Sio Gene Therapies — Axovant Gene Therapies — Investor Presentation (January 2020)
62 slides from Sio Gene Therapies's investor presentation, Jan 13, 2020
Slide 1: Corporate Presentation January 2020
Exhibit 99.1 Corporate Presentation January 2020 1
Slide 2: Diversified pipeline of gene therapies with CNS focus
Diversified pipeline of gene therapies with CNS focus targeting neurodegeneration Gene therapies designed to tackle the specific biology underlying each disease Team with deep gene therapy expertise from research through commercialization Integrated development capabilities and fully secured manufac
Slide 3: Leadership team with decades of gene therapy experience
Leadership team with decades of gene therapy experience Pavan Cheruvu, MD David Nassif, JD Gavin Corcoran, MD FACP Fraser Wright, PhD Chief Executive Officer Chief Financial Officer Chief R&D Officer Chief Technology Advisor Michele Stone, PhD, PMP Greg Stewart, PhD Parag Meswani, PharmD Paul Korner
Slide 4: Three clinical stage CNS-focused gene therapy programs
Three clinical stage CNS-focused gene therapy programs Program Genes Indication Clinical Upcoming Milestones Adult Neurodegenerative Disease Interim data from Cohort 2 AXO-LENTI-PD AADC/TH/CH1 Parkinson’s disease Phase 2 Q1 2020 Rare Fatal Pediatric Disease AXO-AAV-GM1 GLB1 GM1 gangliosidosis Regist
Slide 5: Axovant has cultivated deep relationships with the patient community
Axovant has cultivated deep relationships with the patient community 5
Slide 6: Manufacturing for all programs secured through to commercialization
Manufacturing for all programs secured through to commercialization Preferred partnerships with leading gene therapy manufacturing organizations • World-leading clinical and commercial • Among the largest gene therapy manufacturer of lentiviral gene therapies manufacturing facilities in Europe, with
Slide 7: AXO-Lenti-PD
AXO-Lenti-PD Novel three-gene therapy candidate for Parkinson’s disease
Slide 8: AXO-Lenti-PD Market Opportunity
AXO-Lenti-PD Market Opportunity PREVALENT DISEASE WITH SIGNIFICANT DISEASE BURDEN AND NEED FOR MORE EFFECTIVE TREATMENT OPTIONS PREVALENCE1 DISEASE BURDEN1,2 TREATMENT3,4 COST BURDEN5,6 Affects 1/100 >50% develop motor Today’s gold standard Substantial economic over age 60 problems after 5 years dis
Slide 9: Substantial unmet needs in treating PD
Predictable efficacy, adverse events and dose management are substantial unmet needs in treating PD Unmet needs for addressable patients - efficacy Lack of a disease Loss of levodopa Invasive therapies are stabilizing therapy effectiveness over time limited in their efficacy Unmet needs for addressa
Slide 10: Goals of therapy in Parkinson's disease
Goals of therapy in Parkinson’s disease* “My entire body goes stiff…my mouth is often forced open in a painful position, or my mouth is forced “[Dyskinesia] so severe that ‘it looks like I’m closed with my tongue stuck out.” (Dystonia) having a seizure, and very painful.’” “The sudden inability to m
Slide 11: AXO-Lenti-PD: a novel gene therapy candidate for Parkinson's disease
AXO-Lenti-PD: a novel gene therapy candidate for Parkinson’s disease Three critical enzymes required for endogenous dopamine synthesis • Tyrosine hydroxylase (TH) and Cyclohydrolase 1 (CH1): converts tyrosine to L-dopa • Aromatic L-amino acid decarboxylase (AADC): converts L-dopa to dopamine Tyrosin
