Download Neul – Clinical trials family

Status of Drug Trials
for Rett Syndrome
Jeffrey L. Neul M.D., Ph.D.
Division Chief of Child Neurology
Department of Neurosciences
University of California, San Diego
Rady Children’s Hospital – San Diego
Serotonin in Rett syndrome
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Important neurotransmitter involved in many
clinical features
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Control of breathing
Mood
Anxiety
Decreased in people with RTT and mouse
model
dopamine
serotonin
dopamine norepinephrine serotonin
Sarizotan
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Sarizotan
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5HT1a agonist/D2
antagonist
Previous evaluated to treat
schizophrenia or Parkinson
Disease
Improved breathing in RTT
mice
Newron Pharmaceuticals
A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, SIXMONTH STUDY TO EVALUATE THE EFFICACY, SAFETY AND
TOLERABILITY OF SARIZOTAN IN PATIENTS WITH RETT
SYNDROME WITH RESPIRATORY SYMPTONS
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Phase 2/3
Double Blind, 2 dose levels + placebo
6 mo drug exposure + 6mo blind extension
Primary Outcome: Improvement in apneas
Secondary Outcome: Safety and broad signals of efficacy
Inclusion: Clinical Rett syndrome + MECP2 mutation, + breathing
abnormalities
Age: Over 13 yo
Goal enrollment: 90 (n=30 in each drug level)
Sites
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University of California, San Diego
University of Alabama-Birmingham
Baylor College of Medicine
Rush University, Chicago
Sienna, Italy
India
Anticipated Start Date (at UCSD): Summer 2016
Mitochondrial abnormalities
in Rett syndrome
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Mitochondria are “energy factories” of the
cell
Evidence of abnormal mitochondria in
RTT
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Elevated serum and CSF lactate and
pyruvate in some patients
Abnormal mitochondria morphology
Abnormal expression of proteins involved in
mitochondrial function
Hypothesis: Improving mitochondrial
function will improve clinical features in
RTT
Mitochondrial abnormalities
in Rett syndrome: Triheptahoin
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Triheptahoin
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C7 fatty acid metabolized to C4 and C5 ketone
bodies
Provides alternative energy source to brain
Improves mitochondrial function
Improved seizures in Glut1 deficiency
Preclinical treatment in RTT mouse model
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Improved metabolic profile
Better motor performance
Improved survival
Park et al, PLOSOne, 2014
Triheptahoin clinical trial
Emory University, Daniel Tarquinio
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Phase 2a, open label study of 10 subjects
Clinical RTT and mutation in MECP2
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Primary outcome: Safety and Tolerability
Secondary outcomes:
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Improvement in seizure frequency
Improvement in dystonia severity
Exploratory outcomes:
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>4 seizures per month, >4 dystonic episodes per month
Quality of life
Improved function
EEG and Ambulatory biometric devices (autonomic function,
movement, oxygen saturation, electrodermal activity)
Not yet enrolling
Disease modifying therapies
Male Mecp2 mice
treated with tripeptide from
N-terminus of IGF-I
IGF-I [1-3] = Gly-Pro-Glu
IGF-I trials in Rett syndrome
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Full-length IGF-I (mecasermin) in
children with Rett syndrome
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Boston Children’s Hospital
Trofinetide (NNZ-2566) in adults with
Rett syndrome
Baylor College of Medicine, Houston TX
 University of Alabama-Birmingham
 Gillette Children’s Hospital, St. Paul MN
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IGF-I trials in Rett syndrome
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Full-length IGF-I (mecasermin) in
children with Rett syndrome
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Boston Children’s Hospital
Trofinetide (NNZ-2566) in adults with
Rett syndrome
Baylor College of Medicine, Houston TX
 University of Alabama-Birmingham
 Gillette Children’s Hospital, St. Paul MN
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Children’s Hospital Boston rhIGF-1
clinical trial (NCT01253317)
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Treatment with full length IGF1 (Mecasermin), initiated
December 2010
 Phase I: open-label escalating subcutaneous twice daily
doses (40, 80, and 120ug/kg) for 4 weeks to assess safety
Primary outcome: Safety
Secondary: improvement in cardiovascular function as
