Monitoring International Trends
posted December 2015
The NBA monitors international developments that may influence the management of blood
and blood products in Australia. Our focus is on:
 Potential new product developments and applications;
 Global regulatory and blood practice trends;
 Events that may have an impact on global supply, demand and pricing, such as changes
in company structure, capacity, organisation and ownership; and
 Other emerging risks that could potentially put financial or other pressures on the
Australian sector.
A selection of recent matters of interest appears below. Highlights include:
 Reports of presentations to the annual meeting of the American Society of Hematology,
concerning developments in coagulation factors, RNAi therapeutics, treatments for sickle
cell disease, gene therapy for blood disorders, length of storage of red blood cells, and a
very portable diagnostic device (Section 1).
 The availability of new agents with convenient oral or subcutaneous delivery which will
make routine prophylaxis in hereditary angiodema more likely (Section 2).
 CSL’s trial of its plasma-based CSL112 in the US to reduce the risk of a second heart
attack (Section 2).
 FDA approval of the first genetically engineered treatment for von Willebrand disease
(Section 3).
 Approval by the European Commission of the Sobi-Biogen long-acting recombinant
Factor VIII, Elocta (Section 3).
 CSL’s first shipment of Privigen to the US from Broadmeadows (Section 4).
 Announcement by Grifols of its management succession plan (Section 4).
 Mexico’s approval of Sanofi’s dengue vaccine (Section 5).
 The FDA’s new guidance for blood banks, to protect the US blood supply during a future
Ebola outbreak (Section 6).
 New ways to deliver drugs (Section 7).
 Attempts to develop a vaccine against MERS–CoV (Section 9).
Table of Contents
1. The 57th Annual Meeting and Exposition of the American Society of Hematology
(ASH). Orlando, Florida, 5 to 8 December 2015. ___________________________________ 2
Haemophilia ___________________________________________________________________ 2
Sickle cell disease _______________________________________________________________ 3
Paroxysmal nocturnal haemoglobinuria _____________________________________________ 3
Other _________________________________________________________________________ 4
2.
Other product news _____________________________________________________ 5
3.
Regulatory _____________________________________________________________ 7
1
4.
Market structure and company news _______________________________________ 8
5.
Country-specific events __________________________________________________ 11
6.
Safety and patient blood management _____________________________________ 13
7.
Research _____________________________________________________________ 14
8.
Legal matters _________________________________________________________ 15
9.
Infectious diseases _____________________________________________________ 16
Mosquito-borne disease: malaria, chikungunya, dengue, Ross River virus _________________ 16
Influenza: strains, spread, prevention and treatment _________________________________ 17
MERS-CoV (Middle East Respiratory Syndrome-Coronoavirus) __________________________ 18
Ebola virus disease _____________________________________________________________ 19
Other diseases: occurrence, prevention and treatment ________________________________ 19
1. The 57th Annual Meeting and Exposition of the American Society of
Hematology (ASH). Orlando, Florida, 5 to 8 December 2015.
Haemophilia
a) CSL Behring reported the data from its Phase III PROLONG-9FP clinical program
evaluating the efficacy and long-term safety of its investigational long-acting fusion
protein linking recombinant coagulation factor IX with recombinant albumin (rIX-FP).
The data, from an ongoing extension study and two pivotal Phase III studies,
assessed rIX-FP for routine prophylaxis in previously-treated adults with haemophilia
B, at dosing intervals of up to 14 days. A second abstract reported efficacy and
safety results for rIX-FP in patients undergoing surgery.
b) A study1 reported during a plenary session found that recombinant Factor VIII
replacement products for severe haemophilia A appeared to increase inhibitor
development 1.87-fold compared with plasma-derived products.
c) Biogen and Swedish Orphan Biovitrium in two poster sessions presented new data
demonstrating that their long-acting products Elocta/Eloctate [recombinant human
coagulation factor VIII, Fc fusion protein] and Alprolix (rFIXFc) may effectively
manage target joint bleeding and maintain low annualised bleeding rates in people
with severe haemophilia A and B2.
d) Alnylam Pharmaceuticals reported positive results from its continuing Phase 1 clinical
study with fitusiran, the International Nonproprietary Name (INN) allocated to ALN1
By Flora Peyvandi, associate professor of internal medicine at University of Milan and head of the
internal medicine department and of the Angelo Bianchi Bonomi Haemophilia and Thrombosis Centre
of Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico in Milan, and colleagues. They
conducted a multicentre, open-label, randomized study (in previously untreated patients with severe
haemophilia A) to investigate whether the rate of inhibitory alloantibody development differed
according to the source of Factor VIII replacement—plasma-derived or recombinant.
2 Kerlin, BA, et al.,”Long-term Efficacy of rFVIIIFc Prophylaxis in Pediatric, Adolescent, and Adult
Subjects With Target Joints and Severe Hemophilia A“ and Shapiro, AD, et al.,”Analysis of Target
Joint Bleeding With Prophylactic Use of Recombinant Factor IX Fc Fusion Protein in Patients With
Severe Hemophilia B”.
2
AT3. Fitusiran is an RNAi therapeutic which targets antithrombin (AT) with the goal of
promoting sufficient thrombin generation to restore haemostasis. Results
demonstrated that subcutaneous administration of fitusiran achieved potent and
dose-dependent lowering of AT of up to 88 per cent. AT lowering was associated
with statistically significant and clinically meaningful increases in thrombin generation
and decreases in bleeding frequency in patients with haemophilia. In particular,
fitusiran administration resulted in an 85 per cent reduction in median estimated
annualized bleeding rates in nine evaluable patients. Fitusiran was found to be
generally well tolerated to date, including no clinically significant increases in Ddimer, a biomarker of excessive clot formation. The company expects to begin pivotal
studies of fitusiran in mid-2016.
Sickle cell disease
e) A study3 found the rate of vaso-occlusive crises is not significantly lower for children
and adolescents with sickle cell anemia receiving prasugrel versus placebo. Eli Lilly
and Daiichi Sankyo, the manufacturers of prasugrel, financed the study.
f) Results of a placebo-controlled, double blind study of Global Blood Therapeutics’
GBT440 were reported4 to show that the small molecule haemoglobin modifier
reduced haemolysis and improved anaemia without causing tissue hypoxia in
patients with sickle cell disease. Treatment with GBT440 (Global Blood Therapeutics)
also nearly eliminated all sickle cells in the peripheral blood of patients, according to
researchers. GBT440 works to increase haemoglobin oxygen affinity.
g) One presentation reported on a trial sponsored by the US National Institutes of
Health (NIH)5. TWiTCH evaluated hydroxyurea in its capacity to lower the risk of
stroke in children with sickle cell disease (SCD) by improving blood flow in the brain.
This was a prospective, randomized study involving 26 pediatric treatment centers
around the US, and 120 children aged between 4 and 15, all with severe SCD. The
TWiTCH trial was stopped early, because of clear results for hydroxyurea being at
least as good as transfusion in maintaining blood flow to the brain, as measured by
transcranial Doppler. (This was the primary endpoint of the trial). There was no
significant difference in the incidence of strokes between the two treatment arms, and
no significant problems observed from hydroxyurea on the study, which included
follow-up through two years.
h) Another presentation6 reviewed results from a large international registry of 1,000
HLA-identical sibling transplants performed for patients with severe SCD. The
perfectly-matched allogeneic transplants were carried out between 1986 and 2013, at
88 medical centers in 23 countries. The median age at transplant was 9 years. At
three years after transplant, overall survival was 94 per cent.
Paroxysmal nocturnal haemoglobinuria
i)
Clinical data from Alnylam Pharmaceutical’s ongoing Phase I/II study of its RNAi
therapeutic ALN-CC5 targeting serum C5 were presented. These were from both the
single-ascending dose and multiple-ascending dose parts of the ongoing study in
healthy adult volunteers7. Akshay Vaishnaw, Executive Vice President and Chief
3
By Matthew M. Heeney,from the Boston Children's Hospital, and colleagues. The research was
published online 8 December in the New England Journal of Medicine to coincide with the meeting
4
Lehrer-Graiwer J, et al. Abstract 542.
