 percent and 50 percent,
according to the data presented.
h) Results presented at the ASH Meeting suggested that the effectiveness of
prophylactic platelets to prevent bleeding in patients with haematologic malignancies
is unclear17. While patients given no-prophylaxis platelet transfusion had more days
with grade 2 or higher bleeding and a shorter time to first bleed than patients who
received prophylaxis, rates of bleeding among patients who did receive prophylactic
platelet transfusion were still high.
i)
Dr. Marcos de Lima led a study18 from the University of Texas M.D. Anderson
Cancer Cente which concluded that multiplying umbilical cord-blood cells in the
laboratory might improve recovery for patients needing blood stem cell transplants to
treat blood- borne cancer. The approach involved expanding normal blood cells from
donated cord blood in conditions similar to those in bone marrow, to increase the
supply needed for transplant. Since umbilical cord blood is more easily matched in
patients than donor bone marrow, the recovery period is safer and shorter.
m) Omega-3 fatty acid (n-3FA) supplements do not correlate with higher perioperative
blood loss during spinal fusion procedures, according to a study published in the
December issue of the European Spine Journal.
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) Scientists at the University of Liverpool are leading a new study of immunoglobulin in
complex regional pain syndrome (CRPS). Results are expected to be published in
2016/17. CRPS is an ongoing condition usually diagnosed after trauma to a limb.
b) Dr Seth Masters from the Walter and Eliza Hall Institute in Melbourne and his team
have discovered how the body reacts under stress from a severe infection. The
immune system switch destroys blood stem cells and researchers have discovered
how to turn the switch off. They hope this may mean faster recovery rates from
blood infections and from chemotherapy.
16
In polycythemia vera (PV) bone marrow produces too many red blood cells, increasing the risk of
deep vein thrombosis, pulmonary embolism, stroke and heart attack. Patients with PV usually have
hematocrit levels that range from 50 percent to 70 percent, compared with less than 50 percent in the
wider population.
17
Researchers screened 1,093 patients from 14 UK and Australian hospitals from August 2006 to
August 2011 for the randomized, parallel group, open-label, non-inferiority TOPPS trial. Stanworth
SJ. Abstract #1. Presented at: the 2012 ASH Annual Meeting and Exposition; Dec. 8-11, 2012.
18 Marcos de Lima, M.D., professor, medicine, Case Western Reserve University School of Medicine,
Cleveland, Ohio, formerly M.D. Anderson Cancer Center, Houston; Kanti Rai, M.D.,
hematologist/oncologist, North Shore-LIJ Health System, New Hyde Park, N.Y.; Dec. 13, 2012, New
England Journal of Medicine
12
c) Researchers have found a way to turn a patient’s own blood into usable,
personalized stem cells19. The University of Cambridge team says they can take
regular, adult blood cells and turn them into stem cells, which is much easier than
using adult tissue samples. Furthermore, using the patient’s own blood tricks the
body and there is no rejection involved. The team found that the red blood cells do
not have to be converted immediately; they could freeze and store the regular blood
cells for later use, and then convert them to induced pluripotent stem cells (iPSC)
the patient might need later on. One of the team, Dr. Amer Rhana also said of their
findings: “Tissue biopsies are undesirable, particularly for children and the elderly –
whereas taking blood samples is routine for all patients.”
c) A study in Anesthesiology has pinpointed a gene that may help determine the sepsis
survival rate. Evidence suggests the gene NFKB could be a genetic pathway for
amplifying inflammation in sepsis, a leading cause of hospital deaths. The study
could determine if anti-inflammatory sepsis treatment should be tailored for patients
with certain genetic sequences. Lead author was Dr Michael Adamzik of the
University of Duisberg-Essen, Germany.
d) Advanced Cell Technology of Massachusetts has initiated the process for regulatory
approval of a human trial involving stem cells created by reprogramming adult cells
back to an embryonic-like state. It wants to begin clinical testing of stem-cell derived
platelets that can be used to help treat people with leukemia and other conditions.
