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