Slide 1: Interim Clinical Data Summary: Phase 1b/2a Study of BB-301 in OPMD
Interim Clinical Data Summary: A Phase 1b/2a Open-label, Dose Escalation Study to Evaluate the Safety and Clinical Activity of Intramuscular Doses of an AAV9-based gene therapy (BB-301) Administered to Subjects with Oculopharyngeal Muscular Dystrophy (OPMD) with Dysphagia 1 October 14, 2024
Slide 2: Safe Harbor Statement
Safe Harbor Statement Except for the historical information set forth herein, the matters set forth in this presentation include forward-looking statements, including statements regarding Benitec’s plans to develop and commercialize its product candidates, the timing of the completion of pre-clinica
Slide 3: Agenda
Agenda 01 Introduction to Speakers 02 OPMD Clinical and Pathophysiological Overview 03 Pathophysiology of Dysphagia in OPMD 04 BB-301 Clinical Development Program 05 BB-301 Phase 1b Clinical Data Summary 06 Q&A Session with Professor Emily Plowman, PhD, CCC-SLP, FASHA 3
Slide 4: Professional Biography
Professional Biography: Emily Plowman, PhD, CCC-SLP, FASHA, Professor, Department of Otolaryngology – Head and Neck Surgery, The Ohio State University College of Medicine is Director of the Aerodigestive Research Core across its two sites at the Ohio State University and University of Florida and Di
Slide 5: Key Data Findings
Key Data Findings • Two subjects have received the lowest-dose of BB-301 (1.2e13 vg/subject), and there were no Significant Adverse Events. • Dysphagic symptoms at baseline for Subject 1 (7-years post diagnosis) were more severe than those of Subject 2 (6- years post diagnosis) as assessed by pre-do
Slide 6: Oculopharyngeal Muscular Dystrophy: Clinical and Pathophysiological Overview
Oculopharyngeal Muscular Dystrophy: Clinical and Pathophysiological Overview 6
Slide 7: OPMD: A Chronic, Progressive Disease With No Approved Therapeutics
OPMD: A Chronic, Progressive Disease With No Approved Therapeutics • Oculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant, chronic, myopathic disorder with a typical age of onset in the 40s-50s • OPMD results from a trinucleotide repeat expansion within exon 1 of the polyadenylate bind
Slide 8: OPMD: Clinical Presentation
OPMD: Clinical Presentation • OPMD typically presents with: • Ptosis (eyelid drooping) which can be asymmetric at onset • Choking during meals (dysphagia), leading to prolonged mealtimes and avoidance of specific food • A retrospective chart review was conducted at the Saguenay Neuromuscular Clinic
Slide 9: Current Clinical Management Strategies for Dysphagia Do Not Prevent Disease Progression
Current Clinical Management Strategies for Dysphagia Do Not Prevent Disease Progression • Nutritional recommendations including dietary texture/consistency modifications • Surgical Interventions for moderate to severe dysphagia have temporary effects and may require repeated administration/applicati
Slide 10: BB-301 Inhibits the Production of the Key Disease-Causing Protein in OPMD
BB-301 Inhibits the Production of the key Disease-Causing Protein in OPMD and Delivers a New, Fully-Functional Version of the Protein • BB-301 is a gene therapy designed by Benitec Biopharma Inc. to accomplish two goals: Design of Lead Candidate * BB-301 • Reduce the production of the mutant form of
Slide 11: ddRNAi Platform Enables Both Permanent Silencing AND Replacement of Mutated Genes
ddRNAi Platform Enables Both Permanent Silencing AND Replacement of Mutated Genes in the Target Tissue LIMITATIONS OF CURRENT siRNA TECHNOLOGIES: • Requires repeated administration • Enables only transient silencing of mutated gene • Silencing capacity restricted to a single gene ADVANTAGES OF THE d
Slide 12: BB-301 Demonstrated Robust Molecular Activity in the OPMD A17 Mouse Model
BB-301 Demonstrated Robust Molecular Activity and Complete Restoration of Muscle Strength in the OPMD A17 Mouse Model • Improvements in Muscle Strength in A17 mice were observed at the Lowest Gene Replacement Level • The lowest effective dose tested in the A17 mouse model is currently being evaluate
Slide 13: Swallowing Overview and The Rationale for BB-301 in OPMD
Swallowing Overview and The Rationale for BB-301 in OPMD OPMD Drives Disordered Swallowing Anatomical Structures of the Pharynx and BB-301 Injection Sites • In OPMD, the pharyngeal constrictor muscles are weakened and atrophic and unable to support the propulsion of food or liquid towards the esopha
Slide 14: Pathophysiology of Dysphagia in OPMD
Pathophysiology of Dysphagia in OPMD 14
Slide 15: Distinct Drivers of Dysphagia Noted in the OPMD Study Population