Slide 12: ProSavin: Improved motor function OFF oral levodopa medication
ProSavin: Improved motor function OFF oral levodopa medication Baseline 6 Months Off L-DOPA medication 10-point improvement on UPDRS-III (motor) OFF score 12
Slide 13: ProSavin: Fine motor function improvement
ProSavin: Fine motor function improvement Baseline 6 Months Off L-DOPA medication 13
Slide 14: Lentiviral vector is neurotropic
Lentiviral vector is neurotropic1-2 Immunofluorescence analysis of transgene expression from Transgene expression (TH, AADC, CH1) MPTP-lesioned ProSavin vector five months post injection into rat striatum1 non-human primates2 CHI- TH AADC • Observed transgene expression co-localizes with neuronal sp
Slide 15: ProSavin potentiates L-Dopa therapy in MPTP non-human primates
ProSavin potentiates L-Dopa therapy in MPTP non-human primates Bolus of L-Dopa is efficiently converted into dopamine and confirms generation of dopamine using both exogenous and endogenous pathway1,2 * p<0.05 to Lesion ** p<0.05 to normal 1: Jarraya, et al, Sci Transl Med. 2009;1(2):2ra4 15
Slide 16: Decreased dyskinesia observed in LID-MPTP model with ProSavin
Decreased dyskinesia observed in L-Dopa-induced non-human primate model (LID-MPTP) with ProSavin LID-MPTP + L-DOPA Dyskinesia events in Levodopa-induced-dyskinesia MPTP non-human primates 1600 ON L-Dopa State 1400 1200 ON L-DOPA 1000 20mg/kg 800 * * 600 * * * LID-MPTP model 400 generated via long-te
Slide 17: ProSavin improves Parkinsonian phenotype in MPTP non-human primates
ProSavin improves Parkinsonian phenotype in MPTP non-human primates with statistical significance Result: ProSavin treatment significantly improved both motor and Parkinsonian endpoints in lesioned non-human primates beyond one year1, 2,3 1: Jarraya, et al, Sci Transl Med. 2009;1(2):2ra4 2. ProSavin
Slide 18: ProSavin: Durable and dose-dependent benefit in UPDRS Part III OFF scores
ProSavin: Durable and dose-dependent benefit seen in UPDRS Part III OFF scores Mean UPDRS-III (Motor) OFF Score over 6 years1 UPDRS-III (Motor) OFF Score at Month 122 20.0 18.0 16.0 14.0 12.0 10.0 8.0 6.0 Improvement Improvement at Months 12 UPDRS Part (Motor) III Score 4.0 2.0 0.0 Cohort 1 Cohort 2
Slide 19: ProSavin: Improved dopamine production measured by PET imaging
ProSavin: Improved dopamine production measured by 11C-raclopride PET imaging Decreased Raclopride binding at 6 months indicates competitive displacement from dopamine produced as a result of ProSavin 1: Palfi, et al. The Lancet. 2014;383(9923):1138-1146 19
Slide 20: AXO-Lenti-PD: Re-engineered to increase dopamine production
AXO-Lenti-PD: Re-engineered to increase dopamine production ProSavin ProSavin + 13 different constructs studied in multiple experiments leading to final selection of AXO-Lenti-PD as the optimal design to move forward AXO-Lenti-PD • Gene order • Protein fusion using GS15 linker • IRES sequence Result
Slide 21: AXO-Lenti-PD: Increased dopamine production by 5-10x compared to ProSavin
AXO-Lenti-PD: Increased dopamine production by 5-10x compared to ProSavin Production of dopamine & L-dopa in primary human cortical neurons with ProSavin ProSavin and AXO-Lenti-PD 4.5 SIN LTR IRES IRES SIN LTR 4 CMVp TH AADC CH1 WPRE 3.5 Dopamine 3 L-dopa 2.5 AXO-Lenti-PD (ng/mL) 2 1.5 IRES SIN LTR
