Transcript Jennifer Farmer, MS, CGC Coordinator, Collaborative Clinical Research Network in FA Executive Director, FARA (484) 875 3015 [email protected] Pathway to Clinical Trials.

Jennifer Farmer, MS, CGC
Coordinator, Collaborative Clinical Research
Network in FA
Executive Director, FARA
(484) 875 3015
[email protected]
Pathway to Clinical Trials
Finding treatments and curing a rare disease
• Understanding the
mechanisms
• Drug discovery
• Identify compounds,
drugs, technologies
that can be used to
slow, stop and reverse
the dx
• Drug development
•
•
•
•
Optimizing compound
Pharmacokinetics
Toxicology
Manufacturing
• Clinical research and
trials
• Understand the
disease in patients
and how to measure
change
• Testing safety and
efficacy of the drug in
patients
A Decade of Progress
1996 - 1999
• FA gene
identified
• Diagnostic
Test for FA
• 1st major
Break-through
in
understanding
the cause of
the disease
2000-2003
• Elucidation
of disease
process
• Reduced
amounts of
frataxin
• Altered iron
metabolism
• Impaired
energy
production
3
2004-2007
• Drug
discovery and
development
• Collaborative
Clinical
research
network
• Clinical Trials
FA Treatment Pipeline - 2004
1 Clinical Trial
3 Potential Treatments/Approaches
Available to
Patients
Phase III
Research
(Finding Potential
Therapies/Drugs)
Iron Chelator
(Testing in
Laboratory)
Edison
Pre-Clinical
A0001
Phase I
(Human Safety
Trial)
Idebenone
Phase II
(Human Safety and
Efficacy Trial)
Santhera
(Definitive Trial)
Decrease Oxidative
Stress
and/or Increase
Mitochondrial
Function
Decrease
Iron
Toxicity
Increase
Frataxin
Expression
(Compounds)
Research
(Finding Potential
Therapies/Drugs)
Decrease Oxidative
Stress
and/or Increase
Mitochondrial
Function
Decrease
Iron
Toxicity &
Increase
Fe-S
clusters
NIH/Harvard
Multiple Groups
Epigenetic
Increase
Frataxin or FA gene
Expression
Gene
Therapy
Frataxin
NeuroProteinprotection
Replacement
NeuroTransmission
Modifying
Therapy
FRDA Gene
Transcription
Frataxin
Mitochondrial
Function
MD Anderson, Houston, TX & Murdoch Children’s
Research Institute, Australia
Mayo Clinic, Rochester, MN
University of Pennsylvania
&University of California, Davis
University of South Florida
And Children’s Hospital of Phila
Lundbeck
7 Clinical Trials
8 Approaches
Varenicline / Chantix
Lu AA24493 (cEPO)
Wells Center for Pediatric Research, Indianapolis, IN
University of Minnesota and Mayo Clinic
TAT Frataxin
University of Madrid and University of Oxford
HSV-1 FRDA
Mt Gene
Therapy
University of Pennsylvania
Scripps Institute, La Jolla, CA
RNAi
ApoPharma
MUV, Austria & Other groups
HDAC - New
HDAC - Leading
EPO & EPO mimetics
Fe-S clusters
Iron Chelator – Deferiprone
IPSEN
Pre-Clinical
(Testing in
Laboratory)
EGb761
Repligen
Phase I
(Human Safety
Trial)
INSERM - Hôpital Robert Debré
Phase III
(Definitive Trial)
Pioglitazone
Penwest
Phase II
(Human Safety
and Efficacy Trial)
A0001
Santhera
Available to
Patients
Idebenone
FA Treatment Pipeline - 2009
FARA has supported, and is supporting, these efforts by
providing various combinations of direct funding, essential
clinical infrastructure, advocacy and awareness efforts.
High-Throughput
Screening for New
Drug Discovery
FA Treatment Pipeline - 2009
FARA has supported, and is supporting, these efforts by
providing various combinations of direct funding, essential
clinical infrastructure, advocacy and awareness efforts.