e) EpiVax has a $US 55,000 grant to explore using tregitopes as an immuno-modulator
in chronic inflammatory demyelinating polyneuropathy (CIDP), a nerve disease
treated with intravenous immunoglobulin (IVIg). Tregitopes are linear sequences of
peptides contained within the framework of monoclonal antibodies and
immunoglobulin-G, which activate natural regulatory T cells. They seem to suppress
tissue-destroying immune cells that cause 'organ-specific autoimmune diseases',
and they can modify immune responses to biotherapeutics (including FVIII).
f)
At the ASH meeting In December, researchers at Dana-Farber/Children's Hospital
Cancer Center (DF/CHCC) announced that they had demonstrated in an animal
model the feasibility of activating a form of haemoglobin unaffected by the sickle cell
mutation.
g) An international team has used a combination of genetic analysis in people and
subsequent research in fruit flies to identify genes linked to red blood cell biology
and investigate their function. Their studies confirmed that sets of genes involved in
controlling human red blood cell traits in people are also important for the formation
of blood cells in flies20.
h) With 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 for the disease, and on improvements in diagnostic tools. Some
recent developments are outlined in an appendix to this article.
Imbisaat Geti, Mark L. Ormiston, et.al. “A Practical and Efficient Cellular Substrate for the
Generation of Induced Pluripotent Stem Cells from Adults: Blood-Derived Endothelial Progenitor
Cells” in the on-line journal, Stem Cells: Translational Medicine.
20
P van der Harst et al. “75 genetic loci influencing the human red blood cell” Nature 2012
19
13
Legal Issues
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) In the US in December a federal judge accepted Amgen’s plea agreement on a
charge that it misbranded its anemia drug Aranesp. The agreement will cost the
company $US 150 million in criminal penalties. Amgen will also pay $US 612 million
to settle civil claims by states and whistle-blowers alleging the company also illegally
marketed other drugs.
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) Reported cases of dengue on the Portuguese island of Madeira had exceeded 2,000
by mid- December. This was the first sustained outbreak of dengue in Europe since
the 1920s.
b) Sanofi Pasteur announced that it would soon be bringing its dengue vaccine to
market. The first commercial batches are expected to be available in 2015.
c) In December, Australian authorities eradicated a dozen potentially dangerous
mosquitoes found inside a shipment of Chinese plants. Investigators from the
Department of Agriculture, Fisheries and Forestry discovered the Asian tiger
mosquitoes (Aedes albopictus) inside two glasshouses at a quarantine station near
Melbourne. They are a known vector for arboviruses, such as dengue.
d) A group of research institutes in Georgia have won a contract of up to $US19.4
million from the National Institute of Allergy and Infectious Diseases to use a
systems biology-based approach to studying how host-pathogen interactions are
involved in malaria.
e) The West Nile virus outbreak in the US reached 5,245 cases, including 236 deaths,
by 28 November.
Influenza
Avian influenza
a) Global health workers are concerned about the discovery in Indonesia of a new
strain of the deadly H5N1 avian flu that is both more dangerous and more virulent
than others.The new strain has killed hundreds of thousands of ducks.
b) According to the WHO on 17 December, there had been so far in 2012 32 cases of
avian A(H5N1) influenza virus infection in humans, 20 of whom had died. In Egypt
there were 11 cases and 5 deaths. There were 9 cases in Indonesia, 4 in Viet Nam,
14
3 in Bangladesh and Cambodia, and 2 in China. In 2011 there were 62 cases, of
whom 34 died.Since the emergence of H5N1 influenza in 2003, 610 people are
reported to have become infected, 360 of whom have died.The annual number of
human cases reached a peak of 115 in 2006 and has been followed by a gradual
decline to the 32 cases recorded in 2012.
c) Scientists in China identified strains of avian flu in pigs21. “We recommend strongly
that the pork industry worldwide should monitor the prevalence of influenza in pigs,
considering their important role in transmitting this virus to humans,” explained
Guihong Zhang of the College of Veterinary Medicine at the South China Agricultural
University.
d) Scientists expressed varying views on a draft US government plan to review more
stringently the funding of particular types of H5N1 avian flu research—even requiring
some studies to be secret. The proposal to a meeting of the National Science
Advisory Board for Biosecurity, followed the controversy around potential risk from
"gain-of-function" studies.