measured by respiratory inductance plethysmography and
electrocardiogram
Exploratory evaluation: Function, behavior, biomarkers
Results: safe and some signals of efficacy
Children’s Hospital Boston rhIGF-1
clinical trial (NCT01253317)
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PHASE 2: Double blind, placebo controlled, cross over,
single dose study
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30 people
Randomized to drug or placebo
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20 weeks exposure
10 week wash out
20 week exposure
Primary outcomes-breathing, anxiety
Completed enrollment
Analyzing data to determine next steps
IGF-I trials in Rett syndrome
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Full-length IGF-I (mecasermin) in
children with Rett syndrome
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Boston Children’s Hospital
Trofinetide (NNZ-2566) in adults with
Rett syndrome
Baylor College of Medicine, Houston TX
 University of Alabama-Birmingham
 Gillette Children’s Hospital, St. Paul MN
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Phase 2 Study of Two Dose Levels of
NNZ-2566 ([1-3] IGF-1 analog)
Cohort 0
2:1 Randomization
35mg/kg BID or
Placebo
14 Days Treatment
N=9
Cohort 1
2.1 Randomization
35mg/kg BID or
Placebo
28 days treatment
N=18
Cohort 2
2:1 Randomization
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70mg/kg BID or
Placebo
28 days of treatment
N=29
N=56, Ages 15.9-44.2 (mean 25.3)
Primary Outcome: Safety/Tolerability
Secondary Outcome: Efficacy
Funded by Neuren Pharmaceuticals (Sponsor) and the International Rett
Syndrome Foundation
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70mg/kg BID Dose of NNZ-2566
Demonstrates Evidence of Efficacy
Subject-Level Score
Top 3 Concerns
MBA Change Index
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Achieved its primary endpoint - both dose levels of NNZ-2566 were welltolerated after 28 days of treatment and no safety concerns were identified.
Higher dose exceeded the pre-specified criteria for improvement in core
efficacy measures compared with placebo on group and subject level analysis
CGI-I
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Least Squares mean change from baseline to Day 26 (Direction of benefit = Up)
*modified intent to treat group, n=55
Next steps: A Safety Study of NNZ-2566
in Pediatric Rett Syndrome
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Double-blind, placebo controlled doseranging study
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3 dose levels
Similar in design to first trial (RTT-001)
Younger age range (5-15 yo)
Clinical RTT and MECP2 mutation
Cannot have QTc prolongation
11 weeks total time (56 days on compound)
Primary outcome: Safety
Secondary outcome: Signals of efficacy
Goal enrollment: >64
Next steps: A Safety Study of NNZ-2566
in Pediatric Rett Syndrome
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Enrolling
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Setting up
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University of Alabama-Birmingham
Greenwood Genetics Center, SC
Baylor College of Medicine
Vanderbilt University
Rush University
Boston Children’s Hospital
University of California, San Francisco
University of California, San Diego (summer 2016)
Gillette Children’s Hospital, St. Paul, MN
Colorado Children’s Hospital
Cincinnati Children’s Hospital
www.rettstudy.com
Ketamine Treatment for RTT
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Ketamine is a NMDA antagonist
used for sedation (amnestic)
Evidence for efficacy at low
doses for major depression
Evidence of increased cortical
neuronal excitability in RTT
Preclinical treatment in mice
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Delayed onset of breathing
problems
Improved sensory gating
Improved survival
Kron et al., 2012; Mather et al.,
2014, Patrizi et al, 2014
Ketamine Treatment for RTT
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David Katz, Case Western Reserve
University and Sumit Parikh, Cleveland Clinic
Phase I/II placebo-controlled randomized
crossover
Goal enrollment: 30
Inclusion
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Primary outcome: Safety
Exploratory
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Clinical RTT and MECP2 mutation
Evidence of breathing abnormality
Breathing
Auditory evoked potentials
Functional improvement on rating scales
Not yet started
Lovastatin-NYC
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Montefiore (NYC), Aleksandra Djukic
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Phase II, Open Label, Dose-escalating study in
RTT with MECP2 mutations and can walk
Goal enrollment: N=20, >3yo
32 week treatment, with dose escalation
Outcome measures
Primary: Gait
