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Understanding GM1 Disease

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Understanding GM1 Disease AXO-AAV-GM1 6-Month Topline Safety and Efficacy Low-Dose Cohort (1.5x1013 vg/kg) AXO-AAV-GM1: GENE THERAPY FOR GM1 GANGLIOSIDOSIS Only Clinical-Stage Gene Therapy Program Targeting the Full Spectrum of Patients with Type I and Type II GM1 Gangliosidosis GM1 Gangliosidosis AXO-AAV-GM1 Gene Therapy Rationale • Fatal, pediatric lysosomal storage disorder with monogenic • One time delivery of a functional copy of the GLB1 gene via autosomal recessive inheritance pattern that affects ~450- intravenous administration of AAV9 vector system 900 US+EU patients • Intravenous delivery addresses the multisystem • Single gene (GLB1) defect leads to decreased β-galactosidase manifestations of GM1 gangliosidosis enzyme activity and ganglioside accumulation • Only gene therapy to demonstrate restoration of wild-type • Disease hallmark is progressive neurodegeneration due to survival in a naturally-occurring GM1 feline model storage of GM1 ganglioside in lysosomes • Positive six-month enzyme activity and preliminary clinical • Late infantile/juvenile (Type II) have a life expectancy of 10- outcomes data in late-infantile/juvenile (Type II) children 20 years treated with low-dose gene therapy (1.5x1013 vg/kg) • Currently no treatments available • High dose cohort (4.5x1013 vg/kg) initiated in November 2020; two patients now dosed without complications 2 GM1 Gangliosidosis Background GM1 GANGLIOSIDOSIS: Part of a spectrum of neurodegenerative lysosomal storage disorders with monogenic autosomal recessive inheritance pattern Lysosomal Storage Diseases GM1 Gangliosidosis • >50 related disorders • Mutation in the GLB1 gene leads to impaired β- galactosidase enzyme • Frequency ~1:7,700 total • Without β-galactosidase GM1 builds up in the • Two-thirds are neurodegenerative, including lysosome of the cell GM1 gangliosidosis, Tay-Sachs, and Sandhoff disease • Accumulation of GM1 ganglioside in multiple organ systems causes significant defects: • Naturally occurring large animal models, including felines and sheep • Severe progressive neurological decline • Hepatosplenomegaly • Blindness and ocular deficits • Osteoporosis and skeletal dysfunction • Naturally occurring feline model 4 THE LYSOSOME IS AN IMPORTANT REGULATOR OF CELL FUNCTION Ballabio A, Bonifacino JS. Lysosomes as dynamic regulators of cell and organismal homeostasis. Nat Rev Mol 5 Cell Biol 2020; 21(2): 101-118 Courtesy Dr. Cynthia Tifft STORAGE OF GM1 IS DUE TO A DEFICIENCY IN β-GALACTOSIDASE • GM1 ganglioside is an integral part of the lysosomal membrane • The first step in degradation requires the enzyme β-galactosidase • β-galactosidase removes the first sugar (galactose) from the larger molecule • Without β-galactosidase, GM1 builds up in the lysosome of the cell 6 Courtesy Dr. Cynthia Tifft 4 GM1 GANGLIOSIDOSIS SEVERITY VARIES ACROSS DISEASE TYPES Type I (Infantile) • Onset <6 mo • Skeletal dysplasia • Hepatosplenomegaly • Developmental arrest • Hypotonia Type II (Late-Infantile) • Cherry red macula • Onset 1-2 yrs • Seizures • Difficulty walking • Death at <2 years Type II (Juvenile) ty • Variable skeletal i • Onset 2-5 yrs disease • Impaired ambulation • Decreased cognition sease • Dysarthria i ever • Seizures • Variable skeletal D S • Death in mid-teens disease • Decreased cognition Type III (Adult) • Survival into 3rd decade • Adult onset • Gait disturbance • Dystonia, dysarthria • Decreased cognition • Age at death variable Enzyme Activity 7 Regier DS, Tifft CJ. 1993. GLB1-Related Disorders. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. GeneReviews. Seattle (WA): University of Washington, Seattle. CLINICAL, SKELETAL, NEUROIMAGING, AND BIOCHEMICAL FINDINGS IN GLB1-RELATED DISORDERS GM1 Gangliosidosis Finding Type I Type II Type III Infantile Late Infantile Juvenile Chronic/Adult Onset of symptoms <1 year 1-2 years 3-10 years 10+ years Eye findings CRS CC CC +/– CC Motor abnormalities + + + Extrapyramidal Hepatosplenomegaly + +/– +/– – Cardiac involvement +/– +/– +/– +/– Coarse facial features +/– – – – Skeletal findings + +/– +/– – Seizures + + +/– – Neuroimaging PA PA PA +/– mild atrophy Symbols and abbreviations: (+): present finding; (-): absent finding; (+/–): variable finding in subject population; CRS: cherry red spot; CC: corneal clouding; PA: progressive atrophy 8 WELL-UNDERSTOOD BIOLOGY FOR GM1 GANGLIOSIDOSIS MAKES IT AN ATTRACTIVE TARGET FOR GENE THERAPY GLB1 Gene β-galactosidase GM1 Ganglioside GM2 Ganglioside GM1 Gangliosidosis Underlying neurobiology Clinically relevant Broad distribution achieved supports the use of gene biomarkers paired with via one-time administration therapy for long-term well-accepted and cross-correction enzyme restoration neurodevelopmental mechanism