#160 | CANinform, a Retrospective and Prospective Natural History Study of Canavan Disease: Status and Initial Analyses |
Florian Eichler1, Elise Townsend1, Beth Leiro2, Mike Kiefer1, Anzalee Khan3, Christian Yavorsky3, Kathleen Kirby2, Chrissy Burton2, Stacy Maciel1, Genevieve Laforet2, Adam Shaywitz2, John Balser2, Annette Bley4
1Department of Neurology, Massachusetts General Hospital, Massachusetts, USA; 2Aspa Therapeutics, California, USA; 3 Valis Bioscience, California, USA; 4Department of Pediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Canavan Disease
Epidemiology and Pathophysiology
• Ultra-rare, fatal autosomal recessive leukodystrophy1
• 1:100,000 births/year - US and EU2
- ASPA3 mutations lead to lack of aspartoacylase (ASPA) activity
- ASPA deficiency prevents breakdown of N-acetylaspartate(NAA) into aspartate and acetate3
- Results in failure to develop and maintain myelination in brain3
Healthy NAA | NAA Metabolic Pathway |
Metabolic Pathway | in Canavan Disease |
N-acetylaspartic | N-acetylaspartic |
acid (NAA) | acid (NAA) |
Aspartoacylase | Aspartoacylase |
(ASPA) | (ASPA) |
Acetate | Acetate |
Aspartate | Healthy | Aspartate | Demyelination |
Neuron | of Neurons | ||
ASPA Enzyme Deficiency and NAA Accumulation
Lead to Demyelination in Canavan Disease
Disease Features
• Profound neurodevelopmental delay3 with global cognitive, language, and
4
CANinform Natural History Study
• Rigorous retrospective and prospective Canavan disease natural history study (CVN-101, NCT04126005)
• Intended to support CANaspire gene therapy clinical trial with control group and clinical endpoint selection (CVN-102, CNS 2022 Poster #223)
Assessment of Disease Progression
• Motor and Cognitive Development | • Neurological and Diagnostic | ||||||||||||
• Biochemical and Laboratory | • Parent/Caregiver | ||||||||||||
Data | |||||||||||||
Comparison | and | ||||||||||||
Clinical Endpoint Selection | Anticipated | ||||||||||||
Gene Therapy | |||||||||||||
Safety, Dose Finding, PD, and Clinical Efficacy | Approval | ||||||||||||
Ph 1/2 FIH trial of AAV9 gene therapy for Canavan disease |
• Opened in November 2019; centers in Boston, MA and Hamburg, GER
CANinform Study Status
• Current enrollment (as of 19 Aug 2022) = 48 participants from 16 countries
CANinform Enrollment by Cohort | n | % | |
Total Number Enrolled | 48 | 100 | |
Cohort (at entry) | |||
1 | (0 to 18 mo) | 9 | 18.7 |
2 | (18 to 36 mo) | 10 | 20.8 |
3 | (36 to 60 mo) | 7 | 14.6 |
4 | (> 60 mo) | 17 | 35.4 |
5 | (deceased) | 5 | 10.4 |
CANinform Preliminary Analyses and Findings
Approach and Principles
• Use visual representations of retrospective and prospective data to assess:
» Quantity and quality of data:
- Overall data density
- Coverage of relevant ages, focused on data up to and including 60 months of age:
-
> 30 through 42 months: maximum age at the
12-month primary endpoint for participants dosed at ≤ 30 months in the CANaspire gene therapy trial - > 42 through 60 months: covers an additional
1½ years of long-term follow-upin the CANaspire gene therapy trial
-
> 30 through 42 months: maximum age at the
- Patterns in developmental and disease parameters over time
- Ideal characteristics for selection of informative endpoints:
- Early onset
- Universal/near universal occurrence
- Relative consistency across patients by age
- Neither at floor nor at ceiling
- Clinical meaningfulness
Emerging Motor/Development Expert Endpoint Recommendations
• Determined by:
» Review of CVN-101 natural history study data |
» Consultation with motor raters gathering their |
By-Participant Characteristics and Data Density Examples of Two Promising Assessments: Head Control & Reach and Grasp
Head control | Reach and Grasp | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
• Clinically meaningful: critical skill needed to advance to sitting and for self-feeding | • Clinically meaningful: critical ability for quality of life, e.g., self-feeding | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
• Deficit evident early, occurs universally, and readily measured | • Skill often acquired at a basic level, though delayed (less floor effect) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
• Defined scoring criteria | • Defined scoring criteria | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
CDRS Head Control, Retrospective and Prospective Swimmer Plot | CDC Milestones Reach/Grasp, Retrospective and Prospective Swimmer Plot | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Participants (n = 38) | Participants (n = 39) |
0 | 2 | 4 | 6 | 8 | 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54 56 58 60 | 0 | 2 | 4 | 6 | 8 | 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54 56 58 60 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Age at Assessment (months) Retrospective and Prospective data as of 01Aug2022 | Based on 4-month CDC item "reaches for toy/ | Age at Assessment (months) Retrospective and Prospective data as of 01Aug2022 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
reaches for toy with one hand" | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