Influenza vaccines.
a) Novartis received FDA approval for Flucelvax in November, for use in people 18
years and over. This is the first cell-culture vaccine in US to help protect against
seasonal influenza. Cell-culture technology offers an alternative to traditional eggbased production. Novartis has partnered with the US Department of Health and
Human Services, Biomedical Advanced Research and Development Authority
(BARDA), for the development of the cell-culture manufacturing technology, and for
construction of the production facility in North Carolina. The facility is seen as
enhancing pandemic preparedness.
b) The FDA in December approved GlaxoSmithKline's (GSK's) quadrivalent (fourstrain) influenza vaccine, with two influenza B strains, in people aged three or more.
This is the first injectable quadrivalent flu vaccine licensed in the US. MedImmune's
quadrivalent version of the intranasal vaccine FluMist was approved by the FDA in
February 2012.
c) Sanofi Pasteur applied in October for FDA approval of its quadrivalent flu vaccine.
d) Medicago announced results from a preclinical study on the cross-protection effects
of its H5N1 VLP (virus-like particle) vaccine. The study was conducted in mice
under the National Institute of Allergy and Infectious Diseases' (NIAID) Animal
Models of Infectious Disease Program. Medicago says the results suggest that the
company’s vaccines could provide broad protection against multiple influenza
strains22.
e) Inovio Pharmaceuticals in December reported interim results of a phase I trial that
showed that a single dose of its H1N1 universal SynCon flu vaccine followed with a
dose of a seasonal flu vaccine generated protective immune responses in 40
percent of trial subjects compared with a 20 percent response rate in elderly patients
who received the seasonal flu vaccine alone. Individual SynCon DNA vaccine
"constructs" are designed to provide broad cross-strain protection against existing
21
Online ediction of Journal of Clinical Microbiology
A single, non-adjuvanted, intramuscular dose of H5N1 VLP vaccine protected against a different
H5N1 strain or a strain of a different subtype such as H2N2. However a recombinant non-VLP H5
protein failed to provide similar protection against both strains. The H5N1 VLP vaccine appears to
have induced mucosal immunity in the lungs and plant lipids may have intrinsic adjuvant activity.
22
15
and potential new strains of influenza. Preemptive protection against new strains is
particularly important to the elderly and other immune-compromisd patents.
f)
Researchers from Germany's Friedrich Loeffler Institute say they have found a way
to make a vaccine artificially by copying the flu virus's RNA code. The synthetic
vaccine was tested in mice, ferrets and pigs. Researchers found the vaccine could
also protect against new strains as they emerged. The Influenza Specialist Group,
representing medical and scientific specialists from Australia and New Zealand, said
the development was a step in the right direction.''The work done on this to date is
fairly comprehensive,'' said the group's chairman, Alan Hampson. However, he said
while the research represented a valuable proof of concept in animals, there was still
a long way to go before proving it could be applied to humans.