Available to
Patients
Decrease Oxidative
Stress
and/or Increase
Mitochondrial
Function
Decrease
Iron
Toxicity &
Increase
Fe-S
clusters
Frataxin
NeuroProteinprotection
Replacement
NeuroTransmission
Modifying
Therapy
MD Anderson, Houston, TX & Murdoch Children’s
Research Institute, Australia
FRDA Gene
Transcription
Mayo Clinic, Rochester, MN
Frataxin
University of Pennsylvania
&University of California, Davis
University of Minnesota and Mayo Clinic
Gene
Therapy
Mitochondrial
Function
University of Madrid and University of Oxford
Multiple Groups
Increase
Frataxin or FA gene
Expression
HSV-1 FRDA
Research
(Finding Potential
Therapies/Drugs)
RNAi
Fe-S clusters
Pre-Clinical
(Testing in
Laboratory)
Epigenetic
NIH/Harvard
Phase I
(Human Safety
Trial)
University of Pennsylvania
Phase II
(Human Safety
and Efficacy Trial)
Mt Gene
Therapy
7 Clinical Trials
8 Approaches
Phase III
(Definitive Trial)
High-Throughput
Screening for New
Drug Discovery
Research / Drug Discovery Program
• Targeted research
based on mechanism
of the disease
– Fe-S Clusters
– Gene therapy
• Develop assays for
screening drug
targets at each of
those steps
7
FA Treatment Pipeline - 2009
FARA has supported, and is supporting, these efforts by
providing various combinations of direct funding, essential
clinical infrastructure, advocacy and awareness efforts.
Available to
Patients
Wells Center for Pediatric Research, Indianapolis, IN
7 Clinical Trials
8 Approaches
Phase III
(Definitive Trial)
Research
(Finding Potential
Therapies/Drugs)
Decrease Oxidative
Stress
and/or Increase
Mitochondrial
Function
Decrease
Iron
Toxicity &
Increase
Fe-S
clusters
TAT Frataxin
HDAC - Leading
Pre-Clinical
(Testing in
Laboratory)
HDAC - New
Repligen
Phase I
(Human Safety
Trial)
Scripps Institute, La Jolla, CA
Phase II
(Human Safety
and Efficacy Trial)
Increase
Frataxin or FA gene
Expression
Gene
Therapy
Frataxin
NeuroProteinprotection
Replacement
NeuroTransmission
Modifying
Therapy
High-Throughput
Screening for New
Drug Discovery
Pre – Clinical Drug Development
9
10
New assets for drug discovery and development
• Neuronal and cardiac cellular models
– Stem cell technology
• Characterize and optimize mouse models
• New assays that target frataxin in high throughput drug
screening
• Skipping steps or moving too quickly can lead to failure
– Abandon a good drug candidate
– Take a poor drug candidate to humans
• Improving research tools to identify drugs with highest
likelihood of success as quick as possible
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Induced Pluripotent Stem Cells
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Induced Pluripotent Stem Cells
13
Clinical Trials
Phase I
Phase II
Dose
Finding/
Drug
Metabolism/
Safety
Ia-
Ib-
20-80
Healthy
Volunteers
get 1 dose
& safety
monitor
Healthy
Volunteers
get longer
drug
exposureMTD
Further
Evaluate
Safety &
Efficacy
Phase III
Prove
Efficacy in
Larger
Group/
Compare to
Standard
Phase IV
Evaluates
Long- term
Risks/
Benefits
*(usually
post FDA
approval)
FA Treatment Pipeline - 2009
FARA has supported, and is supporting, these efforts by
providing various combinations of direct funding, essential
clinical infrastructure, advocacy and awareness efforts.
Available to
Patients
7 Clinical Trials
8 Approaches
Phase II
(Human Safety
and Efficacy Trial)
Penwest
Phase III
(Definitive Trial)
Phase I
(Human Safety
Trial)
Research
(Finding Potential
Therapies/Drugs)
A0001
Pre-Clinical
(Testing in
Laboratory)
Decrease Oxidative
Stress
and/or Increase
Mitochondrial
Function
Decrease
Iron
Toxicity &
Increase
Fe-S
clusters
Increase
Frataxin or FA gene
Expression
Gene
Therapy
Frataxin
NeuroProteinprotection
Replacement
NeuroTransmission
Modifying
Therapy
High-Throughput
Screening for New
Drug Discovery
Clinical Trials
Phase I
Phase II
Dose
Finding/
Drug
Metabolism/
Safety
Ia-
Ib-
20-80
Healthy
Volunteers
get 1 dose
& safety
monitor
Healthy
Volunteers
get longer
drug
exposureMTD
Further
Evaluate
Safety &
Efficacy
Phase III
Prove
Efficacy in
Larger
Group/
Compare to
Standard
Phase IV
Evaluates
Long- term
Risks/
Benefits
*(usually
post FDA
approval)
FA Treatment Pipeline - 2009
7 Clinical Trials
8 Approaches
Lundbeck
ApoPharma
IPSEN
EGb761
Phase II
(Human Safety
and Efficacy Trial)
INSERM - Hôpital Robert Debré
Phase III
(Definitive Trial)
Pioglitazone
Available to
Patients
University of South Florida
And Children’s Hospital of Phila
FARA has supported, and is supporting, these efforts by
providing various combinations of direct funding, essential
clinical infrastructure, advocacy and awareness efforts.
