Drug repurposing Applying yesterdays solutions to tomorrows problems
[Applause]
reduce
reuse repurpose and recycle these words
have been ingrained in our minds as we
face the reality of our overflowing
landfills
in an attempt to combat this issue we’ve
been encouraged to look for alternative
uses for the physical materials around
us
and these ideas have ranged from
promoting the purchase of secondhand
clothing
all the way to discovering new ways to
repurpose plastic into bags
shoes and clothes and as a result we’ve
been able to implement several
successful
recycling strategies in many different
fields
but what if we could apply these same
principles to the pharmaceutical
industry
particularly in the field of drug
development currently
it takes over a decade and billions of
dollars to bring a successful drug to
the marketplace
implementing these same recycling
strategies would allow us to bypass
a large portion of the time and cost
associated with traditional drug
development
and ultimately allow us to get effective
treatment to patients
faster i was first introduced to the
idea of drug repurposing
when i first started my research career
and i joined a lab that was focused on
developing a combination therapy
for the treatment of pancreatic cancer
as our understanding of the human body
has expanded we’ve learned that it can
be best described as an integrated
network with
continuous interactions both within and
between organ systems
and as a result we’ve shifted away from
studying diseases as isolated
stand-alone conditions
and towards a more holistic approach
involving the entire body
this interconnectedness of the body can
be seen on the potential side effects
list
of any potential medication a patient
comes into the clinic with symptom a
and is given drug a to treat symptom a
except drug a causes side effects
b to f and so now this patient has to
take additional medication
to treat these additional side effects
and this process can go on and on
oftentimes resulting in a patient taking
a string of medication
now for me studying pancreatic cancer we
know that it’s a complex collection of
diseases characterized by
inflammation and the onset of diabetes
as a lab
we believe that we could take advantage
of the interconnectedness of the body
and that if we developed what we call a
drug cocktail we’d be able to come up
with an effective treatment for the
disease
through reviewing what was already out
in the literature some trial and error
and a little bit of luck
we were able to successfully narrow down
our efforts into just three drugs
success in basic cell studies had us
curious to try to translate our results
to pre-clinical animal trials
and for me this was an important part
important component during my research
career as it was the first time that i
was able to see firsthand the direct
benefit of research
i saw as the my screw tumors and then i
watched the tumors began to shrink
following treatment
and we consistently achieved better
results that is
smaller tumor volumes in animals that
received our drug cocktail
compared to those that received
chemotherapy alone
now what was most amazing about our
results is that our drug cocktail
consisted of only repurposed drugs and
actually you may already know some of
these drugs
like aspirin the anti-inflammatory
you’ve either already used before or at
least have in your medicine cabinets
metformin the anti-diabetic drug and
tamiflu
the antiviral drug often prescribed for
the common flu
and although we were amazed that we were
able to achieve such success with
our repurposed drug cocktail we still
weren’t exactly sure how or why we saw
what we did
and this is something that’s always
puzzled me about the drug research field
we don’t always know how drugs work we
don’t know their complete mechanism of
action from start to finish
oftentimes we just know that they do and
this is the case with tylenol
tylenol is one of the most widely used
pain relievers in the world
and it might surprise you that we don’t
know its complete mechanism of action
we know that it does work and it works
well and we keep taking it and
keep prescribing it now coming from a
family of engineers
i have been wired to be curious and want
to know how and why things work the way
that they do
consequently i set out to figure out how
the components of a drug cocktail worked
and more specifically how they worked in
their newly discovered anti-cancer roles
so aspirin like i mentioned was a
crucial component of our drug cocktail
and although it’s been reported to have
some anti-cancer effects
we aren’t really sure how or why beyond
cancer being associated with
inflammation
and aspirin being an anti-inflammatory
but it was through a rather
serendipitous accident in an experiment
that revealed that aspirin was able to
effectively shut down a critical
cancer-promoting pathway
further analysis revealed that we may in
fact have found a new target
and effect for one of the most widely
available drugs in the market
and it was what i like to call this
happy accident that highlighted the
impact and importance of drug
repurposing
that became the reason i chose to
continue my graduate studies
now the idea of drug repurposing isn’t
brand new it’s been around for years and
it’s been gaining interest due to the
time and cost associated with
traditional drug development
broadly drug repurposing consists of two
crucial components
the first is taking pre-existing
knowledge or technology
that’s approved for use in one condition
and second
is applying it to a new disease or
condition and this is based off of the
idea of polypharmacology
and this is where one drug can have
multiple targets or effects due to
multiple mechanisms of action
and then given the interconnectedness of
the body these targets can be further
interacting
potentiating the effect of a given drug
and now the process of figuring out
which drugs can have these multiple
effects or actions can vary whether it’s
similarities in the disease or
similarities in the drug structure
but most common are those happy
accidents like mine where by chance a
drug is found to have another effect
and this is exactly the case with
selenophil sultanafil was originally
developed
for the treatment of hypertension but it
was a happy accident that was occurring
during clinical trials that revealed
a rather interesting side effect and
this happy accident ended up being the
persistent erections during clinical
trials
which ultimately led to the repurposing
into viagra for the treatment of
erectile dysfunction
but it doesn’t stop there because the
same compound has been further
repurposed under a different dosing
schedule
as ravagio for the treatment of
pulmonary arterial hypertension
and even that doesn’t stop there because
more recently the same compound is
currently being investigated
for the treatment of certain types of
cancers now
not all drugs that are successfully
repurposed come from
happy accidents during clinical trials
some fail in their original condition
for example thalidomide was originally
developed for the treatment of morning