5
Abstract 3. Presented by Dr Russell Ware
Abstract 541.Presented by Dr Barbara Cappelli
7 ALN-CC5 achieved up to 99 percent knockdown of serum C5 and up to 98 percent inhibition of
serum sheep red blood cell haemolytic activity, an assay for complement activity; administration of
ALN-CC5 resulted in low levels of residual C5, which – based on comparisons from separate studies
– were at or below the estimated levels of free C5 observed at therapeutic doses of eculizumab, an
approved anti-C5 monoclonal antibody; the effects of ALN-CC5 were found to be highly durable, with
6
3
j)
Medical Officer of Alnylam, said soon after the meeting: "Based on encouraging data
recently presented at ASH, we’ve now advanced ALN-CC5 into patients with PNH8,
where clinical activity can be measured toward LDH9, a key disease biomarker. If
successful in lowering LDH levels, we believe that ALN-CC5 could emerge as a
differentiated approach to address the continued unmet needs that exist for patients
with PNH and other complement mediated diseases. We look forward to the
continued clinical advancement of ALN-CC5 and expect to report initial PNH patient
data in mid-2016 ahead of an anticipated 2017 Phase 3 start.”
Alexion Pharmaceuticals announced that researchers presented data from the
International Paroxysmal Nocturnal Hemoglobinuria (PNH) Registry10 that advance
the understanding of PNH and the long-term management of the disease, including
the progression of symptoms in untreated patients with PNH and the continued
benefits of the company’s Soliris (eculizumab) treatment irrespective of transfusion
history. Researchers also presented data from a long-term follow-up study evaluating
the effectiveness of Soliris in preventing thrombotic microangiopathy (TMA) in
patients with atypical hemolytic uremic syndrome (aHUS). Both PNH and aHUS are
severe, ultra-rare diseases caused by chronic uncontrolled complement activation.
Other
k) Bluebird Bio presented further data on a subgroup of four of the 13 patients with
beta-thalassemia major on whom it is testing LentiGlobin BB305. These four have a
genetic variation called beta-zero beta-zero that leaves them unable to make any of
the oxygen-carrying molecule beta-globin. On 5 November, the company said three
of the patients hadn’t responded as well to its drug as patients without the variation,
which caused Bluebird’s share price to fall 22 per cent. At ASH, Bluebird
emphasised11 that the group had been able to reduce the volume of transfusions they
needed. The company will start a separate trial for similar hard-to-treat patients, and
continue testing the therapy in patients without the variation. Five patients without the
genetic variation and who can make a limited amount of the oxygen transporting
molecule haven’t needed transfusions for between 7.1 to 16.4 months after therapy12.
l) A number of other papers also reported on gene therapy trials in blood disorders.13
C5 knockdown and complement inhibition results supporting a once monthly and possibly a once
quarterly subcutaneous dose regimen; and ALN-CC5 was shown to be generally well tolerated, with
no clinically significant, drug-related adverse events to date.
8 Paroxysmal nocturnal haemoglobinuria. Alnylam has begun the final phase (Part C) of its Phase I/II
clinical trial with ALN-CC5, a subcutaneously administered RNAi therapeutic targeting complement
component C5 for the treatment of complement-mediated diseases. Part C is being conducted in
patients with paroxysmal nocturnal hemoglobinuria (PNH). It will evaluate the safety and tolerability of
multiple doses of ALN-CC5 and will measure its clinical activity, including knockdown of serum C5
levels, levels of residual C5, inhibition of serum haemolytic activity, and reduction of lactate
dehydrogenase (LDH), a measure of red blood cell haemolysis.
9 lactate dehydrogenase
10 Three posters were presented at ASH from the International PNH Registry, a prospective,
worldwide, observational study of patients with PNH that has so far enrolled more than 4,000 patients.
11
Abstract #201: “Update of Results from the Northstar Study (HGB-204): A Phase 1/2 Study of Gene
Therapy for β-Thalassemia Major via Transplantation of Autologous Hematopoietic Stem Cells
Transduced Ex Vivo with a Lentiviral βA-T87Q-Globin Vector (LentiGlobin BB305 Drug Product)” .An
oral presentation was given by Mark C. Walters, University of California at San Francisco Benioff
Children’s Hospital.
12 The one-time treatment involves removing a patient’s stem cells that make red blood cells,
modifying them with a normal gene to manufacture a protein that fights beta-thalassemia, and then
infusing them back into the body.
13 Eg Abstract 259: “Safety and Clinical Benefit of Lentiviral Hematopoietic Stem Cell Gene Therapy
for Wiskott-Aldrich Syndrome”, delivered by Francesca Ferrua, San Raffaele Telethon Institute for
Gene Therapy (TIGET), Milan, and Abstract 261 “Lentiviral Hematopoietic Stem Cell Gene Therapy
4
m) Janssen Pharmaceuticals and Bayer HealthCare announced the results from a realworld study in 5000 patients showing that, in people with deep vein thrombosis
(DVT), the rates of major bleeding and recurrent blood clots for Xarelto (rivaroxaban)
in routine clinical practice were generally consistent with those observed in Phase III
research. Patients on Xarelto also had shorter hospital stays than those given
standard anticoagulation14.
n) A report15 of a randomized, controlled clinical trial compared the oxygen delivery of
short-storage versus longer-storage red blood cells (RBC) as measured by
transfused patients' blood lactate levels16. The trial included 290 patients between
the ages of six months and five years who visited a university hospital urgent care
facility in Kampala, Uganda, for treatment of severe anemia marked by elevated
blood lactate levels. Participants were randomly assigned to receive either RBCs
stored for one to 10 days, or RBCs stored for 25 to 35 days. Patients were monitored
during the transfusion and for a further 24 hours. The number of patients achieving
the desired blood lactate level of less than or equal to 3mM was not statistically
different between the two groups17. Brain oxygen levels increased in recipients of
shorter-storage and longer-storage RBCs to the same extent.
o) Researchers presented ongoing work18 on the HemeChip, a small mobile device to
detect genetic blood disorders. "While sickle cell newborn screening is standard in
the US, very few infants are screened in Africa because of the high cost and level of
skill needed to run traditional tests," explained project researcher Dr Little, Associate
Professor at the Case Western Reserve University School of Medicine. "This new
mobile technology provides an easy to use, cost-effective tool that takes us closer to
standardizing newborn screenings on mobile devices, thus simplifying diagnosis. It
could make a huge difference in developing nations worldwide, enabling early
treatment for this disease." Hemechip uses a battery-powered technique known as
cellulose acetate electrophoresis to identify varying types of haemoglobin, a protein
that helps red blood cells transport oxygen throughout the body.
2. Other product news
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) La Jolla Pharmaceutical Company has been conducting a Phase 1 clinical trial of
LJPC-401, its novel formulation of hepcidin19. The trial is a is a multicentre, openfor Older Patients with X-Linked Severe Combined Immunodeficiency”, delivered by Suk See De
Ravin, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda,
Maryland.
14 Principal investigator was Professor Alexander G. G. Turpie, of McMaster University and Hamilton
Health Sciences, Ontario. The study was simultaneously published in Lancet Hematology.
15 “Tissue Oxygenation by Transfusion in Severe Anemia with Lactic Acidosis (TOTAL): A
Prospective, Randomized, Non-Inferiority Trial of Blood Storage Duration” was presented orally by
Walter Dzik, Massachusetts General Hospital, Boston. Christine M. Cserti-Gazdewich, University
Health Network, Toronto, presented to the press conference.
16 When tissue oxygen levels are critically low, lactate levels jncrease, and when tissues are
successfully re-oxygenated, lactate levels may fall.
17Of those who received shorter-storage blood, 58 percent reached this desired outcome compared to
61 percent of those who received longer-storage blood.
18
Ung R, Alapan Y, Noman Hasan M, et al. “Point-of-Care Screening For Sickle Cell Disease By
a Mobile Micro-Electrophoresis Platform”.