Other
a) Proteins responsible for mad cow disease have been discovered in the saliva of
cows infected as part of an experiment.
b) A 51-year-old woman from Macao who had a brain operation in Hong Kong was
diagnosed with sporadic Creutzfeldt-Jakob Disease (CJD). The hospital was advised
to contact other patients who had undergone surgery with the same instruments.
c) The FDA gave fast-track approval to a new tuberculosis drug, despite safety
concerns about it during testing. Janssen Therapeutics, part of Johnson & Johnson,
received approval for bedaquiline (brand name Sirturo). Janssen had not completed
the usual three phases of clinical trials. In one trial, "nine patients who received
Sirturo died compared with two patients who received placebo," according to an FDA
statement. "Multidrug-resistant tuberculosis poses a serious health threat throughout
the world, and Sirturo provides much-needed treatment for patients who don’t have
other therapeutic options available," Edward Cox, director of the FDA’s office of
antimicrobial products in the Center for Drug Evaluation and Research, said in a
statement. "However, because the drug also carries some significant risks, doctors
should make sure they use it appropriately and only in patients who don’t have other
treatment options." Bedaquiline is for use as part of combination therapy for adults
with multidrug-resistant tuberculosis lung infections. J&J applied last August for
approval to market the drug in the EU.
d) NIAID is sponsoring a clinical trial to examine Astra Zeneca’s investigational drug’s
early bacteria-killing activity in patients newly diagnosed with drug-sensitive
pulmonary tuberculosis. In laboratory testing, the drug proved active against a wide
range of drug-sensitive and drug-resistant strains of Mycobacterium tuberculosis.
The clinical trial is being led by researchers at the Tuberculosis Research Unit at
Case Western Reserve University in Cleveland.
e) Giant pandas produce a powerful antibiotic in their blood stream that kills bacteria
and fungi. Scientists have been able to synthesis the compound in the lab by
decoding the genes. Dr Xiuwen Yan, who led the research at the Life Sciences
College of Nanjing Agricultural University in China, said “Gene-encoded antimicrobial
peptides play an important role in innate immunity against noxious microorganisms.
They cause much less drug resistance of microbes than conventional antibiotics.”
f)
16
Researchers (led by Matthew Bonds of Harvard Medical School) predicted in PLoS
Biology that countries that lose biodiversity will have a heavier burden of vectorborne and parasitic diseases. "The more organisms you have out there, the more
things there are that can interrupt the life cycle of disease, and the less concentration
you'll have of any vector," said Bonds. A 2002 contribution in the Proceedings of the
National Academy of Sciences had already reported that if there is a rich community
of tick hosts, Lyme disease is diluted among them. Experience in the north- east US
has shown that if ticks carrying Lyme disease have only white-footed mice as hosts,
the disease risk to humans can rise dramatically.
g) CMV infection is widespread and not apparently serious for many who contract it,
though they carry it for the rest of their lives. In pregnant women it can cause
congentital abnormalities in their baby, and in transplant recipients it can be fatal.
Inovio Pharmaceuticals announced in November that testing of multiple synthetic
vaccine constructs for CMV induced robust T cells in mice, demonstrating the
potential for a SynCon DNA vaccine to treat the virus.
h) Researchers at the Gladstone Institutes have identified the molecular mechanism by
which cytomegalovirus (CMV) infects its hosts23 . CMV is one of a family of human
herpes viruses24. It replicates fast, it evades the host's immune defence and it allows
the host cell to survive long enough to produce and spread the virus to neighbouring
cells. CMV applies 'braking mechanism' after initial replication inside the cell.
i)
A recently formed global clinical research consortium 25 proposed a collaborative
clinical research platform to assess prospectively the pathogenesis of illness and
potential therapeutic interventions for patients infected with a novel coronavirus
which has been causing concern in and around the Middle East and Eastern
Mediterranean, and countries who have received infected travellers from the region.
j)
The FDA has approved a monoclonal antibody, raxibacumab, by injection to treat
inhalational anthrax, a form of the infectious disease caused by breathing in the
spores of the bacterium Bacillus anthracis. It is also approved to prevent inhalational
anthrax when alternative therapies are not available or not appropriate.
Raxibacumab is the first monoclonal antibody approved under the FDA’s Animal
Efficacy Rule, which allows efficacy findings from adequate and well-controlled
animal studies to support FDA approval when it is not feasible or ethical to conduct
trials in humans.