Slide 22: AXO-Lenti-PD improves motor function in nonhuman primates
AXO-Lenti-PD produces statistically significant improvements in motor function in nonhuman primates compared to placebo PD clinical score improved with treatment and with 1/5th the dose of ALPD Null LacZ ProSavin (2E+7 TU) ALPD LD (4E+6 TU) * ALPD HD (2E+7 TU) ** • Experiment carried out without L-D
Slide 23: AXO-Lenti-PD: Dose-dependent expression in primate models
AXO-Lenti-PD: Generates dose-dependent expression of AADC, TH, and CH1 in transduced striatal cells in primate models Expression Levels of CH1, AADC, and TH in Transduced Striatal Cells of MPTP non-human primates (A) Representative coronal sections showing histochemical staining for CH1 (left column
Slide 24: AXO-Lenti-PD: Nonclinical Summary
AXO-Lenti-PD: Nonclinical Summary AXO-Lenti-PD restores tonic levels of dopamine in the putamen similar to the healthy physiological state of normal individuals Substantial efficacy and safety data package for both ProSavin (1st generation vector) and AXO- Lenti-PD (2nd generation vector) • 13 pharm
Slide 25: SUNRISE-PD: AXO-Lenti-PD Phase 1/2 clinical study
SUNRISE-PD: AXO-Lenti-PD Phase 2 clinical study PART A Dose Escalation PART B Expansion Cohort vs Sham Surgical Procedure Cohort 3 7 Treated (4.2 x 10 TU) Optimal dose, Primary Cohort 2 expanded Advanced- 7 endpoint Cohort 1 (1.4 x 10 TU) patients, Sham stage evaluation (4.2 x 106 TU) surgical patie
Slide 26: AXO-Lenti-PD: Potential to address greatest patient needs
AXO-Lenti-PD: Potential to address greatest patient needs Consistent patient benefit across multiple objective measures in Cohort 1 at 12 months (n=2) Safety and tolerability Observed to be generally well-tolerated with no serious adverse events related to therapy Improved motor 22-point mean improv
Slide 27: Clinical dose-response observed in motor function across four dose cohorts
Clinical dose-response observed in motor function across four dose cohorts including ProSavin and AXO-Lenti-PD in human subjects UPDRS-III (Motor) OFF Score at Month 12 (cross-study comparison)1 25 20 15 22 10 15 5 11 Average UPDRS Part III (Motor) III AveragePart UPDRS 7 Score Improvement at 12 Mon
Slide 28: AXO-Lenti-PD: Hauser diary
AXO-Lenti-PD: Hauser diary at 3, 6 and 12 months 16.0 “Good” ON Time 14.0 ON time without dyskinesia 12.0 8.0 10.1 ON time with non-troublesome dyskinesia 10.0 10.7 11.3 8.0 ON time with troublesome dyskinesia Hours OFF time 6.0 4.6 2.4 4.0 0.2 2.0 3.0 1.5 2.0 3.4 2.7 1.8 1.4 0.0 Baseline Month 3 Mo
Slide 29: AXO-Lenti-PD: Effect on UPDRS Part III (Motor) OFF score
AXO-Lenti-PD: Effect on UPDRS Part III (Motor) OFF score 30 25 24 20 20 20 22-points average improvement at month 12 15 14 13 12 10 ProSavin Month 6 ProSavin Month 12 Improvement in UPDRS (Motor) Part III OFF Score 5 AXO-Lenti-PD Month 6 AXO-Lenti-PD Month 12 0 ProSavin All Cohorts (n=15) Patient A
Slide 30: UPDRS III OFF Score Change from Baseline Relative to ProSavin
AXO-Lenti-PD: UPDRS III OFF Score Change from Baseline Relative to ProSavin UPDRS III OFF 5 4 2 1 0 -5 -10 -10 -12 -13 Improvement -15 -17 -20 -22 -25 -25 Baseline Month 3 Month 6 Month 12 ProSavin AXO-Lenti-PD Expected Natural History * *UPDRS III Off score is expected to worsen by 3-4 points per y