19 Hepcidin is a naturally occurring peptide hormone that is the body’s regulator of iron absorption and
distribution. Hepcidin prevents excessive iron accumulation in vital organs, such as the liver and
heart, where it can cause significant damage and even lead to death.
5
b)
c)
d)
e)
f)
20
label, dose-escalation trial evaluating the safety, tolerability and effect on serum iron
parameters, and pharmacokinetics of LJPC-401 in patients at risk of iron overload
due to hereditary haemochromatosis (HH),or beta thalassemia or sickle cell disease
(SCD).
Baxalta announced the submission of a Clinical Trial Application (CTA) to the UK
Medicines and Healthcare Products Regulatory Agency (MHRA) to initiate a first-inhuman clinical trial to evaluate the safety and efficacy of BAX 826, an investigational,
extended half-life recombinant Factor VIII (rFVIII) treatment for hemophilia A. "We
are advancing a number of approaches, including BAX 826 as well as our gene
therapy program, to evaluate potential new options for hemophilia patients that can
offer efficacy while also easing the treatment burden with a goal of once-weekly or
even less frequent infusions," said John Orloff, head of Research and Development
and chief scientific officer, Baxalta. The open-label, dose-finding study of BAX 826
aims to enroll 30 patients; Baxalta expects to begin treating participants in the study
by early 2016. BAX 826 is a next-generation rFVIII treatment based on the full length
ADVATE [Antihemophilic Factor (Recombinant)] molecule. The compound is
modified using proprietary polysialic acid (PSA) technology licensed from Xenetic
Biosciences, to extend its circulating half-life.
Cerus Corporation announced that Smilow Cancer Hospital at Yale-New Haven has
enrolled the first patient in the Phase IV INTERCEPT Platelets Entering Routine Use
(PIPER) study, a prospective, open-label, non-inferiority, post-marketing surveillance
study. The PIPER study is expected to enrol around 3,000 patients at up to 20 US
hospitals20.
Hereditary angiodema is caused by low levels of functional C1-inhibitor. It is not a
common disease, but has been an alarming one, leading as it does to acute attacks
with major swelling which can be life-threatening. In recent years plasma derived C1inhibitor replacement drugs Cinryze and Berinert have become available so therapy
has been satisfactory, assuming diagnosis is both timely and accurate, which is not
always the case. They are also efficacious and safe as prophylactic agents, but they
require twice-weekly intravenous administration. New agents with convenient oral or
subcutaneous delivery are becoming available, so routine prophylaxis is expected to
become more common, replacing the emphasis on on-demand treatment. New
agents include BioCryst's avoralstat and BCX-7353, Dyax's DX-2930, and CSL
Behring's CSL-830.
CSL believes its plasma-based drug CSL112 could greatly reduce the risk of a
second heart attack among sufferers21. It works by rapidly removing cholesterol from
the arteries of heart attack patients. CSL is carrying out a phase IIb trial of CSL112 in
1200 heart attack patients in the US. Half the patients have been given a treatment of
CSL112 — four infusions once a week for a fortnight — and half have been given a
placebo22. CSL will now monitor the incidence of a second heart attack among the
group over the next year. If the results prove successful, CSL will launch a phase III
trial involving more than 10,000 patients in mid-2017.
Arch Therapeutics has clearance to begin a clinical trial in Western Europe for its
AC5 surgical haemostatic device. The trial will examine bleeding wounds created
The PIPER study will monitor the transfusion of conventional and INTERCEPT-treated platelets in
hematology/oncology patients. PIPER will evaluate the incidence of severe pulmonary adverse events
requiring assisted mechanical ventilation, a clinical concern in transfusion medicine as it relates to
repeated platelet transfusions in patient populations at risk for lung injury.
21 About 735,000 people in the US and 55,000 people in Australia have a heart attack each year. Of
these about 15 per cent will have a second heart attack.
22 A separate sub-group trial involving patients suffering from moderate renal failure will run alongside
the main CSL112 trial.
6
during a dermatological procedure in fewer than 50 patients. The endpoints include
product-related adverse effects and time to haemostasis.
g) ProMetic Life Sciences will conduct a double-blind placebo controlled phase II clinical
trial in patients suffering from cystic fibrosis (CF) and related diabetes and liver
steatosis, using its compound PBI-4050. CF is a condition which compromises
pulmonary, pancreatic and hepatic functions. “PBI-4050 has been shown to
significantly reduce fibrosis in several key organs in preclinical models and this,
irrespective of how the injuries were induced or whether they were acute or chronic in
nature”, stated Dr Lyne Gagnon, VP of R&D preclinical at ProMetic. “For this reason
and because of the positive effects recently observed in type 2 diabetic patients, we
believe that PBI-4050 could provide significant clinical benefits to patients affected by
this medical condition”.
3. Regulatory
The NBA monitors overseas regulatory decisions on products, processes or procedures
which are or may be of relevance to its responsibilities.
a) The US Food and Drug Administration (FDA) has approved the first genetically
engineered treatment for von Willebrand disease, the most common inherited
bleeding disorder. Vonvendi, made by Baxalta, has been approved for treating
patients aged 18 and older. Baxalta says the drug should be available in 2016, and
that its price has not yet been determined.
b) Bayer said that the European Committee for Medicinal Products for Human Use or
CHMP has recommended BAY 81-897323 for approval in the EU for the treatment
and prophylaxis of bleeding in patients with haemophilia A for all age groups. A final
decision will be made by the European Commission.
c) Swedish Orphan Biovitrum and Biogen announced that the European Commission
has approved Elocta (rFVIIIFc) for the treatment of haemophilia A in all 28 European
Union member states, as well as Iceland, Liechtenstein and Norway. Elocta, a
recombinant factor VIII Fc fusion protein with an extended half-life, will be the first
haemophilia A treatment in the EU to offer prolonged protection against bleeding
episodes with prophylactic injections every three to five days. Elocta is indicated for
both on-demand and prophylaxis treatment of people with haemophilia A of all
ages24.
d) Green Cross Corporation, a South Korean biopharmaceutical company, submitted its
Biologics License Application for IVIG-SN (human normal immunoglobulin G for
intravenous administration) to the FDA. The application was submitted for the
treatment of primary immunodeficiency diseases (PID), a class of inherited genetic
disorders that causes an individual to have a deficient or absent immune system.
e) The FDA cleared the use in civilian trauma settings of the XSTAT 30 wound
dressing, an expandable, multi-sponge dressing used to control severe, lifethreatening bleeding from wounds in areas such as the groin or armpit where a
tourniquet cannot be placed. The clearance expands the device's indication from use
23
BAY 81-8973 is Bayer's new unmodified full-length recombinant factor VIII compound. In clinical
trials, it controlled bleeds and protected from bleeds in hemophilia A patients when used
prophylactically two or three times per week.
24 The EC approval was based on data from Elocta's pivotal, phase III A-LONG clinical study, which
demonstrated the efficacy, safety and pharmacokinetics of rFVIIIFc in previously treated males 12
years of age and older with severe haemophilia A, and from the phase III Kids A-LONG clinical study,
which demonstrated the efficacy and safety of rFVIIIFc in previously treated male children with
haemophilia A under 12 years of age. Elocta is the trade name for rFVIIIFc in Sobi's territory, which is
also approved under the name Eloctate® [Antihemophilic Factor (Recombinant), Fc Fusion Protein]
for the treatment of haemophilia A in the U.S., Canada, Australia, New Zealand and Japan.
