ASH News Daily 2013 - Day 3 - (Page A-13)
Monday, December 9, 2013
PHARMACOLOGY
Novel Drug Discovery and Development:
More Than Meets the Eye
BY PRASHANT KAPOOR, MD
dition, three acclaimed researchers
masterfully unraveled the modernday
tortuous and complex drug discovery
and development processes
with a focus on novel cancer therapeutics.
Dr. Mark Crowther, McMaster
University, Ontario, Canada,
delved into the intricacies of drug
development pathways that go beyond
the approval of drugs by the
regulatory bodies. Additionally, he
discussed the inherent limitations of
traditional post-marketing surveillance,
the challenges encountered
during such unsupervised phase IV
research, the lessons learned thereof,
and the effective strategies to deftly
overcome such difficulties.
Attendees were also provided a
D
broad overview of the unconventional
near "real-time" pharmacovigilance
programs. Toxicities can
potentially be missed even in the
most well-conducted, large phase III
trials and may come to light only in
the post-approval phase, occasionally
leading to an abrupt and tragic
drug withdrawal in a style reminiscent
of a tragic denouement in a cap-
THROMBOSIS
The Clot Thickens
BY MARC S. ZUMBERG, MD, AND
ANITA RAJASEKHAR, MD, MS
the risk of bleeding, as does anticoagulant
W
e were taught in medical
school that thrombocytopenia
increases
therapy. However,
we know now that both can also
be associated with thrombosis.
Yesterday's session, Updates
in Aggressive Thrombotic Disease,
which will be repeated at
10:30 a.m. in Riverside Rooms
R02-R03 in the convention center,
highlighted some of these
hematologic
paradoxes. Hepa-
rin-induced thrombocytopenia
(HIT), antiphosholipid antibody
syndrome (APLS), and cancer
can all be associated with thrombocytopenia,
yet they are some of
the most aggressive thrombotic
disorders hematologists treat.
These diseases were the focus of
this session.
Chaired by Dr. Wendy Lim,
McMaster University, the session
began with a discussion on HIT by
Dr. Gowthami Arepally, Duke University,
Durham, NC. Heparin use
is ubiquitous in most medical centers,
and the majority of inpatients
are therefore at risk for developing
HIT, which occurs in 0.1 to 5 percent
of hospitalized patients. Dr. Arepally
reviewed the epidemiology
and variable clinical presentations
of HIT. She then focused on a diagnostic
approach aiming to minimize
both the over- and under-diagnosis
of HIT. Dr. Arepally closed her portion
of the session addressing the
pitfalls of current diagnostic testing,
including the high sensitivity but low
specificity of many of the commercially
available ELISA-based assays.
Next, Dr. Lim focused on APLS,
which is defined by venous, arterial,
or obstetric thrombotic complications
in conjunction with persistently
positive antiphospholipid
antibodies. She detailed the specific
clinical and laboratory criteria required
for the diagnosis of APLS.
Dr. Lim stressed the differing throm-
botic risks based on the laboratory
pattern of antiphospholipid antibodies.
Catastrophic APLS (CAPS),
multi organ failure occurring over
a short-time period and with histopathologic
evidence of small vessel
occlusion, was also reviewed. Dr.
Lim finished with the controversies
involving the length of anticoagulation,
intensity of anticoagulation,
and other adjunct therapy for both
APLS and CAPS.
Finally, Dr. Charles Francis, University
of Rochester Medical Center,
NY, covered the hot topic of thrombosis
and cancer, which was recently
the focus of a series of articles in the
Blood journal. One in five VTEs occur
in cancer patients, and VTE is
the second leading cause of death,
morbidity, delays in care, and cost
in this group. Dr. Francis reviewed
patient-related, cancer-related, and
treatment-related factors that help
predict thrombotic risk and better
guide prophylactic anticoagulation.