Slide 31: AXO-Lenti-PD: Effect on UPDRS Part II OFF score
AXO-Lenti-PD: Effect on UPDRS Part II (Activities of Daily Living) OFF score 30 26 25 20 16 15 Score 13 13-point (44%) 10 improvement at month 12 10 ProSavin Month 6 5 4 4 ProSavin Month 12 Improvement in UPDRS Part II (ADLs) OFF OFF II (ADLs)Part UPDRS in Improvement AXO-Lenti-PD Month 6 0 AXO-Lent
Slide 32: UPDRS II OFF Score Change from Baseline Relative to ProSavin
AXO-Lenti-PD: UPDRS II OFF Score Change from Baseline Relative to ProSavin UPDRS II OFF 0 -3 -4 -4 -5 -10 -13 44% improvement -15 Improvement -20 -20 -22 -25 Baseline Month 3 Month 6 Month 12 ProSavin AXO-Lenti-PD 32
Slide 33: AXO-Lenti-PD: Effect on quality of life as measured by PDQ-39
AXO-Lenti-PD: Effect on quality of life as measured by PDQ-39 Patient A 70 62.8 Patient B Average 60 49.6 50 Average 30% (14.7 39.7 point) reduction 40 36.5 from baseline* 35.3 31 34.9 30 34.6 22.4 PDQ-39 SI(%) 19.2 20 16 17.6 10 0 Baseline Month 3 Month 6 Month 12 *Minimally Clinically Important Di
Slide 34: AXO-Lenti-PD Market Opportunity
AXO-Lenti-PD Market Opportunity NASDAQ: AXGT
Slide 35: Addressable patient population: US and EU3
Addressable patient population: US and EU3 (UK, France, Germany) Parkinson’s disease represents a multibillion-dollar opportunity for gene therapy Total PD Patient Population: ~1.7M Opportunity for significant expansion of Age 30-75, and H&Y Score 3-4: the addressable patient population: ~300K UPDRS
Slide 36: 12-month change in selected measures of advanced therapies
12-month change in selected measures of advanced therapies * (Cross-study comparison) VY-AADC1,2 Vercise DBS3 ProSavin4 AXO-Lenti-PD4 5 (Cohort 1) 3 (Cohort 1) 5 (Cohort 2) 2 (Cohort 1) Treatment 115 6 (Cohort 2) 5 (Cohort 3) 4 (Cohort 2) 6 (Cohort 3) Sample Size 8 (Posterior) Control Open-label 37
Slide 37: AXO-AAV-GM1 and AXO-AAV-GM2
AXO-AAV-GM1 and AXO-AAV-GM2 First clinic-ready gene therapies for GM1 gangliosidosis, Tay-Sachs and Sandhoff diseases
Slide 38: GM1 and GM2 gangliosidosis: devastating pediatric diseases
GM1 gangliosidosis and GM2 gangliosidosis (Tay-Sachs/Sandhoff disease): devastating pediatric diseases Fatal, pediatric lysosomal storage disorders with monogenic autosomal recessive inheritance pattern GM1 Gangliosidosis Tay-Sachs/Sandhoff Disease • Mutation in the GLB1 gene leads to impaired • Mut
Slide 39: Incidence and prevalence of GM1 gangliosidosis and Tay-Sachs/Sandhoff disease
Incidence and prevalence of GM1 gangliosidosis and Tay- Sachs/Sandhoff disease GM1 Gangliosidosis Tay-Sachs/Sandhoff Disease Incidence: ~1 per 100K births per year1 Incidence: ~1 per 150K births per year6 ~90 US+EU births per year ~60 US+EU births per year Type 1 Infantile* Type 2 LI/Juv* Type 1 Inf
Slide 40: Natural history of infantile GM1 gangliosidosis and Tay-Sachs/Sandhoff disease
Natural history of infantile GM1 gangliosidosis and Tay-Sachs/Sandhoff disease1,2 Clinical course illustrates rapidly progressive and uniformly fatal nature of both diseases 100% 90% 80% ~50% mortality by 3.5 years 70% Dysphagia Requiring 60% Feeding Tube Lose Head 50% Control ~75% mortality by 5 ye
Slide 41: Attractive targets for gene therapy