sickness
but the occurrence of serious birth
defects had it quickly withdrawn from
the market
it wasn’t until we had a more careful
look at the chemical structure of the
compound that we were able to show
that it was an effective treatment for
leprosy and even more recently it’s been
approved for the treatment of multiple
myeloma
now when we talk about using repurposed
drugs we don’t necessarily mean
taking them in the same way shape or
form as we have in the past
oftentimes the dose or the dosing
schedule changes
and this is an idea that precedes the
concept of drug repurposing
and actually dates all the way back to
the 16th century
it was paracelsus the father of
toxicology who said
all substances are poisons there is none
which is not a poison
the right dose differentiates a remedy
from a poison
and this is why the idea of dose and
dosing schedule is a crucial component
of the complex drug discovery stage
and although this id this process can be
complicated it can be divided into
several steps through stages
the first being drug discovery drug
discovery is where as many as 10 000
potential candidates are screened
any promising candidates are then tested
in pre-clinical animal studies
and they are monitored for potential
effects or safety for testing in humans
the next step is the clinical phase
where promising drugs are tested
in patients and phase one trials is many
um the drug is tested in a healthy
patient population
this is to ensure that the drug doesn’t
cause more harm than it does good
the fda estimates that only about half
of the drugs pass phase one studies
in phase two trials the drug is tested
in the target population
and is monitored for any potential side
effects only about a half
only about a third of these drugs passed
the space two trials successfully
and finally in phase three studies the
drug assessed in a larger target
population
to ensure that an optimal dosing
schedule has been achieved
only a quarter of drugs passed this
phase successfully this clinical portion
takes on average seven years and results
into just one or two potential
candidates
these candidates are then sent to the
fda for potential review and hopeful
approval
and this process alone can take two
years and even if a drug is granted fda
approval there’s still long-term
following or monitoring or a phase four
trial to ensure that there is safety in
real world use
collectively this drug discovery process
adds to a staggering 12 years and over 2
billion dollars
and this includes the cost of all the
drugs that don’t gain fda approval
so given these daunting success rates or
high failure rates high costs and a slow
pace of drug discovery
drug repurposing has become a more and
more attractive alternative
as it involves the use of de-risked
compounds so to put things into
perspective
repurpose drugs gained approval in a
shorter time span of three to seven
years
and at less than 60 percent of the cost
of new drugs that enter the market
and this is because the pre-clinical and
early clinical trials provide
invaluable information on the toxicity
and tolerability
which translates to a greater than 30
percent success rate for repurposed
drugs
compared to the less than 10 success
rate of new drugs entering the clinical
stage of development
but despite these promising numbers drug
repurposing is still associated with its
own set of challenges
the first and potentially most important
is a long-standing skepticism
people particularly patients can be
reluctant or skeptical to believe that a
drug
especially a generic drug can do
anything other than what they’ve
believed it to do for years
it’s important that we adopt a more
open-minded approach to drug
repurposing as patient education is a
crucial component for therapy success
two other bottlenecks associated with
generic drug repurposing that seems to
go hand in hand
are financial incentive and intellectual
property or patents
we’re at the point where generic drug
repurposing is considered to be in a
state of purgatory
and this is likely due to the lack of
financial incentive
which is a major driving force for
getting a drug to the market
there is no current way for a
pharmaceutical company to charge a
higher price for a drug to treat a new
condition
while patients can continue paying a
lower price to treat the original
condition
and this is likely why no generic drug
has been repurposed
without modification of its dose or its
dosing schedule
both of which would provide patent
protection however
most of the repurposing uses for generic
drugs have already been reported in the
literature
and this public disclosure reduces
palatability
and no patent means no profit and no
profit
means no incentive and even if a method
of use patent can be secured for a new
use for a generic drug
there still might not be any profit
especially if this drug is available for
many manufacturers
as a physician can just as easily
prescribe another manufacturer’s drug
until a payment system is implemented
that allows the company
to reasonably recover its investment on
repurposing a generic drug
generic drug repurposing will not
effectively take place in the
pharmaceutical industry
now it’s evident that these challenges
can’t be overcome by quick fixes
and rather require a collaborative
effort between the pharmaceutical
industry and regulatory officials
but it’s important that we don’t let
these challenges distract us from the
main issue at hand
and the main goal of healthcare which is
to get effective treatment
to patients faster fortunately though we
are moving in the right direction
we need to continue to push for
preliminary findings of repurposed
generic drugs into the clinic
where they can continue to help people
and this is where advocacy groups
non-profits
and foundations play a big role this
generated interest
has pushed us further in the right
direction and we’ve come up with
innovative ways to even further expedite
this process
it’s the breadth and depth of scientific
knowledge available to us from
pre-clinical and clinical trials in
combination with
technological advancements that now
actually permit us to mine information
and in this way we can engineer those
happy accidents that match a generic
drug
to a new target as opposed to only
relying on the serendipitous process
that it once was
so now you may be thinking how you can
play a role in this well in addition to
this being a crash course on drug
repurposing
i hope that this sparked your curiosity
into the untapped potential
of the drug that we may already have in
our medicine cabinets together
with regulatory bodies private companies
academic groups
and non-profits we can collectively
assemble those puzzle pieces necessary
to get the effective treatments to the
patients that need them most
so instead of approaching drug discovery
as each of us ripping a page from our
notebooks and starting from scratch when
something doesn’t work
let’s apply those same recycling
principles and bring those pages
together
and effectively complete the puzzle of
successful treatment of diseases
thank you
you