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Breathing
Visual recognition using eye tracking device
EEG abnormalities
Quality of Life
Recruiting subjects
Acknowledgements
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Daniel Tarquinio, Emory University, Atlanta GA
Aleksandra Djukic, Children’s Hospital at Montefiore,
Albert Einstein Medical School, New York, NY
Bruria Ben-Zeev, Sheba Medical Center, Israel
David Katz, Case Western University, Cleveland, OH
Walter Katz
Rett Syndrome Natural History Study – Alan Percy
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NIH
Rettsyndrome.org
Rett Syndrome Research Trust
Thank you
Copaxone trials
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Copaxone: An artificial copolymer of peptide
pool composed of random sequence of 4
amino acids : glutamine, lysine, alanine and
serine
Used for >20yrs for Multiple Sclerosis
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Elevated serum BDNF levels were detected in
MS patients only during copaxone
Increases BDNF in brain of RTT mice
Control
Copaxone
Ben-Zeev et al, 2011
Copaxone trials-NYC
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Montefiore (NYC), Aleksandra Djukic
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Phase II, Open Label, Dose-escalating study
in RTT with MECP2 mutations
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Need to be able to walk
Goal enrollment: N=20, >10yo
 24 week treatment, with dose escalation
 Outcome measures
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Primary: Gait
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Breathing
Visual recognition using eye tracking device
EEG abnormalities
Copaxone trials-NYC
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Montefiore (NYC)
Stopped after 10 people completed trial
 Results:
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Gait: 7/10 improved gait speed (13.1%-95.2%)
 Breathing: 5/10 showed improved breathing
holding index
 Visual recognition: 5/7 showed improvement in
cognitive assessment of face stimuli
 EEG: Epileptiform discharges decreases in 4/4
who had them at baseline
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Copaxone trials-Israel
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Sheba Medical Center (Israel), Bruria Ben Zeev
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Phase II, Open Label, Dose-escalating study in RTT
with MECP2 mutations and EEG abnormalities
Goal enrollment: N=10, 5-15 yo
24 week treatment, with dose escalation
Outcome measures
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Primary
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Safety
Improvement in EEG abnormalities
Secondary
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Improved breathing
Decreased seizures
Improved sleep
Improved behavior
Changes in Height and Weight
Copaxone trials-Israel
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10 people recruited
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One had increase in seizure frequency and decided to
stop the trial
4/10 mild irritation at injection site
After 3 mos one subject had flushing, mild generalized
edema tremor and breath holding immediately after
injection
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2 wks later 2 more subjects reported similar (immediate)
but more prolonged and prominent response after
injection
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Subsequent injections ok, continued on study
one subsided spontaneously after few hours of observation in
ER
One had significant generalized edema ,breathing difficulties
followed by seizure and requiring adrenaline injection by
paramedic and hospitalization, remission after 24 hours
Report to IRB – Decision to hold study and
investigate SAE
Copaxone trials-Israel
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IRB Review
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Evaluation of events and input on safety from
Montefiore
Decision to reopen study
4 more subjects recruited
3 months into the study
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similar severe response in one subject
Edema, flushing, prolonged breath holding and
possibly seizure immediately after injection –severe
enough to call paramedic team and transfer to close
ER – Spontaneous remission in 1-2 hours
 Response frightening enough to very experienced
parents
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IRB review of SAE – decided to stop study
Copaxone trials-Conclusion
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Montifiore
Safe
 Positive signals of efficacy
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Israel
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Multiple SAE
Future - uncertain