7
by the military only. XSTAT 30 is cleared for use in patients at high risk for
immediate, life-threatening, and severe haemorrhagic shock and non-compressible
junctional wounds, when definitive care at an emergency care facility cannot be
achieved within minutes. XSTAT 30 is not indicated for use in certain parts of the
chest, abdomen, pelvis or tissue above the collarbone. The dressing can be used for
up to four hours25. The FDA cleared XSTAT 30 through the 510(k) review process
after the manufacturer demonstrated the product was substantially equivalent to the
XSTAT, which was granted marketing authorization for battlefield use in April 2014.
f) European and US regulators have been investigating whether a defective bloodclotting test device affected a trial involving Bayer's anti-blood clotting drug Xarelto
(rivaroxaban). The Rocket AF trial compared Xarelto with warfarin for the prevention
of strokes and systemic embolisms in patients with irregular heartbeat.
g) Boehringer Ingelheim announced that it had received final approval from the FDA for
its Pradaxa (dabigatran etexilate mesylate) to be used to prevent deep vein
thrombosis or pulmonary embolism in patients who have had hip replacement
surgery. The approval is for a new use for the drug, which was launched in 2010.
“This milestone represents the fourth FDA-approved indication for PRADAXA in five
years — a testament to the company’s continued leadership in the evolution of
anticoagulation care for patients and clinicians,” Boehringer Ingelheim’s SVP
medicine and regulatory Dr. Sabine Luik said. “PRADAXA has the longest real-world
experience of any novel oral anticoagulant”.
h) Boehringer Ingelheim’s Praxbind, which reverses the effects of its anticoagulant
Pradaxa, has been approved in Europe. The European Commission’s approval is
based on data from an interim analysis of the RE-VERSE AD study, where the drug
showed complete and sustained reversal for at least 12 hours in almost all patients.
As Praxbind works only to reverse the effects of Pradaxa, it could give Boerhinger’s
drug an edge in the crowded Novel Oral Anti-Coagulant market, as there has been
no approved antidote to the Factor Xa inhibitors. US firm Portola Pharmaceuticals is
working on andexanet alfa, but it is still some way from approval.
4. 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) CSL Behring has opened an office in Moscow and says it is looking for ways to
partner with the government. CEO Paul Perreault said in a statement that it may be
possible to transfer CSL Behring's plasma collection technology to Russia, and
added he can see a point at which the firm might set up some of its plasma collection
technology or manufacturing there. Novo Nordisk and AstraZeneca both opened
manufacturing operations in Russia this year. Russian President Vladimir Putin
insists that those companies that want to profit from his country's growth will need to
invest and transfer technology there.
b) CSL is undertaking a $A 210 million expansion of its Broadmeadows plant. It will
produce albumin from blood collected from CSL's American collection centres for the
25
The device is available in packages of one or three syringe-style applicators containing 92
compressed, cellulose sponges that have an absorbent coating. The sponges expand and swell to fill
the wound cavity, creating a temporary physical barrier to blood flow. The number of sponges needed
for effective hemorrhage control will vary, depending on the size and depth of the wound. Each
applicator can absorb about a pint of blood, and up to three applicators may be used on a patient.
XSTAT 30 is manufactured by RevMedX, of Oregon.
8
c)
d)
e)
f)
g)
h)
i)
j)
26
first time. Initial separation of blood into its plasma components happens at the
company's Kankakee/Illinois factory before it is sent to global plants to be prepared
for export. CSL is experiencing significant demand in China. Its sales of albumin rose
16 per cent in constant currency terms in the 2014 financial year-its third consecutive
year of double-digit growth. The Victorian government made an undisclosed
contribution to the investment26.
CSL has shipped to the US the first production of Prvigen from its Broadmeadows
plant. This Australian facility producing Privigen has the capacity to manufacture
products with an export value of $A 2 billion or more annually.
Pfizer and Allergan are merging in a $US 160 billion deal. Pfizer said it expected the
merger to result in savings of $US 2 billion in the first three years. The effective tax
rate the enlarged company will pay will be between 17 and 18 per cent after the deal
closes, compared with the 26 per cent that Pfizer had to pay the American IRS in
2014. The new company will be the world’s largest drug company.
Baxalta announced the official opening of its global innovation centre in Cambridge,
Massachusetts. Baxalta’s innovation efforts focus on therapies in haematology,
immunology and oncology. The company expands its pieline based on an external
innovation model, sourcing compounds externally through in-licensing or
acquisitions. The company has about 40 programs in development, and plans to
launch 20 new products by 2020. It sees its advantages as an experienced
leadership team, existing global capabilities and footprint in more than 100 countries.
Cerus Corporation signed a three-year deal to supply the Mississippi Valley Regional
Blood Center with its INTERCEPT Blood System for platelets and plasma. The
Center is based in Davenport, Iowa, and is the exclusive provider of blood products
to 88 hospitals in Illinois, Iowa, Missouri, and Wisconsin.
KaloBios Pharmaceuticals announced it was acquiring worldwide rights to a
compound being developed for the treatment of Chagas disease. It is purchasing the
rights to Benznidazole from privately held Savant Neglected Diseases LLC for an
upfront payment of $US 2 million, regulatory milestones and a royalty based on
product sales.
A patent application filed27 by Google Life Sciences28 is for a needle-free blood draw
device for use in any sort of diagnostic including blood glucose or for use in a
handheld device. The method relies upon a negative pressure barrel that would
release microparticles with enough force to pierce the skin and elicit tiny blood
droplets. The vacuum barrel would then draw in at least part of that blood.
Humacyte, of Research Triangle Park, North Carolina, has raised $US 150 million in
financing from a group of global investors. The funds will support the company’s
Phase III clinical trials for its HumaGraft treatment, which is intended for patients
undergoing hemodialysis29. In 2014 the FDA assigned fast track status to
HumaGraft30.
ProMetic and Omnio have entered into an agreement under which ProMetic has
secured exclusive license rights to both issued and pending patents for the use of
In its submission to the Innovation Inquiry, CSL warned that Australia was not an attractive location
for "entrepreneurial manufacturing" or commercialising intellectual property because of high corporate
tax rates, declining skills, high labour costs and complex government interactions.
27 The date of original filing was May 2014, but it is U.S. Patent and Trademark policy to publish
patent filings 18 months after an application is made.
28 Google announced in August that it would become parent company Alphabet ($GOOG) that houses
companies including the search engine-oriented Google and med tech-based Google Life Sciences.
29 Hemodialysis performs the job of the kidneys in patients experiencing kidney failure – the last stage
of chronic kidney disease. It filters blood removing excess water and waste, then returns the blood to
the patient.
30 This is for drugs that have the potential to offer significant improvement in treatment compared with
products already on the market.
9
plasminogen31 related to wound healing. ProMetic also gained access to preclinical
data and proof of concept efficacy data in patients. Pierre Laurin, President and CEO
of ProMetic commented: "Dr Ny and his esteemed colleagues at Omnio have
decades of hands-on experience demonstrating the ability of plasminogen to
accelerate the healing of otherwise very hard-to-treat wounds. Combining their
unique knowhow with our own clinical experience from our ongoing US plasminogen
clinical trial bodes very well for improving the future management of diabetic
wounds”.
k) ProMetic Life Sciences has entered into a strategic partnership with ProThera
Biologics for the development and commercialization of human plasma-derived Interalpha Inhibitor Proteins32. The agreements provide ProMetic with global, exclusive
intellectual property rights to commercialize products for two clinical indications and
both companies have strategic interest in the other's IAIP-related therapeutic areas
through a royalty-bearing cross-license agreement. ProMetic and ProThera each will
perform development services in order to advance IAIP to the clinic by 2017.
