BridgeBio Pharma : BBIO - Canavan GTx BBP-812 - CNS meeting 2022 - CANinform Natural History Study

#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
  • 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