Appendix: Alzheimer’s Disease Research
As mentioned earlier, with 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 for the disease, and on improvements in diagnostic tools.
a) Two studies recently published in The New England Journal of Medicine identified a
rare variant of the TREM2 gene as a potent risk factor for late-onset Alzheimer's
disease. Some risk variants previously reported have been linked to familial earlyonset Alzheimer's disease. Others associated with late-onset of the disease have
generally been identified as conferring low risk, with the well-known exception of the
ε4 allele of apolipoprotein E, whose odds ratio is reportedly three. The newlyidentified variant is suggested to increase disease risk by a similar factor. The two
studies were led by Decode Genetics and the Alzheimer's Genetic Analysis Group
respectively. In an editorial in NEJM, Harald Neumann (University of Bonn) and
Mark Daly (Massachusetts General Hospital) suggested that the Alzheimer's
23
Melissa W. Teng, Cynthia Bolovan-Fritts, Roy D. Dar, Andrew Womack, Michael L. Simpson,
Thomas Shenk, LeorS. Weinberger. “An Endogenous Accelerator for Viral Gene Expression Confers
a Fitness Advantage”. Cell, 2012; 151 (7): 1569 DOI: 10.1016/j.cell.2012.11.051
24 that also include Epstein-Barr virus (which causes mononucleosis) and varicella-zoster virus (which
causes chickenpox
25 The International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC)
17
Genetic Analysis Group found a greater number of variants in TREM2 linked to
Alzheimer's disease as it drew upon a more diverse population than DeCode's
Icelandic study
b) Bristol-Myers Squib terminated development of the drug avagacestat for the
treatment of Alzheimer's disease. The decision is due to lack of efficacy, determined
after an analysis of data from a completed Phase II study in patients with mild-tomoderate AD and an ongoing Phase II trial in predementia AD.
c) Merck has started a Phase II/III clinical trial designed to evaluate the safety and
efficacy of MK-8931 versus placebo in patients with mild-to-moderate Alzheimer's.
Merck says the study is important to an understanding of the potential of the BACE
inhibitor mechanism and MK-8931 in multiple stages of Alzheimer's disease.26
d) The University of Minnesota's Center for Drug Design has developed a compound
that, in mice, prevented the neurodegeneration associated with Alzheimer's disease.
In the pre-clinical study, researchers found evidence that a synthesised compound
designated psi-GSH enables the brain to use its own protective enzyme system,
glyoxalase, against the disease process27.
e) Eli Lilly will conduct an additional late-stage study of its experimental Alzheimer’s
treatment solanezumab. The drug failed to meet the main goal of two large studies,
but it did slow progression in people milder stages of Alzheimer’s. The new study,
for these patients only, will begin by the third quarter of 2013.
f)
Past studies in animals have shown it is possible to prevent the formation of brain
plaques, made of amyloid beta protein, which are considered by many to be a
symptom and possibly the cause of Alzheimer’s disease. Now Eli says it may have
found a way to remove plaque from the brains of forgetful, old mice. The deposited
plaques are insoluble, whereas amyloid beta free-floating around the brain is
soluble. Lilly researchers genetically engineered an antibody that could cross the
blood-brain barrier and bind itself to the deposited amyloid beta. It cleared around
50 percent of pre-existing plaques in the mice without causing damage to tiny
vessels in the brain28. Lead researcher Ronald DeMattos said "We don't know how
it translates in humans until we test human antibodies in clinical trials." Lilly may
begin clinical trials using a human antibody within a year.