ProMetic has received an initial 11.25 per cent equity stake in ProThera with such
equity position to be increased to 22.5 per cent following the achievement of an
early-stage development milestone. Further, ProMetic will exclusively manufacture
IAIP for clinical trial requirements and commercial sales for all indications.
l) Privately held Hawaii Biotech announced that the US Army awarded the company a
Small Business Innovation Research Phase I contract to develop an effective dengue
vaccine to protect military personnel. Hawaii’s Big Island has been managing a
dengue outbreak this year.
m) In Cambridge, Massachusetts, Flagship Ventures launched Rubius Therapeutics, to
develop functionalized red blood cells for the treatment of a number of serious
diseases33. Flagship has made an initial capital commitment of $US 25 million to
enable Rubius to enter clinical testing. Rubius says red-cell therapeutics (RCTs)
possess pharmacodynamic and pharmacokinetic advantages over traditional
therapeutics, not least because of their inherent ability to engage and modulate the
immune system and circulate for extended periods in the body. "Red blood cells can
now be produced in culture and engineered to possess enormous biotherapeutic
properties," said Harvey Lodish, professor of biology and bioengineering at MIT who
has joined the firm's board of directors. "They spend as much as four months in
circulation, providing an opportunity for long and tunable therapeutic treatments. Red
cells also have profound effects on the immune system and may ultimately transform
the way we treat autoimmune diseases and allergies." Avak Kahvejian, founding
CEO of Rubius and partner in Flagship VentureLabs, said: "Through its rapid
prototyping capability, Rubius has generated and tested over 50 different RCTs for a
31
Plasminogen is synthesized by the liver and circulates in the blood. Activated plasminogen,
plasmin, is a fundamental component of the fibrinolytic system and is the main enzyme involved in the
lysis of blood clots and clearance of extravasated fibrin. Plasminogen is involved in wound healing,
cell migration, tissue remodelling, angiogenesis and embryogenesis.
32 ProMetic describes Inter-alpha Inhibitor Proteins thus: Inter-alpha Inhibitor Proteins (IAIP) are a
family of naturally occurring proteins found in high concentration in human plasma and play an
important role in the regulation of host immune response. Research shows that IAIP play a key role in
fighting acute inflammatory diseases including whole-body inflammation (shock syndrome or sepsis),
due to infection, trauma or injury. IAIP exert their effects through multiple anti-inflammatory pathways,
but importantly they function by binding to, and neutralizing, the toxic effects of extracellular histones
released from dying cells. There is now a broad and growing recognition that IAIP are one of the
body's first lines of defence against severe inflammation and they serve as important
immunomodulators. IAIP treatment has been shown to be effective in many pre-clinical models of
acute inflammatory disease and decreased IAIP levels in patients correlate with increased morbidity
and mortality for multiple diseases.
33
Erytech in Lyon (France) have already developed a potential therapy for certain cancers using this
method of drug delivery to a phase II trial stage.
10
n)
o)
p)
q)
r)
wide array of indications including autoimmunity, oncology and infectious disease.
The company is now poised to drive lead programs into the clinic, build a drug
pipeline and further develop the Rubius Erythrocyte Design (RED) platform. We are
expanding our R&D and management teams, and setting the stage for our next
phase of growth." The company has broad patent protection of its platform and
therapeutic products. Itis currently testing RCTs in animal models.
Grifols has reached an agreement with MassBiologics (MBL) of the University of
Massachusetts Medical School that gives Grifols exclusive rights to market and
distribute MBL's tetanus and diphtheria toxoids adsorbed (Td) vaccine34 in the US
other than in Massachusetts. Grifols now offers two tetanus therapies in the US. For
tetanus-prone wounds in persons with incomplete or unknown history of tetanus
immunization, Grifols HyperTET S/D (tetanus immune globulin [human], derived from
human plasma) is the sole product on the US market that provides immediate,
passive immunity against tetanus; the Td vaccine is a complementary therapy that
yields longer-term, active immunity for tetanus.
Akebia Therapeutics has signed a deal with Mitsubishi Tanabe Pharma Corp., based
in Osaka, under which MTPC will have the rights to sell Akebia's aanemia drug in
Japan, Taiwan, South Korea, Indonesia, India and other Asian countries. The
Japanese company will pay Akebia tiered royalty payments on sales of vadadustat.
Mitsubishi will also pay $US 60 million toward the Phase III trial of the drug on top of
a $US 40 million up-front payment. Vadadustat mimics the way the body reacts to
high altitudes by blocking the hypoxia inducible factor, the main way the body
regulates the production of red blood cells. Akebia says that method of maintaining
haemoglobin levels is safer than erythropoiesis stimulating agents (ESAs) such as
Epogen, Aranesp or Procrit. Akebia reported final results from a mid-stage, 94patient trial in September.
The Board of Directors of Grifols has unanimously approved the 'succession plan'
proposed by Víctor Grifols Roura, the incumbent Chairman and Chief Executive
Officer of the company. From 1 January 2017 Victor Grifols Roura will be succeeded
by his brother, Raimon Grifols, and his son, Víctor Grifols Deu, who will become joint
and several chief executive officers of the company. Víctor Grifols will continue
holding his position as non-executive chairman of the board of directors. The
succession plan establishes 2016 as a transition year in order that the handover is
carried out smoothly.
Biogen and Arsia Therapeutics are collaborating to improve administration of drugs
for haemophilia patients by enabling subcutaneous versions of treatments that are
currently subject to intravenous infusion. Biogen will utilize Arsia’s proprietary
formulation technology. Arsia will receive an upfront payment and could be eligible to
receive development, regulatory, launch and sales milestones of up to $100 million if
multiple products are successfully commercialized. Arsia may also receive royalties
on certain products arising from the collaboration.
Dr. Reddy's Laboratories completed the purchase of worldwide exclusive intellectual
property rights for Fondaparinux sodium, its generic anti-coagulant drug from its
Australian partner, Alchemia Limited, for $US 17.5 million.
5. 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.
34
MassBiologics' Td vaccine was licensed by the FDA in 1970. The vaccine is indicated for active
immunization for the prevention of tetanus and diphtheria and is approved for use in people seven
years of age and older.
11
a) Saudi Arabia’s first plasma fractionation plant is expected to fulfil 30 per cent of the
Kingdom’s requirements for blood products. The plant is being funded by the Public
Investment Fund with French expertise.
b) Mexico has approved the use of Sanofi’s dengue vaccine, Dengvaxia. Some 40,000
people will receive the treatment in an initial phase. The vaccine will be available only
to children over the age of nine, and adults under 49 who live in areas where the
disease is endemic.
c) The US Centers for Disease Control and Prevention (CDC) in the 2014 STD
Surveillance Report says that reported cases of three nationally notifiable sexually
transmitted diseases–chlamydia, gonorrhea, and syphilis–have increased for the first
time since 200635. STDs continue to affect young people36—particularly women-most severely, but increasing rates among men contributed to the overall increases
in 2014 across all three diseases. Jonathan Mermin, director of CDC’s National
Center for HIV/AIDS, Viral Hepatitis, STD, and Tuberculosis Prevention, said: “STDs
affect people in all walks of life, particularly young women and men, but these data
suggest an increasing burden among gay and bisexual men.”37
d) Chinese regulators in the field of academic publishing for scientific articles have
banned dishonest practices. The directive forbids Chinese scientists from using a
third party to write journal articles, or to submit articles, or to substantially revise
articles. It bans providing fake peer review information, or giving authorship to
scientists who have not substantially contributed to the research. The directive from
the country's leading science organizations and ministries, including the Chinese
Academy of Sciences and the Ministry of Education, comes after several
international science journals this year rejected or retracted submissions from
Chinese scientists, citing academic dishonesty38.
e) Cerus Corporation announced that the INTERCEPT Blood System for platelets and
plasma has been approved for commercialization in Brazil by the Agência Nacional
de Vigilância Sanitária (ANVISA). This is the first time that a system to inactivate
pathogens in platelet and plasma components will be available in Brazil. “With
serious outbreaks of viruses such as dengue, zika, and chikungunya becoming more
common in Brazil, transmission of pathogens via blood transfusion remains an
ongoing threat,” commented Carol Moore, SVP, Regulatory Affairs and Quality at
Cerus.
f) The New Zealand Ministry for Primary Industries (MPI) Director General issued a
statement warning of a potential risk associated with imported frozen berries
following four human cases of hepatitis A. "Australian officials recalled imported
frozen berries there in February [2015]. Recent outbreaks in other countries also
35
The 1.4 million reported cases of chlamydia, a rate of 456.1 cases per 100,000 population, is up 2.8
per cent since 2013. Rates of primary and secondary syphilis–the most infectious stages of syphilis–
and gonorrhea have both increased since 2013, by 15.1 per cent and 5.1 per cent, respectively. In
2014, there were 350,062 reported cases of gonorrhea (a rate of 110.7 per 100,000) and 19,999
reported cases of primary and secondary syphilis (for a rate of 6.3 per 100,000).