0: Holds head upright and steady; within normal limits | Age at Informed Consent | Present | Age at data cut | Age at Informed Consent | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1: Holds head upright momentarily, wobbles | Retrospective Data | Prospective Data | Absent | Retrospective Data | Prospective Data | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2: Unable to hold head upright | extracted from | obtained by | Pre-Extraction | extracted from | obtained by | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Pre-Extraction | Data Collected | Age at data cut | medical records | direct assessment | Data Collected | medical records | direct assessment | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
motor impairment
• Fatal; 73% reach the age of 10 years5
• Care is supportive/palliative,6,7 no approved treatments
Clinical Development Challenges
- Paucity of natural history data; disease trajectory not well characterized
- Need to identify informative, clinically meaningful efficacy endpoints
CANinform Natural History Study Design and Methods
Retrospective (All Participants)
• Available retrospective CDRS Data: 41 participants (3/41 higher-functioning outliers)
- 9 participants have all 11 CDRS items in the same age window
- Available retrospective CDC Milestone Data: 41 participants (3/41 higher-functioning outliers)
- Prospective Motor Function Rater Data: 28 participants
Prospective (Participant Opt-In)
observations and clinical sense |
• Several motor constructs have arisen as: |
» Most relevant to Canavan disease consistent with CDRS |
concepts of interest |
» Most likely to capture clinically meaningful improvement |
for children treated at ≤ 30 months of age in the |
CANaspire gene therapy trial |
- Head control in the upright position |
- Sitting ability (prop sit with hand support, |
hands-free sitting) |
- Reach and grasp function |
Participant Count by Age | CDRS Head Control, Retrospective & Prospective Data Density: | Participant Count by Age | |||||||
(N = 176 Observations) | 12 | Participant Counts by Age and CDRS Score | (N = 179 Observations) | ||||||
0: Holds head upright and steady (within normal limits) | |||||||||
10 | |||||||||
1: Holds head upright momentarily, wobbles | |||||||||
8 | 2: Unable to hold head upright | ||||||||
6 | |||||||||
4 | |||||||||
2 | |||||||||
0 | 0 | 2 | 4 | 6 | 8 | 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54 56 58 60 | |||
Age at Assessment (months) | Retrospective and Prospective data as of 01Aug2022 | ||||||||
CDC Milestones Reach/Grasp, Retrospective & Prospective Data Density: | ||||||
12 | Participant Counts by Age and CDC Score | |||||
Present | ||||||
10 | ||||||
Absent | ||||||
8 | ||||||
6 | ||||||
4 | ||||||
2 | ||||||
0 | 0 | 2 | 4 | 6 | 8 | 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54 56 58 60 |
Age at Assessment (months) Retrospective and Prospective data as of 01Aug2022
• Systematized extraction of disease-related and motor/developmental |
data from patient records |
• In-clinic physical and neurological examinations (COVID-19 conditions permitting)
- Visual fixation and tracking |
GMFM-88 Head Control, Prospective Item 21: Lifts Head Upright, Maintains 3 Seconds* | HINE-2 Reach/Grasp, Prospective Voluntary Grasp Item |
• Experts in pediatric motor function and development followed a detailed |
extraction plan using two different tools to document the presence or |
absence of Canavan disease key concepts of interest: |
» Canavan Disease Rating Scale (CDRS)5 |
- Records signs, symptoms and developmental skills typically seen in |
children with Canavan disease, rated on a scale from 0-2 |
0 | 1 | 2 | |
Normal function | Mild Impairment | Severe Impairment | |
11 Scoring Categories | |||
• Epileptic Seizures | • Responsive social smile |
• Motor function assessments by extensively trained expert physiotherapist raters (remote post-COVID-19)
Developmental and Motor Scales
(Adapted Post-COVID-19 for Remote Testing by Video)8
Development/Motor
*TIMPSI: Test of Infant Motor Performance Screening Items
GMFM-88: Gross Motor Function Measure, 88 Items
*Bayley 4: Bayley Scales of Infant Development
HINE-2: Hammersmith Infant Neurological Examination, Section 2
- Standing/weight-bearing (for high-functioning outliers) |
Visual Fixation | Head Control |
GMFM-88 items 21-22; | |
and Tracking | HINE-2 Head Control item |
Response to Sensory Stimuli |
Reach and Grasp | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sitting | IMP item 66; HINE-2 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Voluntary Grasp item | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
GMFM-88 items 23-25 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
3.0 | 0 | = Does not initiate | 3.0 | ||||||
2.5 | 1 | = Initiates | 2.5 | ||||||
2 | = Partially completes | ||||||||
2.0 | 3 | = Completes | 2.0 | ||||||
Score | Each symbol represents | Score | |||||||
1.5 | 1.5 | ||||||||
an individual participant | |||||||||
1.0 | 1.0 | ||||||||
0.5 | 0.5 | ||||||||
0.0 | 0.0 | ||||||||
0 | 2 | 4 | 6 | 8 | 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54 56 58 60 |