g) Luca Santarelli, head of neuroscience at Roche, said of Alzheimer’s disease: “The
disease is possibly caused by amyloid and tau, which start depositing at least 15 or
20 years before you see symptoms. We’re going at this at an earlier stage when
patients don’t have dementia …and the way we do that is to utilize a molecular
biomarker, which we measure in cerebral spinal fluid and through that aid, we are
able to identify patients as early as 3 to 5 years before they develop dementia. This
gives us a point of intervention possibly when function and structure of the brain is
still better preserved….. the study involving RG-1450 (gantenerumab) was recently
increased in scope and doubled in size enrolling 770 patients and that could give it
potential to be randomized-controlled trial for use in registration. To our knowledge
this is the only monoclonal antibody that is being tested at this stage of the
26
The amyloid hypothesis suggests that the formation of the particular amyloid peptide that leads to
amyloid plaque deposits in the brain is the basic cause of Alzheimer's disease. BACE is regarded as
a key enzyme in the production of this peptide. If inhibiting BACE decreases the production of the
peptide it may reduce amyloid plaque formation and slow disease progression. Merck researchers
have already presented findings of a multiple dose Phase I study which demonstrated that MK-8931
can reduce the target amyloid in cerebral spinal fluid by more than 90 percent in healthy volunteers.
27
The discovery appeared online in the American Chemical Society journal ACS Chemical
Neuroscience and offers a new target for the design of anti-Alzheimer's and related drugs.
28
Results were published in Neuron on 5 Decmber 2012.
18
disease.”…… DIAN (Dominantly Inherited Alzheimer’s Network at Washington
University) is a prevention trial and (gantenerumab) will be tested in (160) people
who carry the gene that makes them produce more amyloid in the brain….. We have
four compounds in clinical development. There’s another monoclonal antibody that is
in Phase II called crenezumab. We also have a monoamine oxidase B (MAO-B)
inhibitor in a Phase IIb dose-ranging study. This targets the inflammatory aspect of
age-related neurodegeneration. And we have an oral BACE1 inhibitor in Phase 1…..
Our research right now is very focused on the proteins, because that’s where we
think the disease is originating… We have to realize it’s a very difficult area of
research. In spite of knowing for almost two decades these proteins cause damage
to the brain, we still have a lot to learn… There’s better understanding of the disease
and when to intervene, though. We’re trying to intervene earlier and using molecular
diagnostics as opposed to waiting until dementia has already started and then rely
on pure clinical diagnosis, which still leads to a large number of patients.”
h) Bionomics is moving an Alzheimer's drug candidate towards clinical trial. It will
conduct formal toxicology studies and GMP manufacturing scale-up studies for
BNC375, a positive allosteric modulator of the alpha-7 nicotinic acetylcholine
receptor. It is claimed to improve memory and reduce learning defects in
neurodegenerative diseases including Alzheimer's. Bionomics said that in preclinical testing its candidate performed better than alternatives including Donepezil.
Its claimed characteristics include rapid action and compatibility with other
medications such as acetylcholinesterase inhibitors.
i)
Two new studies29 suggest that one of the standard tests used in Alzheimer’s, the
Alzheimer’s Disease Assessment Scale—Cognitive Behavior section (ADAS-Cog),
may be too insensitive to detect minor improvements in drug trials30. Other
researchers do not accept that the ADAS-Cog was the reason recent drug trials
were unsuccessful31, but many agree new tests are needed.
j) A recent study32 shows a new way to diagnose Alzheimer’s disease. Dr. Jeffrey R.
Petrella, director of the Alzheimer’s disease Research Lab at Duke University
Medical Center said “Our study looks at whether more sophisticated diagnostic tests
such as magnetic resonance imaging (MRI), positron emission tomography (PET)
and spinal fluid protein analysis might provide additional prognostic information,
compared to more readily available cognitive and blood testing." The study
observed 97 patients with MCI from the Alzheimer’s Disease Neuroimaging Initiative,
where patients are followed to track disease progression. The Duke team analyzed
MRI and FDG-PET results, along with cerebrospinal fluid proteins and compared
these to cognitive outcomes at two to three years. They found that by combining
this data with routine clinical tests, the accuracy of predicting conversion to
Alzheimer’s over clinical testing alone increased significantly. The combined testing
reduced false classifications, dropping the rates from 41.3 percent to 28.4 percent.