He shared with me that the real
difficulty in treatment is that these
patients have "frequent recurrences,
yet significant bleeding
complications, as well as side effects
of chemotherapy including
thrombocytopenia." The session
ended with a review of the data
highlighting the superior efficacy
of LMWHs over VKA antagonists
and approaches to difficult
treatment scenarios.
These talks each illustrated
aggressive thrombotic conditions
we routinely care for as
hematologists. Each talk focused
on prognostic models or risk
factors to help predict risk and
therefore minimize occurrence.
Further, management and treatment
decisions concerning each
of these conditions were highlighted.
This
session
should
be considered a "must see" for
anyone treating these difficult
thrombotic disorders.
Dr. Zumberg and Dr. Rajasekhar
indicated no relevant conflicts of interest.
uring yesterday's session, A
Fresh Look at Drug Approval:
Moving Away from Tra-
tivating country story.
The goal of expeditious drug development
for diseases with limited
effective therapies may be a lofty
one, but not uncommonly reached
in the current era of novel therapeutics.
Dr. Crowther also reviewed two
crucial FDA programs, the "breakthrough
therapies" and "accelerated
approval," that are critical for granting
fast drug access to patients. Indeed,
cancer drugs can get fast-track
approval using such programs specifically
designed for diseases with
an unmet need for effective therapies,
without compromising the
punctiliousness of our traditional
protocols. His talk culminated with
an illustrative example of a recently
approved oral anticoagulant, dabigatran
etexilate.
Dr. Victoria Richon, Sanofi On-
cology, Cambridge, MA, beautifully
outlined the impediments
and opportunities associated with
drug discovery for rare diseases.
Ironically, many such rare diseases
are all too familiar to 2013 annual
meeting attendees. Dr. Richon took
the audience back to 1983 when the
Orphan Drug Act (ODA) that catapulted
the growth of drugs for rare
diseases was introduced. Her talk
was peppered with examples of
cancer drugs that received marketing
approval in the last few years.
She also highlighted the four crucial
steps involved with the drug
discovery process: a) identification
of a "druggable" molecular target
that drives the cancer subtype; b)
pre-clinical validation of the target;
c) selection of a drug candidate that
inhibits the molecular target utilizing
cell-based and animal models;
and d) bringing the drug from
bench to the bedside by testing the
identified drugs in patients from
defined cancer subpopulations.
Using this four-step approach, she
elucidated the development of one
such class of drugs, the DOT1L inhibitors
targeting methyltransferase
activity of the unique enzyme
DOT1L that plays a significant role
in mixed lineage leukemia (MLL)AF9
driven leukemogenesis and is
identified as a therapeutic target.
To quote another speaker at the
session, Dr. Michael Grever, Ohio
State University Comprehensive
Cancer Center, "We want to accelerate
drug development, but we
don't want to compromise safety."
Dr. Grever guided the attendees
through the ideal approach to safe
drug development and approval.
Post-marketing experience merely
reflects the tip of the iceberg and
often belies the arduous process
of a successful drug development,
which is typically associated with
a staggering price tag. The "target"
audience (no pun intended) appreciated
the labor-intensive process of
drug development.
An apt case in study would be
that of chronic lymphocytic leukemia
(CLL) therapeutics, exemplifying
the rather checkered and
celebrated history of the drug development
process. Fludarabine,
a purine analog, has been the cornerstone
of CLL treatment for over
two decades. Ibrutinib, a Bruton's
tyrosine kinase inhibitor that has
recently been approved for mantle
cell lymphoma, is a promising
anti-CLL therapy as well and has
received "breakthrough therapy"
status, a coveted trophy of sorts,
granted by the FDA to a select few,
with the sole aim of streamlining
the development process.
If you missed the session, you can
attend the repeat session this morning
from 10:30 a.m. to 12:00 noon
in Room 243-245 at the convention
center.
Dr. Kapoor indicated no relevant
conflicts of interest.
ASH NEWS DAILY
Page A-13
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