36
Despite being a relatively small portion of the sexually active population, young people between the
ages of 15 and 24 accounted for the highest rates of chlamydia and gonorrhea in 2014 and almost
two thirds of all reported cases.
37 Primary and secondary syphilis among men who have sex with men (MSM) has been increasing
since at least 2000. In 2014, rates increased among MSM, who account for 83 percent of reported
cases among men when the sex of the partner is known. More than half of MSM (51 percent)
diagnosed with syphilis in 2014 were also HIV-positive.
38
In March, BioMed retracted 43 papers after an investigation that raised suspicions of fake peer
reviews. Chinese state media said 41 of the papers came from Chinese scientists. In August Berlinbased publisher Springer retracted 64 articles-nearly all by Chinese authors-because of false peer
reviews. Chinese state media reported more recently that an investigation by the Chinese Association
for Science and Technology had found that fake peer reviews were "a tip of the iceberg" and that the
buying and selling of journal articles was common.
12
suggest this link," he said. The Ministry has established a surveillance program,
including additional testing, focussed on imported frozen berries. The ministry said
fresh berries or products containing frozen berries had not been implicated in its
investigation.
6. Safety and patient blood management
We follow current issues in patient safety and achieving favourable patient outcomes.
a) The FDA has issued new guidance for blood banks and related establishments, to
protect the US blood supply during a future Ebola outbreak. The recommendations
are to apply when at least one country has current widespread transmission. In that
case donor questionnaires should be updated to assess donor risk for the Ebola
virus39. When donor screening reveals possible exposure to the Ebola virus, the FDA
recommends blood banks and related establishments defer donation.40 When a blood
bank or related establishment has collected blood or blood components from a donor
who should have been deferred for risks related to residency, travel, or close contact,
the establishment should quarantine and destroy all undistributed blood and blood
components from the donor. The establishment should also notify consignees who
received the supplies that they should do the same. Upon learning a donor was later
diagnosed as having the Ebola virus, the establishment should contact the FDA and
appropriate state and local health authorities. If the affected blood products were
transfused, consignees should also notify the physician of record for each recipient.
All undistributed blood and blood components from the donor should be quarantined
and destroyed.
b) Researchers in Sweden found that heart surgery patients given blood stored for more
than six weeks faced no greater harm than those who received blood donated within
the previous two weeks. Study author Dr. Ulrik Sartipy, an associate professor in the
department of molecular medicine and surgery at the Karolinska Institute in
Stockholm, said: "In our study, which is by far the biggest of its kind, including all heart
surgery patients in all of Sweden over a 16-year period, we find no evidence that
prolonged storage of blood units has negative effects on patient survival or risk of
complications."41
c) A study42 in 251 patients by Ariela Marshall, from the Mayo Clinic in Rochester,
Minnesota, and colleagues found that about 20 per cent of patients given fresh frozen
39
The FDA recommends screening for History of Ebola virus infection: history of residence in or travel
in the past 8 weeks to a country with widespread transmission of the Ebola virus; history of close
contact in the past 8 weeks with a person confirmed to have the Ebola virus or any person under
investigation for infection; and history of notification by a public health authority that the prospective
donor may have been exposed in the past 8 weeks to a person with the virus.
40 For a donor who has resided in or visited a country with widespread transmission, defer the
donation for 8 weeks from the date of departure; for a donor with a history of Ebola infection, defer the
donation indefinitely or until additional data regarding the persistence of the virus in survivors
becomes available; for a donor who has had close contact with any person under investigation for
Ebola infection, or who has been confirmed infected, defer donation for 8 weeks after the last
contact.; and for a donor who has been notified by a public health authority that he or she might have
been exposed to the Ebola virus, defer the donation for 8 weeks following the possible exposure.
41 The findings were reported in a research letter published in the 20 October issue of Journal of the
American Medical Association.
42 Published online 8 December in the Journal of Thrombosis and Haemostasis.
13
plasma (FFP) to reverse warfarin anticoagulation develop pulmonary complications43,
with the highest risk seen with more than three units of FFP44.
7. 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) A study from the Jacobs School of Engineering at the University of California at San
Diego reports that nanoparticles can be an effective delivery system for drugs in the
treatment of cardiovascular disease and systemic bacterial infections.
A biodegradable polymer was used to create the nanoparticle cores as the body can
metabolize them after the drugs are delivered. The engineers disguised nanoparticles
as human platelets. Cloaking also increases binding to the damaged blood vessels
preferentially, meaning they automatically prefer the damaged areas in the body.
b) Researchers at the University of British Columbia have developed self-propelled
particles capable of delivering coagulants against the flow of blood to treat severe
bleeding. Christian Kastrup, an assistant professor in the Department of Biochemistry
and Molecular Biology and the Michael Smith Laboratories said: “Bleeding is the
number one killer of young people, and maternal death from postpartum haemorrhage
can be as high as one in 50 births in low resource settings……. People have
developed hundreds of agents that can clot blood but the issue is that it’s hard to push
these therapies against severe blood flow, especially far enough upstream to reach
the leaking vessels. Here, for the first time, we’ve come up with an agent that can do
that.” The team created gas-generating calcium carbonate micro-particles that are
applied in powder form. They release carbon dioxide gas, to propel them toward the
source of bleeding. The carbonate forms porous micro particles that can bind with the
clotting tranexamic acid, and transport it through wounds and deep into the damaged
tissue.
c) In another experiment Assistant Professor Kastrup and his graduate students injected
platelets with DNA and other ingredients needed to make RNA. The RNA, when
extracted from the platelets and immersed in a soup of cellular biochemicals,
produced proteins that glowed when exposed to certain types of light. This
experiment45 suggests platelets could be fortified with useful genes, eg making
platelets even better at blood clotting, programmed to release more coagulation
enzymes. They could also be developed to release RNA or proteins that decrease
inflammation.
d) Researchers from the Global Medical Science Center at the Fukushima’s Medical
University have signed a Memorandum of Understanding with Pluristem therapeutics
to develop future therapies. They will use Pluristem’s placenta-based PLX-R18 cell
therapy to investigate a treatment for Acute Radiation Syndrome (ARS). “Fukushima
researchers intend to study our cells for repair of bone marrow function within the
context of acute radiation syndrome, and of cancer treatment using high levels of
radiation,” said Karine Kleinhaus, Managing Director of Pluristem. “PLX-R18 cells are
43
including 12 per cent transfusion-associated circulatory overload (TACO), 1per cent transfusionrelated acute lung injury (TRALI), and 7 per cent pulmonary oedema that did not meet the criteria for
TACO
44 After controlling for age, sex, initial systolic blood pressure, and intravenous fluids given in the
emergency department, receipt of more than three units of FFP remained significantly associated with
pulmonary complications.
45 described in an article in the German chemistry journal Angewandte Chemie International Edition
14
designed to repair production of the three blood cell types produced by the bone
marrow: red cells, white cells and platelets.” The research collaboration is supported
by the US National Institutes of Health (NIH), concurrently investigating PLX-R18 in
preclinical tests in animal models. PLX-R18 is Pluristem’s second placental-derived
cell therapy product in development, the other being PLX-PAD. Both are made using
the firm’s patented 3D manufacturing process.
e) In the US, researchers at Lawrence Livermore National Laboratory are using 3D
bioprinting to print 'living' blood vessels. "It's going to change the way we do biology,"
said Lab research engineer Monica Moya, the project's principal investigator. "This
technology can take biology from the traditional petri dish to a 3D physiologically
relevant tissue patch with functional vasculature."
f) A study46 by researchers from Otago and Japan suggests the appetite-regulating
hormone ghrelin could eventually be used clinically for the early treatment of critical
limb ischemia (CLI)47. Otago physiology department researchers Dr Rajesh Katare, Dr
Daryl Schwenke and colleagues have shown administering ghrelin daily over two
weeks markedly improved blood flow in affected limbs. They found ghrelin, also
known as the ‘‘hunger hormone'', promoted growth of new structurally and functionally
normal blood vessels, improved cell survival, and decreased tissue fibrosis. Further
animal-related research will be conducted with human trials some years away.
g) A study by researchers at Griffith University suggests that unconjugated bilirubin 48, an
endogenous antioxidant, may protect the heart against ischemia reperfusion injury49.