"In an ideal world, you'd obtain all information available—regardless of cost or
number of tests—for the best prediction of cognitive decline. However, there's a
29
published in Alzheimer's & Dementia December 18.
Jeremy Hobart, a neurologist at the Plymouth University”s Peninsula Schools of Medicine and
Dentistry, and his team found that the test could not distinguish small changes in early- stage
patients. It bunched patients into groups of test scores, rather than along a continuous spectrum.
30
31
“The negative results are due to the small effect size of the drug being tested and not the
measurement instrument,” Stephen Salloway, director of neurology and the Memory and Aging
Program at Butler Hospital in Providence, Rhode Island, told Nature. “I wish I could blame it on the
test.” He added: “These papers are very timely because we need new tests . . . that are more
sensitive.”
32 Journal of Radiology, December 2012
19
trade-off between adding testing—some of which may add little new information—
with the inconvenience, cost and risk to the patient. Though all the tests added some
unique information, FDG-PET appeared to strike the best balance, adding the most
prognostic information for patients with mild cognitive impairment,” Dr. Pretella said.
k) Researchers at the University of Pennsylvania, led by Virginia Lee, director of the
Center for Neurodegenerative Disease Research, injected a synthetic version of the
toxic protein associated with Parkinson's disease into the brains of healthy mice. In
a paper in Science in November, they reported how the toxic protein spread from
cell to cell in a prion-like fashion, causing the death of l dopamine-making neurons.
The mice displayed impaired motor coordination and balance. The team is now
testing an antibody therapy to stop the toxic misfolded proteins from spreading in the
mice. If it works, it could provide a possible therapy to test in people with
Parkinson's disease, and the concept may translate to AD.
l)
Todd Sherer, chief executive of the Michael J. Fox Foundation for Parkinson's
Research, spoke with scientists researching protein misfolding across a number of
neurodegenerative conditions, exploring ways to prevent cell- to – cell spread.
m) Kurt Giles, of the Institute for Neurodegenerative Diseases at the University of
California, San Francisco, co- authored a paper in the Proceedings of the National
Academy of Sciences, showing that the amyloid-beta protein associated with
Alzheimer's shares prion-like characteristics. The research team included the
institute's director Stanley Prusiner, whose discovery of prions won a 1997 Nobel
Prize. Researchers injected amyloid beta protein into one side of mice brains. They
followed the spread of the disease using a light-generating molecule. The toxic
protein set off a chain reaction of misfolding throughout the brain, as it does in AD.
n) These findings may have implications in cardiac disease too, says Avijit
Chakrabartty, of the University of Toronto. His lab has been working on amyloid
cardiomyopathy, caused by misfolding of a particular protein. Clot busters and other
heart-disease drugs don't work in these patients because it is not cholesterol but
misfolded protein clogging their arteries. One version of this disease runs in
families, and treatment is available. But so far there is no way distinguishing cases
that do not involve a genetic mutation. The Toronto team is looking for a test for the
misfolded protein in the blood.
o) Elan Corporation announced in November that it had enrolled the first patient in a
Phase II clinical trial of ELND005 (Study AG201) for the treatment of
agitation/aggression in patients with moderate to severe Alzheimer’s disease.
p) An FDA-approved treatment for insulin resistance in diabetics shows promise as a
way to improve cognitive performance in some people with Alzheimer's. Using
genetically engineered mice, University of Texas Galveston researchers found that
the anti-insulin-resistance drug rosiglitazone improved learning and memory while
normalizing insulin resistance. The researchers believe that the drug reduced the
negative influence of Alzheimer's on the behaviour of a key brain-signaling molecule.
The molecule, called extracellular signal-regulated kinase (ERK), becomes
hyperactive in the brains of Alzheimer's patients as well as in the mice at a disease
stage corresponding with mild cognitive impairment in human Alzheimer's. This
excessive activity leads to improper synaptic transmission between neurons,
interfering with learning and memory.
20