Attractive targets for gene therapy: well-understood biology underlying both diseases HEXA Gene: HEXB Gene: GLB1 Gene Tay-Sachs disease Sandhoff disease β-galactosidase β-Hexosaminidase A (α-β heterodimer) GM1 Ganglioside GM2 Ganglioside GM3 Ganglioside GM1 Gangliosidosis GM2 Gangliosidosis Underlyi
Slide 42: AXO-AAV-GM1
AXO-AAV-GM1 AAV gene therapy for GM1 Gangliosidosis
Slide 43: AXO-AAV-GM1: Gene therapy approach to restore deficient enzyme
AXO-AAV-GM1: Gene therapy approach to restore deficient enzyme AXO-AAV-GM1 delivers a functional copy of the GLB1 gene via AAV9 • Single gene defect leads to decreased β-gal enzyme CBA-GLB1 activity and ganglioside accumulation • Well-validated AAV approach in CNS indications Takes advantage of cros
Slide 44: GM1 gangliosidosis feline model (video)
GM1 gangliosidosis feline model (video) Untreated: 6.4 months Intravenously treated: >2 years Source: Auburn University. 44
Slide 45: Intravenous delivery approach for multisystem manifestations of GM1
Intravenous delivery approach intended to address the multisystem manifestations of GM1 gangliosidosis β-galactosidase GM1, oligosaccharides, keratan sulfate Cerebral atrophy Cardiac abnormalities Hepatosplenomegaly Cherry-red spot Skeletal dysplasia 45
Slide 46: Widespread β-gal enzyme activity across the CNS in a GM1 feline model
Widespread β-gal enzyme activity achieved across the CNS in a GM1 feline model β-gal activity in GM1 felines after one-time IV dosing of 1.5E13 vg/kg • Broad distribution of β-gal staining across the brain and spinal cord with IV injection of AAV9-β-gal • Significant long-term coverage with strong e
Slide 47: Intravenous GM1 gene therapy demonstrated efficacy in a feline model
Intravenous GM1 gene therapy demonstrated efficacy in a feline model1 GM1 felines treated with 1.5E13 vg/kg via intravenous injection at 5 weeks of age Survival extension and stabilization of clinical Brain MRI revealed normal brain architecture rating score of neuromuscular function1 at 2 years of
Slide 48: AXO-AAV-GM1: Proposed Phase 1/2 adaptive design clinical study
AXO-AAV-GM1: Proposed Phase 1/2 adaptive design clinical study Part A – Safety & Efficacy (n=5) Part B – Efficacy (n= ~10) Intravenous dosing with 1.5E13 vg/kg Clinical measures (Type II patients): Next steps: • Safety and tolerability • Initial data from Part A expected • Developmental changes meas
Slide 49: AXO-AAV-GM2
AXO-AAV-GM2 AAV gene therapy for Tay-Sachs and Sandhoff diseases
Slide 50: HEXA enzyme activity correlates with disease severity
HEXA enzyme activity correlates with disease severity 1,2 Late-Infantile/ Infantile Adult2,4 Asymptomatic (Most common) Juvenile3 • Age of onset: ~5 mo • Age of onset: 2-6 yrs • Age of onset: ~18+ yrs • Compatible with a • Median survival: 3-4 yrs • Median survival: 10-15 yrs • Relatively normal lif
Slide 51: AXO-AAV-GM2: Direct-to-CNS gene therapy approach
AXO-AAV-GM2: Direct-to-CNS gene therapy approach AXO-AAV-GM2 delivers two vectors encoding HEXA and HEXB genes directly to the CNS to produce β- Hexosaminidase A enzyme CB-CI-HEXA • Dual AAVrh8 vectors target CNS and provide subunit expression and subsequent enzyme reconstitution CB-CI-HEXB Dual int
Slide 52: Long-term effects of gene therapy in Sandhoff disease cats
Long-term effects of gene therapy in Sandhoff disease cats Untreated: ~4 months of age Treated: ~30 months of age 52
