Transcript Clinical Trials Where are we? ANNE RUTKOWSKI, MD CURE CMD CHAIRMAN KAISER SCMPG Getting from Point A to Point B Preclinical Trials Clinical Trials.

Clinical Trials
Where are we?
ANNE RUTKOWSKI, MD
CURE CMD CHAIRMAN
KAISER SCMPG
Getting from Point A to Point B
Preclinical Trials
Clinical Trials
Roadmap to Clinical Trials
 Built to last
 Focused
 Dollars
Built to Last
Built to Last: Cement foundation and ensure
sustainability of efforts
What are the bricks of this foundation:
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Annual Research funding
CMD Animal models to Jackson Laboratories
CMD International Registry (CMDIR)
CMD Genotype and Phenotype study (NCBI)
CMD Medical Management: Consensus Care Guidelines,
CMD Clinic Checklist
CMD Banks: BioBank and Tissue Bank
CMD TLC: “Traveling Local Clincs”
CMD Educational outreach: CMD Videos, Cure CMD
Newsletter, CMD Perspectives, Online support groups
How do we ensure sustainability as an all
volunteer organization?
 Keep overhead low
 Keep cost of individual bricks low
 Set up shared cost models
 Economies of scale (JFF, AFBS)
 Give volunteers positive feedback
Who are the volunteers?
Who are the volunteers?
Who are the volunteers?
Who are the volunteers?
Who are the volunteers?
Who are the volunteers?
Who are the volunteers?
Who are the volunteers?
Who are the volunteers?
Who is “we” when “we” go to clinical trial?
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Families
Clinicians
Allied health professionals
Pharmaceutical sector
NIH
Advocacy
Focused
 What is the blueprint?
 What are the types of clinical trials that we are interested in?
 What are the positive attributes and challenges per subtype?
 What tools are needed?
3 Kinds of Clinical Studies/Trials
 Clinical research
 Target BMI (weight) for optimal growth?
 Best way to detect early heart involvement in L-CMD?
 Adverse event rate
 Intervention trials
 Exercise
 Breathing training prior to surgery
 Drug trials
Modifiable Risk: Lessons from Cystic
Fibrosis
How was the CF Foundation able to make these
gains?
 Clinical Research
 Defining consensus guidelines
 Establishing CF case report forms
 Applications for Centers of Excellence
 Mandated data reporting
 Transparency in comparing centers against a
national average
 Using data to define evidence for medical practice
Blueprint: LAMA2 drug pipeline
Available to patients
Phase3
Phase 2
Phase1
Preclinical
Research
Omigapil
IgF
TgF Beta Laminin
111
Agrin
NBP
Positives to LAMA2 drug discovery
 Several mouse models that replicate the disease
 You can see an effect on not only muscle function, but survival
 Mouse now available at Jackson Laboratories
 Standard operating protocols have been developed with
TREAT-NMD
 Homogeneous population
 Mechanisms:
 Good sense of multiple mechanisms involved: inflammation,
fibrosis, degeneration, failed regeneration, apoptosis
Challenges to clinical trials in LAMA2 Related
CMD
 Disease onset is early with stabilization and some
improvement in clinical course (ages 3-10 yrs)
 To target muscle may need to treat within first 2-3
years of life
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Delayed diagnosis
Treatment of infants: what outcomes?
Ability to follow commands
 Ability to assess motor strength
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 Gene therapy: it is a long gene
 Combinatorial therapy may be the most effective
 Difficulty in convincing a pharma company to take a
combination drug into clinical trial
Blueprint: Col6 drug pipeline
3.5
3
2.5
2
Phase1
Preclinical
Research
1.5
1
0.5
0
Omigapil
Cyclosporine
Stem cell
Debio-025
Positives to Col6 clinical trial
 Disease course mirrors a “DMD” like course
 Use motor outcome measures
 Use breathing endpoints (once validated against adverse event
rate)
Challenges to clinical trials in Col6
 Variability of disease severity
 All 3 animal models currently developed are good for
gene therapy or protein replacement (stem cell)
strategies, but mice do not show disease
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Testing small molecule drugs is challenging as cannot identify
an effect
 Mechanisms:
 Need to be verified in more than one lab (apoptosis)
 Need to understand the role of adhesion and what drives
contractures and impact on satellite cells and regeneration
Blueprint: aDG clinical trials
2.5
2
1.5
Phase1
Preclinical
Research
1
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Prednisone
increase
LAMA
binding
increase
LARGE
gene therapy
Positives of aDG clinical trial development
 A potential treatment exists: prednisone
 Genes are small and could be packaged into viral
vectors for gene therapy
 LGMD2I cohort resembles “DMD” course
 Mechanism:
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Need to be further queried
Sarcolemmal injury
Separate dystrophic process
Challenges for aDG drug development
 Variable spectrum
 Brain involvement
 Developmental
 Synaptic plasticity?
 Blood brain barrier
 Will a drug approved for one aDG subtype obtain
FDA label approval for other aDG subtypes?
L-CMD
 Soon to be published animal model for L-CMD
 Need to identify mechanisms of disease
 How does an intranuclear protein lead to dystrophy?
 Why is the heart involved?
 What are potential treatment targets
SEPN 1 Related Myopathy
 Animal model does not show disease
 Mechanism:
 Mechanism needs to be verified- does difficulty handling cell
stress (redox reactions) lead to downstream effects that cause
dystrophy?
 Additional mechanisms need to be identified: calcium
handling?
 Can we design disease in a dish?
 Plans to take N-Acetylcysteine into clinical trial are
stalled on identifying appropriate endpoints
RYR1 CMD
 Disease variability
 No CMD mouse model
 Good zebrafish model (HTS)
 Mechanisms:
 Validated cellular stress mechanism (redox)
 Identify additional mechanisms
 N-Acetylcysteine shows an effect in research and
preclinical studies (zebrafish, human cell lines)
CMD, Undiagnosed
 Key points:
 Medical management can be optimized without a diagnosis
 Participate in new gene discovery studies
 New genes are being discovered annually:
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Col4 mutation leading to WWS
Blueprint: CMD collaborative network
 A clinical trial takes more than one site, and often
more than one country
 Building a network
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Preclinical: CMD Myomatrix 2012
Clinical:
Traveling Local Clinics (TLCs): San Diego, Beijing
 Establishing effective collaboration (Col6 FVC Consortium)
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What tools?
Preclinical:
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Animal models
2. Cell lines
3. “Disease in a Dish”
4. High throughput screens
Clinical:
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Case Report Forms
2. CMD Clinic Checklist
3. CMD Videos
4. CMD Outcomes
5. CMD Biomarkers
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Imaging
Blood biomarkers
Dollars
What is cost?
 Labor (cost to families, cost of trial)
 Supplies (drug manufacture)
 Overhead
What does funding do?
Where do we stand?
Bottom line: Progress is being made
 Foundation has been built in 3 years
 Tools are being lined up
 Blueprint shows several options- no cures,
“treatments”
 Dollars to push drugs into trial
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Research grants
Decision point to push for a clinical trial
Collaborative funding