“Inflammation is the main culprit of damage to the body, and is caused by over-active
white blood cells that release free radicals. It appears our natural bilirubin can protect
from these free radicals during chronic inflammatory diseases like cardiovascular
disease, kidney disease, and diabetes,” said lead author Andrew Bulmer. “We believe
that this protection could be related to recently identified anti-oxidative property of the
bilirubin molecule.”
8. Legal matters
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) A New Jersey man says Janssen Research sold anti-stroke drug Xarelto without
warning the public of its dangerous potential side effects50. He complained he
developed life-threatening gastrointestinal bleeding on 28 February, some six months
after he started taking the drug. He claims that the defendants negligently and/or
46
Published in the journal Endocrinology
an advanced form of peripheral artery disease, involving the severe obstruction of blood flow to the
extremities. Major amputations are often required, and in half of the cases, death results within five
years. The leading risk factors are diabetes, obesity and age.
48 Bilirubin is the yellow pigmented breakdown product of heme catabolism, caused by the body's
clearance of aged red blood cells, which contain hemoglobin.
49 The study was published in the January 2016 issue of the International Journal of Cardiology.
50
Stuart Elfenbein filed a lawsuit on 23 November in the U.S. District Court for the Eastern District of
Louisiana against Janssen Research & Development, formerly known as Johnson & Johnson
Pharmaceutical Research and Development; Janssen Ortho; Janssen Pharmaceuticals Inc., formerly
known as Janssen Pharmaceutica Inc. or Ortho-McNeil-Janssen Pharmaceuticals Inc.; Bayer
Healthcare Pharmaceuticals Inc.; Bayer Pharma AG; Bayer Corp.; Bayer Healthcare; and Bayer AG,
alleging fraud and negligence. U.S. District Court for the Eastern District Case number 2:15-cv-06264
47
15
fraudulently represented that the drug was tested and found safe. He seeks a jury trial
and damages of more than $75,00051.
9. 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 disease: malaria, chikungunya, dengue, Ross River virus
a) A study of malaria infection among children in the East Sepik Province of Papua New
Guinea suggested a strategy to reduce infections by Plasmodium vivax and
Plasmodium ovale. Study leader was Dr Leanne Robinson of the Population Heath
and Immunity Division of the Walter and Eliza Hall Institute52. Robinson and a
consortium of Australian, Swiss, UK and Spanish researchers showed that adding
primaquine to a cocktail of standard antimalarial drugs dramatically reduces relapse
rates among children. Primaquine targets a phase in the life cycle of both P. vivax
and P. ovale parasites, called a hypnozoite, which lies dormant in liver cells.
b) The Australian Institute of Tropical Health and Medicine at James Cook University in
North Queensland is a collaborating recipient of a grant to further develop a malaria
vaccine. Funds from the Bill and Melinda Gates Foundation will also be with other
scientists in the Walter and Eliza Hall Institute in Melbourne, and in US institutions.
“There is an urgent need for a broadly effective vaccine to attack all strains, species
and life stages of malaria,” AITHM Director Louis Schofield said. “However, this is a
major challenge: five malaria parasite species infect humans, and the parasites are
complex and hard to target. Some forms infect people through the bite of a mosquito;
other forms proliferate in the blood and cause disease, and yet different forms are
passed from human to mosquitoes to complete the cycle. Our prototype vaccine
attempts to overcome these barriers by attacking most species and stages in the
malaria life cycle”.
c) Scientists have produced a strain of mosquitoes carrying genes that block malaria
transmission, with the idea that they could breed with other members of their species
in the wild and produce offspring that cannot spread the disease53. They used geneediting on a species called Anopheles stephensi that spreads malaria in urban India.
"It can spread through a population with great efficiency, increasing from 1 percent to
more than 99 percent in 10 generations, or about one season for mosquitoes,"
University of California-San Diego biologist Valentino Gantz said. One group of
scientists in 2014 said it created a strain carrying a gene leading nearly all offspring
to be male, which could cause wild populations to plummet. In contrast, this new
51
He is represented by attorneys William L. Bross, W. Lewis Garrison Jr., Kathryn Harrington, Taylor
Bartlett and Jeanie Sleadd of Heninger Garrison Davis in Birmingham, Alabama
52 Leanne J. Robinson et al., “Strategies for Understanding and Reducing the Plasmodium vivax and
Plasmodium ovale Hypnozoite Reservoir in Papua New Guinean Children: A Randomised PlaceboControlled Trial and Mathematical Model”, PloS Medicine, 53 The research was published in the
Proceedings of the National Academy of Sciences.
53 The research was published in the Proceedings of the National Academy of Sciences.
16
development only prevents mosquitoes from carrying malaria so should generate
less ecological damage.
d) Researchers at Washington University School of Medicine in St. Louis have identified
in mice “broadly neutralizing” antibodies that protect against infection by multiple,
distantly related arthritogenic alphaviruses – including Chikungunya – that cause
fever and debilitating joint pain54. Senior author Michael Diamond, a professor of
medicine and director of the Division of Infectious Diseases and Vaccine
Development in the Center for Human Immunology and Immunotherapy Programs
said: “What we’ve identified here are antibodies that actually neutralize several
different alphaviruses.” The researchers found ten antibodies that react against three
or more alphaviruses, and also identified a small piece of the alphavirus called an
epitope that is identical across the arthritogenic alphavirus family.
e) A joint research project by scientists at the University of Queensland and the
University of Sydney has discovered a virus, carried by Aedes vigilax mosquitoes,
which may make it harder for them to become infected with disease-causing viruses
such as Ross River virus. Parramatta River virus appears not to infect humans or
animals. The scientists are now looking to see if the same or similar virus is carried
by the Aedes egypti mosquito responsible for transmitting dengue.
f) The number of confirmed cases of Ross River virus rose in Queensland this year. In
the Wide Bay region, for instance, there have been 185 confirmed cases, compared
with 149 in 2014.
Influenza: strains, spread, prevention and treatment
g) At the Ninth Vaccine & International Society of Vaccines Congress in Seoul, Vaxart’s
representatives reported success in two vaccine studies, an oral norovirus vaccine
and an H1N1 influenza tablet. Vaxart CEO, Wouter Latour, said: "The second
presentation highlighted data from a recent Phase 1 clinical study demonstrating that
Vaxart’s H1N1 influenza tablet vaccine generated neutralizing antibodies in 92
percent of subjects after a single dose.” He explained: “Vaxart’s lead programs
include tablet vaccine candidates for seasonal influenza, norovirus and Respiratory
Syncytial Virus. The vaccines are based on a versatile vector-based platform that is
designed to be suitable for a wide range of infectious diseases.” The advantage of
Vaxart’s temperature-stable tablets is that they can be shipped and stored without
refrigeration. They are easier to distribute than injectable vaccines, which can cause
needle stick injury and medical waste.
h) In Expert Review of Vaccines, Dr Michael Jarvis (a molecular virologist from
Plymouth University School of Biomedical Sciences) identified self-disseminating
vaccines as one potential way forward to deal with future pandemics of animal origin,
with potential to cut off such diseases at the animal source before they spread to
human populations. Self-disseminating vaccines use virus-based vectors-viruses that
are unique to individual species but which have no significant impact on that species'
health. This facilitates vaccination across populations where it is difficult to inoculate
every animal.
i) A study at the University of Helsinki suggests that genomic information from
circulating influenza viruses can help in producing better targeted seasonal
vaccines55. Scientists developed an approach for reliable real-time tracking and
prediction of viral evolution based on whole-genome sequences of influenza viruses.
j) Eight countries, including Japan and Morocco, suspended imports of French poultry
after the H5N1 bird flu virus was found in southwestern France, where many foie
JM Fox et al., “Broadly neutralizing alphavirus antibodies bind an epitope on E2 and inhibit entry
and egress”, Cell. online 5 November, 2015
55 Researchers from the Institute for Molecular Medicine Finland analysed thousands of complete
genome sequences of influenza A(H1N1) and A(H3N2) strains representing different geographic
regions. They collaborated with researchers from Singapore and UK.