Slide 53: Long-term effects of gene therapy in Tay-Sachs disease sheep
Long-term effects of gene therapy in Tay-Sachs disease sheep Untreated: ~7.5 months of age Treated: ~13 months of age 53
Slide 54: Combined intraparenchymal and CSF dosing delivers optimal outcomes
Combined intraparenchymal and CSF dosing delivers optimal outcomes Bilateral thalamic + unilateral ICV (BiTh/ICV) injections in SD cats transduce entire neuraxis and dramatically improve function with significantly increased survival (P < 0.0001) Neuraxial Distribution of Reconstituted Enzyme with C
Slide 55: AXO-AAV-GM2: Initial data from first-in-human gene therapy for Tay-Sachs
AXO-AAV-GM2: Initial data from first-in-human gene therapy for Tay- Sachs Disease from UMass 2 patients dosed with AXO-AAV-GM2, under investigator-initiated protocols • TSD-001: 30-month old advanced infantile Tay-Sachs disease patient • TSD-002: 7-month old early symptomatic infantile Tay-Sachs dis
Slide 56: TSD-002 – Second patient dosed with AXO-AAV-GM2
TSD-002 – Second patient dosed with AXO-AAV-GM2: expanded access protocol A mildly symptomatic infantile TSD patient dosed bilaterally into thalamus and cisterna magna Age: 6 month old, female Family History: Two untreated older siblings with Thalamus Tay Sachs disease Cisterna • Siblings exhibited
Slide 57: TSD-002 Brain MRI: normal brain anatomy and increased myelination
TSD-002 Brain MRI: normal brain anatomy and increased myelination, consistent with normal brain development at this age Safety • Left arrow: Thalamus • Right arrow: Brain stem Pre-treatment Bioactivity and new myelination • Top arrow: Corpus callosum • Bottom arrow: Internal capsule 3 3 month post-T
Slide 58: First two patients dosed: stabilization of motor skills by CHOP INTEND
First two patients dosed with AXO-AAV-GM2: Observed stabilization of motor skills as measured by CHOP INTEND* 64 61 61 59 60 First Expanded Access Patient 60 58 58 56 (TSD-001) 52 • CHOP INTEND baseline total score 48 of 14, increasing to 18 44 40 36 Second Expanded Access Patient 32 (TSD-002) 28 23
Slide 59: Natural history of infantile GM2: Tay-Sachs and Sandhoff diseases
Natural history of infantile GM2: Tay-Sachs and Sandhoff diseases Clinical course illustrates rapidly progressive and uniformly fatal nature of infantile form of both diseases AGE (MONTHS) 0 1 2 3 4 Gain Loss Sitting without propping Most early motor milestones are gained and subsequently Gain Loss
Slide 60: AXO-AAV-GM2: Proposed Phase 1/2 adaptive design clinical study
AXO-AAV-GM2: Proposed Phase 1/2 adaptive design clinical study for infantile and juvenile Tay-Sachs/Sandhoff disease patients Part A – Dose-Ranging Part B – Efficacy (n = ~7) (n = ~10) Clinical measures: Next steps: • Safety and tolerability • Part A study initiation in 2020 • Enzyme activity in CSF
Slide 61: Corporate Summary as of 9/30/19
Corporate Summary as of 9/30/19 Axovant Gene Therapies Nasdaq: AXGT Cash and cash equivalents1 $60.3 million Working capital1 $19.6 million Long-term debt 1 $11.7 million Shares outstanding2 ~ 22.8 million ~38 full time employees2 Offices in New York City, NY and Raleigh, NC 1: As of September 30, 2
Slide 62: Every day matters. Every life matters.
Every day matters. Every life matters. 62
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