measures 9 CROSS-CORRECTION PRINCIPLE ALLOWS SPECIFIC EXTRACELLULAR LSD ENZYMES TO TRANSDUCE THE LYSOSOMES OF OTHERWISE ENZYME-DEFICIENT CELLS 10 Preclinical Summary INTRAVENOUS DELIVERY TO ADDRESS THE MULTISYSTEM MANIFESTATIONS OF GM1 GANGLIOSIDOSIS Cisterna magna Intravenous Delivery Delivery Invasiveness Medium Minor CNS Outer surface of brain Whole brain and spinal Distribution and spinal cord* cord CEREBRAL CARDIAC ABNORMALITIES ATROPHY • Heart Low, highly variable • Liver-Spleen HEPATOSPLENOMEGALY SKELETAL DYSPLASIA Body vector delivery to body • Gastrointestinal Distribution organs • Musculoskeletal CHERRY-RED SPOT • Peripheral nerves 12 *Data on file ONLY GENE THERAPY TO DEMONSTRATE RESTORATION OF WILD-TYPE SURVIVAL IN A GM1 FELINE MODEL1 GM1 Felines Treated with 1.5E13 vg/kg via Intravenous Injection at 5 Weeks of Age 10 9 8 7 6 IV infusion 5 4 3 Clinical Rating Score Rating Clinical 2 1 0 1 6 11 16 21 26 31 36 Age (months) 13 Normal GM1 feline + one-time gene therapy GM1 feline 1: UMass Data on File; WPRE included in construct administered to felines Note: Felines were treated with the first-generation construct and the AXO-AAV-GM1 vector has been optimized prior to dosing patients in the ongoing clinical trial. WIDESPREAD Β-GAL ENZYME ACTIVITY ACHIEVED ACROSS THE CNS IN A GM1 FELINE MODEL WITH IV ADMINISTRATION Broad distribution of β-gal staining across the brain and spinal cord with IV dosing of 1.5E13 vg/kg Significant long-term coverage with strong expression 14 McCurdy, et al, Sci Transl Med. 2014;6(231):231ra48. INDEPENDENT STUDY CONFIRMS AAV9 IV ROUTE OF ADMINISTRATION HAS SUPERIOR CNS DISTRIBUTION IN GM1 FELINES All feline animals were treated with 1.5e13 vg/kg and used a similar vector backbone 1: Data from Auburn University presented at ASGCT 2020 Meeting Note: Felines were treated with a vector that includes a WPRE component; AXO-AAV-GM1 does not include this component. INDEPENDENT STUDY DEMONSTRATES AAV9 GENE THERAPY IV ROUTE OF ADMINISTRATION IS MOST EFFECTIVE IN EXTENDING SURVIVAL AND IMPROVING CLINICAL FUNCTION All feline animals were treated with 1.5e13 vg/kg and used a similar vector backbone 16 1: Data from Auburn University presented at ASGCT 2020 Meeting Note: Felines were treated with a vector that includes a WPRE component; AXO-AAV-GM1 does not include this component. AAV9 IV ROUTE OF ADMINISTRATION DEMONSTRATED TO BE MOST EFFECTIVE IN THE FELINE MODEL CONCLUSIONS 17 1: Data from Auburn University presented at ASGCT 2020 Meeting Note: Felines were treated with a vector that includes a WPRE component; AXO-AAV-GM1 does not include this component. EXTENSIVE PRECLINICAL DATA SUPPORT DIFFERENTIATED CLINICAL APPROACH AAV9 outperforms AAVRh10 across Optimized Vector administration routes Independent preclinical studies Intravenous administration has superior CNS show consistent superiority of Optimized Delivery distribution and βGal activity with potential to vector, delivery and efficacy with address multisystem manifestations AXO-AAV-GM1 IV delivery Restoration of white and grey matter, and cortical Stabilization of neuromuscular Restored Cortical volume, as measured by MRI observed in feline decline and survival prolongation Volume model observed in naturally occurring feline model Only gene therapy to demonstrate restoration of wild Superior Outcomes type survival in naturally occurring feline model 18 Study Design, Assessments, and Baseline Demographics AXO-AAV-GM1: CLINICAL STUDY DESIGN STAGE 1: DOSE-RANGING Ongoing STAGE 2: EFFICACY STUDY 6-month data readout High-dose Cohort December 2020 4.5 x 1013 vg/kg Low-Dose Cohort 1.5 x 1013 vg/kg Type I (infantile) and Type II (juvenile) Stage 1 and Stage 2 will include a mix of Type I (infantile) and Type II (late-infantile/juvenile) ROUTE OF • Intravenous ADMINISTRATION • Safety and tolerability • Developmental changes and disease progression measured by: Vineland-3 Adaptive Behavior Scales, Bayley Scales of Infant Development (Type I only) and Clinical Global Impressions Scale CLINICAL • Changes to MRI/MRS MEASURES (TYPE II) • Motor function and disease severity • Skeletal survey, swallow/speech assessment • Exploratory objectives include systemic and CSF biomarkers and neurological symptoms • High dose cohort (4.5x1013 vg/kg) initiated in November 2020; two patients now dosed without complications NEXT STEPS • Continued dosing of infantile (Type I) and late-infantile/juvenile (Type II) patients in high-dose cohort of ongoing study • Obtain data in both Type I and Type II children as part of clinical and regulatory strategy to obtain broad indication 20 ClinicalTrials.gov Identifier: NCT03952637 AXO-AAV-GM1: CLINICALLY MEANINGFUL ASSESSMENTS OF THERAPEUTIC RESPONSE Growth Scale Value (GSV) Vineland-3 Adaptive Behavior Assessment (VABS-III) • GM1 presents with regression
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