Download Developing a cure for Black Bone Disease

A layman’s guide to
AKU research
Hana and Oliver
1. Overview of AKU
2. Nitisinone
3. Drug development
4. Other therapies
1. Overview of AKU
How AKU is inherited
Why HGA is so damaging
Q&A
A brief introduction to genetics
Genes are
recipes
On how to
make proteins
Some proteins
are enzymes
Enzymes break
down or
combine
substances to
create news
ones
What happens when things go wrong?
A mutated
gene
Damaged
protein
Enzymes
don’t work
properly
Certain
substances
aren’t
broken down
or created
What does the enzyme normally do?
Protein
Phenylalanine
Tyrosine
Hydroxylphenylpyruvic
Hydrozylphenylpyruvic acid
Homogentisic acid
Maleylacetoacetic acid
Carbon dioxide and water
How do enzymes work?
How do enzymes work?
How do enzymes work?
Where do mutated genes come from?
•Mutations can be:
•Spontaneous
•Inherited from parents
•Over 80 different mutations can cause AKU
•AKU is recessive
•Need to inherit a copy of mutated gene from each parent
•People with only 1 copy are called carriers
•Carriers do not have any symptoms
How is the mutated gene inherited?
MUM
25%
M
D
CARRIER
DAD
25%
M
D
CARRIER
25%
M
D
NON-CARRIER
25%
M
AKU
D
Distribution around the world
Why is HGA so damaging?
•HGA accumulates at 2,000 times the normal rate
•It combines with oxygen to form a black pigment
•This black pigment attaches to cartilage, turning it
black and brittle in a process called ochronosis
•Ochronotic cartilage is more prone to wear and tear
causing joint deterioration
Why is HGA so damaging?
•Ochronosis can also harden the vessels and valves in
the heart which makes them less effective at
managing the flow of blood
•The pigment can also form stones in the kidneys,
bladder or prostate
Any
questions?
2. Nitisinone
How nitisinone works
The AKU animal model
Off label use
Q&A
How does nitisinone work?
Protein
Phenylalanine
Tyrosine
Hydrozylphenylpyruvic acid
Homogentisic acid
Maleylacetoacetic acid
Carbon dioxide and water
The animal model and other research
•University of Liverpool looked at how AKU mice responded
to nitisinone
•Mice on nitisinone had reduced HGA in the blood and less
pigmentation in their knee joints
•If nitisinone was given early enough, mice developed no
signs of AKU
•Research at the NIH showed nitisinone lowered HGA levels
by up to 95%
Off label use
•When a drug approved in condition A is used in condition
B
•Nitisinone is approved for use in HT-1 but is used off label
in AKU
•In the UK allowed if in patients’ best interest
•Prescriber has greater legal responsibility
•May be funding restrictions
Why is off label use not enough?
•Policies on off label use vary between countries and
regions
•No guarantee off-label use will continue
•Especially as health budgets are tightened
•Clinical trials will increase our understanding of how
nitisinone and AKU interact
Any
questions?
3. Drug Development
4 stages of drug development
Control groups
Safety measures
Why is DevelopAKUre different?
Q&A
Growing up  from lab to pharmacy shelf
Foetus
(preclinical)
Baby
(Phase I)
Child
(Phase II)
Teenager
(Phase III)
Young adult
(Phase IV)
Foetus – preclinical
•Clinical loosely means ‘in humans’
•Pre clinical research is everything done before human research
•Includes animal and cell models
•Shows whether the drug works in these models
•Provides important safety information
•Whole idea of the drug is new and fragile
•Very distant possibility the drug could grow up to save lives
Baby – Phase I
•Beautiful new baby is ready for
testing in the human world
•Safety is a major concern – needs
constant monitoring
•Drug is tested in small group of
healthy volunteers
•An optimal dose is identified
•Nitisinone was tested in 10 healthy
volunteers during development for use
in HT-1
Child – Phase II
•More experienced in the world
•Can give your drug more of a free reign
•But you still need to make sure it’s safe
•Time to see what your drug can really do
•Does it work in your target disease?
•Drug is tested in larger group of patients with the disease
Teenager – Phase III
•You’re now fairly sure the drug works but just how
well?
•Phase III trials are in very larger groups including
1000s of patients
•Different in rare diseases
•E.g. SONIA 2 includes 140 patients
•Drug is beginning to pave its way in the world
•Still keeping a close eye to make sure there are no surprises
•Most expensive, time consuming and difficult phase
•If successful – can apply for approval
Young adult – Phase IV
•Drug is now grown up and fairly self-sufficient
•Many people are monitoring it but ultimately your responsibility
•Continue to monitor safety
•Sometimes require phase IV trials
Need for a control group
•Gold standard of clinical trials is the randomised controlled
trial
•Randomised: randomly allocated into groups
•Controlled: Match treated group with a non-treatment
group
•Placebo group often used to remove placebo effect
•Exceptions e.g. SONIA studies
Safety measures in clinical trials
•Lab experiments and previous research in humans
Getting a trial approved
•Trial protocol
•Submission to regulator and ethics committees
During the study
•Regular monitoring by researchers
•Data Monitoring Committee
Why is DevelopAKUre different?
•Larger group of patients: 140 vs 40
•Longer trial: 4 years vs 3 years
•Multiple endpoints
•Advice from the European Medicines Agency
Any
questions?
4. Other therapies
Enzyme therapy
Gene therapy
Q&A
How else could we treat AKU?
Quick recap:
•AKU is caused by a mutated gene which produces a
faulty enzyme
•Nitisinone works by stopping the enzyme earlier in the
chain
Alternatives:
•A: Inject the working enzyme – this is enzyme therapy
•B: Replace the faulty gene so it makes the working
enzyme – this is gene therapy
Which is better?
Gene therapy
Enzyme therapy
•Effectively a total cure
•Give patients functioning
•Patients would start producing
enzyme which allows them to
their own enzyme in the same
break down HGA
way people without AKU do
•But would still produce faulty
•But is a very new technology
enzyme so there would be a
•First gene therapy was only
mix of functioning and faulty
approved in 2012
enzymes
•Would need to be given
regularly
Current research into enzyme therapy
•Working with Protein Technologies
•Dr Farid Khan from the University of
Manchester
•Has been tested in the animal model
and results have been good
•Mice had reduced HGA levels
•But the enzyme needs to be stored
carefully as it lasts for a short time after
being made
Next steps with enzyme therapy
•Testing a different method for producing the enzyme so it
lasts longer
•Will then need to test it again in the animal model
•If results are positive  apply to start tests in human
volunteers
•Will probably be at least 10 years until approval for
treating patients
Current research into gene therapy
•Working with Dr Richard Harbottle from
the German Cancer Research Centre in
Heidelberg
•2 types of gene therapy – viral and non
viral
•Have created a liver specific vector
•Animal model showed enzyme was
produced but only lasts for a few days
Next steps with gene therapy
•Next steps similar to enzyme therapy
•Planning to produce another longer lasting vector
•Test again in animals before humans
•At least 10 years before it will be approved
•The AKU Society are working on a joint funding application
for both projects
Any
questions?
Thank you
for listening