UP FRONT
Pulling Back the Curtain: Robert P. Gale, MD, PhD
attack; I never tried this approach but recommend The New York Times if the occasion
arises, so at least you will finish your days
with high-quality journalism!
My first visit to the Soviet Union was in
1974, during the darkest days of the Cold
War, and these visits continued frequently. I
have many talented Russian colleagues with
whom I continue to collaborate on consequences of the Chernobyl nuclear power fa-
cility accident in 1986. I have similarly close
relationships with Japanese colleagues with
whom I collaborated after the Tokaimura
and Fukushima accidents and with Brazilian
colleagues after the Goiania accident.
Interestingly, bone marrow transplantation and the discovery of molecularly
cloned hematopoietic growth factors resulted from efforts to deal with the threat of
nuclear war. Today we use these technolo-
gies to save lives, perhaps a fulfillment of
the Bible verse, Isaiah 2:4, “and they shall
hammer their swords into plowshares.”
So, it is only logical my colleagues and
I would use these technologies to rescue
victims of nuclear and radiation accidents.
We all need to remember that when it
comes to nuclear weapons and nuclear
power facilities, as in all of medicine, prevention is better than cure.
ADYNOVATE [Antihemophilic Factor (Recombinant), PEGylated]
Lyophilized Powder for Solution For Intravenous Injection
Brief Summary of Prescribing Information: Please see package insert for full Prescribing Information.
INDICATIONS AND USAGE
ADYNOVATE, Antihemophilic Factor (Recombinant), PEGylated,
is a human antihemophilic factor indicated in adolescent and
adult patients (12 years and older) with hemophilia A
(congenital factor VIII deficiency) for:
• On-demand treatment and control of bleeding episodes
Table 2: Adverse Reactions Reported for ADYNOVATE
MedDRA
Preferred
Term
Number of
Subjects n (%)
(N=169)
Percent per
Infusion
(N = 13579)
Diarrhea
1 (0.6%)
0.01%
Nausea
2 (1.2%)
0.01%
Nervous System Disorders
Headache
5 (3.0%)
0.06%
Vascular Disorders
Flushing
1 (0.6%)
0.01%
MedDRA
System Organ Class
Gastrointestinal Disorders
• Routine prophylaxis to reduce the frequency of bleeding episodes
ADYNOVATE is not indicated for the treatment of
von Willebrand disease.
CONTRAINDICATIONS
ADYNOVATE is contraindicated in patients who have had prior
anaphylactic reaction to ADYNOVATE, to the parent molecule
(ADVATE), mouse or hamster protein, or excipients of ADYNOVATE
(e.g. Tris, mannitol, trehalose, glutathione, and/or polysorbate 80).
WARNINGS AND PRECAUTIONS
Hypersensitivity Reactions
Hypersensitivity reactions are possible with ADYNOVATE.
Allergic-type hypersensitivity reactions, including anaphylaxis,
have been reported with other recombinant antihemophilic factor
VIII products, including the parent molecule, ADVATE. Early signs
of hypersensitivity reactions that can progress to anaphylaxis may
include angioedema, chest tightness, dyspnea, wheezing, urticaria,
and pruritus. Immediately discontinue administration and initiate
appropriate treatment if hypersensitivity reactions occur.
Neutralizing Antibodies
Formation of neutralizing antibodies (inhibitors) to factor VIII can
occur following administration of ADYNOVATE. Monitor patients
regularly for the development of factor VIII inhibitors by appropriate
clinical observations and laboratory tests. Perform an assay that
measures factor VIII inhibitor concentration if the plasma factor VIII
level fails to increase as expected, or if bleeding is not controlled
with expected dose.
Monitoring Laboratory Tests
• Monitor plasma factor VIII activity by performing a validated onestage clotting assay to confirm the adequate factor VIII levels have
been achieved and maintained [see Dosage and Administration (2)].
• Monitor for the development of factor VIII inhibitors. Perform the
Bethesda inhibitor assay to determine if factor VIII inhibitor is
present. If expected factor VIII activity plasma levels are not
attained, or if bleeding is not controlled with the expected dose of
ADYNOVATE, use Bethesda Units (BU) to determine inhibitor levels.
ADVERSE REACTIONS
Common adverse reactions (≥1% of subjects) reported in the
clinical studies were headache and nausea.
No events of hypersensitivity were reported.