54
17
gras and poultry producers are located. France has also detected low pathogenic
H5N3 bird flu.
k) Nigeria has been reporting outbreaks of H5N1, and Vietnam has been confirming
outbreaks of H5N6. Human cases of avian influenza A(H7N9) are continuing to occur
on the Chinese mainland.
MERS-CoV (Middle East Respiratory Syndrome-Coronoavirus)
l)
m)
n)
o)
p)
q)
56
At 17 December Saudi Arabia had since 2012 had 1278 cases of laboratoryconfirmed MERS-CoV, including 550 deaths (42.9 per cent) and 728 recoveries (56.9
per cent), to that time. 12 per cent of infections had been acquired in the healthcare
setting as health care workers, 33 per cent had been acquired in the healthcare
setting as patients, 14 per cent had been acquired by household contact, 38 per cent
were primary cases, and 3 percent were unclassified. Globally, since September
2012, the World Health Organisation (WHO) had been notified of 1620 laboratoryconfirmed cases of infection with MERS-CoV, including at least 581 related deaths.
Hemispherx Biopharma Europe NV/SA, received a positive opinion for its new Middle
East Respiratory Syndrome (MERS) treatment from Europe’s Committee on Medical
Products (COMP). COMP recommended that the company’s Alergon N Injection
receive orphan medical product designation for MERS. "Alferon has great
experimental potential as an early onset therapeutic for this dread disease,”
Hemispherx President Tom Equels said. “Hemispherx is dedicated to making Alferon
available for MERS clinical trials, emergency uses and early access programs
consistent with all applicable laws.”
GeneOne Life Science, which partnered with Inovio Pharmaceuticals to develop a
MERS vaccine (GLS-5300) filed an Investigational New Drug Application (IND) for
GLS-5300 with the FDA. The companies expected to move quickly into a phase I
clinical trial in healthy volunteers. In a preclinical study reported in Science
Translational Medicine, the vaccine has been shown to induce 100 per cent
protection from a live virus challenge in mice, camels and monkeys, or non-human
primates. In monkeys, all vaccinated animals in the study were protected from
symptoms of MERS when challenged with a live MERS virus.
Purdue University researchers have identified molecules that inhibit the activity of an
essential enzyme in the MERS virus56.
Studies looking for potential reservoirs for MERS-CoV found that the virus is
widespread in camels57 in Nigeria but not in bats58 in Egypt and Lebanon. The virus
infecting camels in Nigeria is a distinct strain from the virus in the Middle East. In the
bat study, researchers identified other coronaviruses in various samples from wild
bats, but not MERS-CoV.
European scientists have genetically engineered a smallpox virus, Modified Vaccinia
Ankara–MVA, to display Mers virus spike protein on its surface59. The MERS spike
protein is thought to be a major target for the immune response. Scientists believe
that cloaking MVA with this spike would train the immune system to recognize and kill
MERS. The vaccine was able to protect camels from developing MERS symptoms.
Scientists hope to test the vaccine in humans at risk from infection and also to stop
the spread of infection in camels. Another experimental vaccine for camels has
shown some promise, while a new study has found five variants of the MERS
coronavirus to have been circulating between camels and people.
Andrew Mesecar and Arjun Ghosh in the Journal of Biological Chemistry
1o December, Eurosurveillance
58 9 December Emerging Infectious Diseases
59 A report appeared in the journal Science
57
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Ebola virus disease
r) Experts from the [US] National Eye Institute [NEI] travelled to Liberia to investigate
the long-term effects of Ebola on the eye among hundreds of survivors following the
2014 outbreak. Based on literature reports from the 1990s, it was expected that
some survivors of the latest Ebola epidemic would develop uveitis, an inflammatory
eye disease. NEI's investigation is part of a larger study called PREVAIL III
(Partnership for Research on Ebola Vaccines in Liberia) sponsored by NIAID
[National Institute of Allergy and Infectious Diseases] and the Liberian Ministry of
Health. The goal is to understand the long-term health implications of Ebola virus
disease among those who survived acute infection with the virus, many of whom
report a variety of ailments from headaches and tinnitus, to joint and muscle pain,
eye fatigue, and blurry vision. Ebola is known to linger in the eye after a person’s
blood is virus-free. This does not necessarily put other people at risk of becoming
infected because the virus is inside the eye, not on the surface. There is not yet
evidence that live virus is present in survivors' tears. But transmission associated
with the eye could be a concern in the future if eye surgery should be needed.
s) Bavarian Nordic began a new staged Phase III clinical study of the Ebola prime-boost
vaccine (its MVA-BN Filo vaccine) in combination with the Ad26.ZEBOV vaccine from
Crucell Holland, a subsidiary of Johnson & Johnson. The study is designed to
evaluate the safety and immunogenicity of the combination regimen. The trial is
being coordinated by the London School of Hygiene and Tropical Medicine and
sponsored by Janssen, also a Johnson and Johnson subsidiary.
t) Canadian company Medicago was awarded a contract by the Public Health Agency
of Canada (PHAC) to develop two antibodies to fight the Sudan strain of the Ebola
virus. Medicago will produce these antibodies at its facility in Quebec City. This will
build on existing work directed at the Zaire strain which is responsible for the recent
outbreak in West Africa. The Sudan strain has previously been associated with largescale outbreaks in Africa. Medicago's technology uses plants as miniature factories
that can quickly produce large quantities of vaccines or antibodies.
u) Gilead has been working on an experimental anti-viral for Ebola. The Scots nurse
who was readmitted to London’s Royal Free hospital with late complications from
Ebola agreed to receive it. GS-5734, a novel nucleotide analogue in development for
the potential treatment of Ebola, was discovered as part of Gilead’s programme to
screen compounds in its libraries for activity against a range of potential emerging
viruses. Gilead announced that in animal studies treatment initiated on day three
post-infection with Ebola led to 100 per cent survival of the monkeys. The company
went on to initiate a Phase I clinical trial in healthy human volunteers to determine the
safety, tolerability and pharmacokinetics of the drug.
v) A clinical trial of a new Ebola vaccine (ChAd3-EBO-Z)60 has found that it is well
tolerated and stimulates strong immune responses in adults in Mali, West Africa and
in Baltimore61. If the vaccine is found to be safe and effective, it could offer crucial
protection for contacts of patients with confirmed Ebola disease in future epidemics,
helping to interrupt transmission. Larger trials of the vaccine sponsored, by GSK
Biologicals, have already begun.
Other diseases: occurrence, prevention and treatment
w) Sanofi Pasteur launched an injectable trivalent inactivated polio vaccine under the
name ShanIPV. The vaccine will be manufactured by SanofiPasteur’s affiliate
60
developed by the Vaccine Research Center (VRC) of the National Institute of Allergy and
Infectious Diseases (NIAID), part of the US National Institutes of Health, and
GlaxoSmithKline (GSK). Other key partners in the study included the University of Oxford’s
Jenner Institute and the World Health Organization.
61
according to a study published in the journal Lancet Infectious Disease
19
Shantha Biotechnics, based in Hyderabad. A release issued by this company said:
“Keeping with WHO’s Global endgame strategy, India is introducing an additional
dose of IPV at 14 weeks of age. This is to be given in addition to the regular oral
polio vaccine.”
x) In India nine per cent of all paediatric tuberculosis patients are resistant to
rifampicin, one of the first-line drugs used in the treatment of the disease.
20