*While torso supported in sitting position by examiner Age at Assessment (months) | Data cutoff 18Jul2022 |
0 | = No grasp | ||||
1 | = Uses whole hand | ||||
2 | = Index finger and thumb but immature grasp | ||||
3 | = Pincer grasp | ||||
Each symbol represents an individual participant | |||||
0 | 2 | 4 | 6 | 8 | 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54 56 58 60 |
Age at Assessment (months) | Data cutoff 18Jul2022 |
• Floppiness | • Visual tracking |
• Spasticity | • Head control |
• Macrocephaly | • Reaches for objects |
• Feeding | • Sits without support |
• Language | |
Minimum Score = 0 | Maximum Score = 22 |
(appropriate for age) | (severely affected) |
- CDC Developmental Milestone Checklist7
- Based on checklist of expected developmental milestones published by the US Centers for Disease Control
- Sample of typical milestones from 2-18 months
- Developmental skills across all domains rated as Absent or Present
CDC Developmental Milestone Checklist
Disease Severity
CDRS: Canavan Disease Rating Scale | ||||
Impact on Family | ||||
Vineland 3: Adaptive Behavior Scales, Expanded Interview Form | ||||
PedsQoL-FIM: Pediatric Quality of Life Inventory (Family Impact Module) | ||||
Canavan Disease Questionnaire | ||||
Added for Remote (US only) | ||||
*Original in-person assessments discontinued | ||||
AIMS: Alberta Infant Motor Scale | ||||
post-COVID in the US; German site continued | ||||
IMP: Infant Motor Profile | ||||
to conduct all assessments in person | ||||
Response to Sensory Stimuli | ||||
• The same assessments are being performed by the same raters in the
Supported Standing and Weightbearing
HINE-2 standing item (for higher functioning pts)
Acknowledgments: Many thanks to everyone whose contributions made this work possible - the patients and families who generously participated in this study; our expert team of data extraction specialists and motor function raters; site staff at MGB and UKE; Veristat clinical, data management, and biostatistics teams; Valis Biosciences Clinical Trials Science and Technology Solutions; Aspa clinical and patient advocacy teams; and our advocacy partners: Canavan Foundation, Canavan Research Illinois, and the National Tay-Sachs and Allied Diseases Association.
clinicaltrials.gov treatcanavan.com aspatx.com
Head Control: Data Features and Implications for Use as a Clinical Endpoint
• Favorable data density at early ages
- Most natural history participants are at floor so evidence of clinical efficacy would require improvement in function
- Participants with a CDRS Score of 0 (Holds head upright and steady / within normal limits) at any time during age interval:
- > 30 through 42 months: 2/13 participants
- > 42 through 60 months: 2/11 participants
- GMFM-88:Only 3 natural history participants could complete the activity at any age (≤ 60 mos)
- Head control findings were consistent across CDRS retrospective and prospective and GMFM-88 prospective natural history data
Summary and Next Steps
Reach and Grasp: Data Features and Implications for Use as a Clinical Endpoint
- Participants with a CDC 4-month skill "Reach for Toy/Reach for Toy with One Hand" present at any time during age interval:
- > 30 through 42 months: 7/13 participants
- > 42 through 60 months: 10/16 participants
- HINE-2:Some participants had low-level voluntary grasp ability
- Because the CANaspire gene therapy trial doses children up to the age of 30 months, it is important to follow skills that are above the floor during the follow-upperiod
- Look for maintenance of skill when present
- Look for acquisition of skill when absent
References: 1) Bokhari 2020 https://www.ncbi.nlm.nih.gov/books/NBK430816. 2) Orphanet (https://www. orpha.net/consor/cgi-bin/OC_Exp.php?&Expert=141). 3) Matalon 2018 NCBI Bookshelf 4) Matalon 1998 Eur J Paediatr Neurol 5) Bley et al. Orphanet J Rare Dis 2021 16:227. 6) Traeger 1998 Pediatr Neuro. 7) Zubler, et al. Pediatrics. 2022;149(3):e2021052138. 8) Kiefer et al. Transitioning from in-personto remote motor assessment of children with Canavan disease. Abstract presented at 2022 Autumn Conference of the International Society for CNS Clinical Trials and Methodology Sept 8-9,Boston, MA.
CANaspire gene therapy trial (CVN-102)
- Assessment scales selected with input from families, patient advocates, and clinicians to assess the most clinically meaningful developmental skills across multiple domains
Presented at the Child Neurology Society Annual Meeting
San Francisco, CA, USA
October 8-12, 2022
- CANinform has continued to collect retrospective and prospective natural history data with remote adaptations in response to the pandemic
- CANinform is beginning to shape our understanding of the most informative and clinically meaningful endpoints for Canavan patients in the CANaspire gene therapy trial
- A more detailed interim analysis of CANinform data is planned to inform ultimate endpoint selection
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BridgeBio Pharma Inc. published this content on 27 September 2022 and is solely responsible for the information contained therein. Distributed by Public, unedited and unaltered, on 13 October 2022 20:21:02 UTC.