Immunogenicity
The risk of the development of factor VIII inhibitors with the use of
ADYNOVATE was evaluated in 2 completed and 3 ongoing clinical
trials. Study subjects consisted of adult (n=143 with ≥ prior 150 EDs)
and pediatric PTPs [(< 6 years of age with ≥50 prior EDs (n= 3),
≥6 years of age with ≥150 prior EDs (n= 23)]. In 120 adult and pediatric
PTPs who were treated for at least 50 exposure days with ADYNOVATE,
the factor VIII inhibitor frequency was 0 (95% CI of 0 to 0.03) for the
risk of any factor VIII inhibitor. None of the 169 individual subjects
who received at least one infusion of ADYNOVATE developed
neutralizing antibodies to factor VIII.
Immunogenicity also was evaluated by measuring the development
of binding IgG and IgM antibodies against factor VIII, PEGylated
(PEG)-factor VIII, PEG and Chinese hamster ovary (CHO) protein
using validated ELISA assays. None of the 169 treated subjects with
at least one infusion of ADYNOVATE developed a persistent binding
antibody response to any of these antigens. Thirteen subjects in total
showed pre-existing antibodies to factor VIII (n=1), PEG-factor VIII
(n=12) and/or PEG (n=3) prior to the first exposure to ADYNOVATE.
Eight subjects who tested negative at screening developed
transient IgG antibodies against factor VIII (n=5), or PEG-FVIII (n=3)
at one or two consecutive study visits. Binding antibodies that were
detected prior to exposure to ADYNOVATE or that transiently
developed during the study could not be correlated to an impaired
treatment efficacy, altered PK parameters or adverse reactions.
No subject had pre-existing or treatment-emergent antibodies to
CHO protein.
The detection of antibodies that are reactive to factor VIII is
highly dependent on many factors, including: the sensitivity
and specificity of the assay, sample handling, timing of sample
collection, concomitant medications and underlying disease.
For these reasons, comparison of the incidence of antibodies to
ADYNOVATE with the incidence of antibodies to other products
may be misleading.
Clinical Trials Experience
Because clinical trials are conducted under widely varying
conditions, adverse reaction rates observed in the clinical trials
of a drug cannot be directly compared to rates in clinical trials of
another drug and may not reflect the rates observed in practice.
The safety of ADYNOVATE was evaluated in 169 previously treated
patients (PTPs) with severe hemophilia A (factor VIII less than 1% of
normal), who received at least one dose of ADYNOVATE in 2 multi-center,
prospective, open label clinical studies and 3 ongoing clinical studies.
The median duration of participation per subject was 333 (min-max:
1-593) days and the median number of exposure days to ADYNOVATE
per subject was 96 (min-max: 1-170). Table 2 lists the adverse
reactions reported during clinical studies.
Baxalta, Advate, Adynovate, and Baxject are trademarks of
Baxalta US Inc.
Patented: see www.baxalta.com/productpatents/.
Baxalta US Inc.
Westlake Village, CA 91362 USA
In a typical day, what is your rose
and what is your thorn?
Obviously, the rose is my wife. And, the
thorn, or the greatest challenge to me, is
participating in dumb things. Remember bank robber Willie Sutton’s amazement when an FBI agent ask him why he
robbed banks? His reply, “That’s where
the money is.”
Perhaps the politically correct way to
say this is “poorly done work that
consumes resources, time, and careers, but that can’t possibly reach
definitive answers.” There’s a saying
that “No science is better than bad
science,” and I’ve learned how true
that is over the course of my career.
And I’m not exactly sure where to
place the daily two hours of brushing
and flossing.
What accomplishments are you
most proud of in your career?
The philosopher Bertrand Russell
said, “Most people would rather die
than think; many do.” I hope some of
my analyses and writings have caused
people to think more critically about
the substantial challenges we face in
hematology and oncology.
More concretely, I’m proud of
our accomplishments in the fields
of leukemia therapy and bone marrow transplantation. I am especially
proud of the work my colleagues
at the Center for International
Blood and Marrow Transplantation
(CIBMTR), led by Mary Horowitz,
MD, have done – coordinating the
contributions of hundreds of transplant experts from more than 60
countries.
I am also pleased that my colleague Eli Canaani, PhD, of the
Weizmann Institute of Science in
Israel and I were able to molecularly clone BCR/ABL1, the gene that
causes chronic myeloid leukemia.
That information led to the development of drugs that come close to curing this disease in some people.
Those are my greatest accomplishments in medicine, but, of
course, my greatest accomplishment
in life is my family.
How do you spend your time
outside of medicine?
With my wife and our children. I
have six beautiful girls, so keeping
suitors away is a full-time job. I’ve
started taking lessons from Ulysses
and Telemachus.
When not discouraging suitors
or brushing and flossing, I swim, jog,
snowshoe, ice climb, ski, kayak, and
skydive – one at a time, though. ●
U.S. License No. 2020
Issued 11/2015
15E001-ADY-US
June 2016