Decrease Oxidative
Stress
and/or Increase
Mitochondrial
Function
Decrease
Iron
Toxicity &
Increase
Fe-S
clusters
Increase
Frataxin or FA gene
Expression
Gene
Therapy
Frataxin
NeuroProteinprotection
Replacement
Varenicline / Chantix
Research
(Finding Potential
Therapies/Drugs)
Lu AA24493 (cEPO)
Pre-Clinical
(Testing in
Laboratory)
Iron Chelator – Deferiprone
Phase I
(Human Safety
Trial)
NeuroTransmission
Modifying
Therapy
High-Throughput
Screening for New
Drug Discovery
Clinical Trials
• A clinical trial is a biomedical or health-related
RESEARCH studies in HUMAN beings that follow a predefined PROTOCOL.
– Strict instructions for conducting the studies
– Double-blind placebo controlled trial
– Who can participate – inclusion and exclusion criteria, number of
subjects
– When study visits need to occur, safety and efficacy measures
– Plan for data safety and monitoring, analysis of study results
18
Clinical Trials – Be Informed
• How do you know if a trial is happening?
– ClinicalTrials.gov
– FARA patient registry – www.curefa.org/registry
• Are you a candidate for the clinical trial?
– Inclusion and exclusion criteria
• age, gender, the type and stage of a disease, previous
treatment history, and other medical conditions
• identify appropriate participants and keep them safe and help
ensure that researchers will be able to answer the questions
they plan to study
– Before joining a clinical trial, a participant must qualify for the
study.
19
Clinical Trials – Be Informed
• How do you decide about participation in a trial?
– Informed consent is the process of learning the key facts about a
clinical trial before deciding whether or not to participate. It is
also a continuing process throughout the study to provide
information for participants.
• Benefits and risks
• Procedures or tests required
• How will the trial affect your daily life and how long
will it last…. Travel???
• Who is in charge of my care?
• Payment, reimbursement
• Results
20
Clinical Trials – Be Informed
• Can a participant leave a clinical trial after it has begun?
Yes. A participant can leave a clinical trial, at any time.
• What if you don’t qualify for the trial, can you still get the
drug?
– Expanded access - FDA regulations enable manufacturers of
investigational new drugs to provide for "expanded access" use
of the drug
• clinical investigators are actively studying the experimental
treatment in well-controlled studies, or all studies have been
completed
• there must be evidence that the drug may be an effective treatment
in patients
• the drug cannot expose patients to unreasonable risks given the
severity of the disease to be treated.
21
Clinical Research in FA
• Current Clinical Research Studies in FA
– Collaborative Clinical Research Network in FA – Natural history
– Cardiac MRI Study, Ohio State University
– Hearing study, Wilmington, DE
• Current Clinical Trials in FA
– Phase III – Idebenone – US extension study (Philadelphia, PA
and Los Angeles) and European study
– Phase II – Chantix (Philadelphia, PA and Tampa, FL)
– Phase II – cEPO (Europe)
– Phase II – Pioglitizone (France)
– Phase II – Deferiprone extension study (Europe, Canada)
• Upcoming
– Phase II – A0001 (Philadelphia, PA)
• FARA Patient Registry
Collaborative Clinical Research Network in Friedreich’s
Ataxia (CCRN in FA)
• PI: Dr. David R. Lynch
• Sites:
•
•
•
•
•
•
•
•
Children’s Hospital of Philadelphia, PA – Dr. David Lynch
University of California Los Angeles, CA – Dr. Susan Perlman
University of Chicago, IL – Dr. Chris Gomez
University of Minnesota, MN – Dr. Khalaf Bushara
University of Iowa, IA – Dr. Kathy Matthews
University of Rochester, NY – Dr. Bernard Ravina
University of Florida – Dr. Tee Ashizawa and Dr. Sub Subramony
Murdoch Childrens Research Institute, Australia – Dr. Martin Delatycki
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Hope, Confidence and Urgency
• Brain not affected
• We understand the cause of the disease
• Gene is intact – just need to make more frataxin
• We are approaching treatment from multiple directions
• Treatment trials are now!
• Treatment will come through an iterative process
– Slow, stop, and reverse
– Newborn screening
• Insights into FA are having impact on advancing
treatments for other conditions
• We have a dedicated fast-moving and highly
collaborative research community
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Hope, Confidence and Urgency
Acting alone, there is very little we can accomplish. Acting together, there is
very little we will NOT accomplish!
Keith
Andrus
Samantha and Alexandria Bode
with Mary Stuart Masterson
Evan Luebbe and
Tiki Barber