Distinct Drivers of Dysphagia Noted in the OPMD Study Population • OPMD subjects enrolled into the OPMD Natural History Study and the BB-301 Phase 1b/2a Clinical Study have been shown to be impacted by excessive accumulation of pharyngeal residue post-swallow • OPMD subjects enrolled into the OPMD N
Slide 16: Impaired Pharyngeal Clearance Leads to Aspiration, Aspiration Pneumonia, and Death
Impaired Pharyngeal Clearance Leads to Aspiration, Aspiration Pneumonia, and Death Approximately one third of subjects had respiratory diagnoses listed as the cause of death: • Impaired swallowing (dysphagia) can lead to aspiration pneumonia • Pneumonia can result from the aspiration of food and/or
Slide 17: Sequential Swallowing is a Normal Physiologic Process in Healthy Subjects
Sequential Swallowing is a Normal Physiologic Process Observed in Healthy Subjects During the Consumption of Large Volumes of Thin Liquid (e.g., ³90 mL of Water) • Sequential swallowing is defined as the completion of two or more consecutive swallows in rapid succession where the hyolaryngeal comple
Slide 18: Pathologic Sequential Swallowing Detected for OPMD Subjects on VFSS
During VFSS Assessments, Pathologic Sequential Swallowing was Detected for OPMD Subjects During the Consumption of Low Volumes of Thin Liquids (i.e., <15 mL of Thin Liquid) • For the BB-301 Phase 1b/2a Study, the achievement of physiologic pharyngeal muscle relaxation during the swallowing of low-vo
Slide 19: BB-301 Clinical Development Program
BB-301 Clinical Development Program 19
Slide 20: BB-301 Clinical Development Program (Estimated Timeline for Cohort 1)
BB-301 Clinical Development Program (Estimated Timeline for Cohort 1) Subject (2024) (2024) (2024) (2025) (2025) (2025) (2025) October November December January February March April 1 (Treated 4Q2023) 2 (Treated 1Q2024) 3 Projected Dosing 4 Projected Dosing 5 Projected Dosing 6 Projected Dosing • Fi
Slide 21: BB-301 Clinical Development Program and Key Assessments
BB-301 Clinical Development Program and Key Assessments Characterization of patient OPMD Natural BB-301 Phase 1b/2a Open- Endpoints disposition at baseline: History Study Dosing label Dose Escalation Study (NCT06185673) • Primary: (26wk) (1 Day) • Degree of, and rates of, Safety and tolerability* (5
Slide 22: Key Subject-Reported and Videofluoroscopic Endpoints
Key Subject-Reported and Videofluoroscopic Endpoints The key secondary endpoints of the OPMD Natural History Study and the BB-301 Phase 1b/2a Clinical Study (NCT06185673) facilitate serial characterization of: • Subject-Reported Oral-Pharyngeal Dysphagia (via the use of a validated 17-item patient r
Slide 23: Subject-Reported Oral-Pharyngeal Dysphagia: Sydney Swallow Questionnaire (SSQ)
Subject-Reported Oral-Pharyngeal Dysphagia: Sydney Swallow Questionnaire (SSQ) Key SSQ Example Questions Subject-reported oral-pharyngeal dysphagia as assessed by the SSQ: • The questionnaire uses a 100-mm long visual analogue scale for all but 1 question • Possible scores range from 0 to 1700, with
Slide 24: Swallowing Efficiency: As Measured by Total Pharyngeal Residue
Swallowing Efficiency: As Measured by Total Pharyngeal Residue • C2-C4 length act as an anatomical scalar • “Total Pharyngeal Residue” measurement comprises the amount of material remaining in the pharynx after the first swallow of the bolus • Measurement (yellow, green, and blue) occurs on the firs
Slide 25: What Constitutes Clinically Meaningful Improvements in Swallowing?
What Constitutes Clinically Meaningful Improvements in Swallowing? Clinical researchers and caregivers report clinically meaningful improvement would be defined by: • Improvement in Subject-Reported Outcomes post BB-301 dose (i.e., reductions in the Sydney Swallow Questionnaire [”SSQ”] Total Scores)
Slide 26: Interim Low-Dose BB-301 Phase 1b Clinical Data Summary
Interim Low-Dose BB-301 (1.2e13 vg/subject) Phase 1b Clinical Data Summary for the First Two Study Subjects Demonstrates Strong Correlations Between Videofluoroscopic Swallowing Study Results and the Sydney Swallow Questionnaire Scores 26
Slide 27: Pre-Dose Characteristics of Subjects and Correlations Between SSQ and VFSS TPR
Pre-Dose Characteristics of Subject 1 and Subject 2 Demonstrate Strong Correlations Between SSQ Scores and VFSS TPR Results • Milder Dysphagic Symptoms Noted for Subject 2 vs. Subject 1 Based on SSQ Scores and VFSS TPR Results • Global inefficiency of swallowing for Solid Food, Thin Liquid, and Thic
Slide 28: Subject 1: SSQ Sub-Scores Correlate with VFSS TPR Assessments
Subject 1: Key SSQ Questions and Pre-Dose SSQ Sub-Scores Correlate Directly with VFSS TPR Assessments VFSS TPR Correlate SSQ Question Average Pre-Dose SSQ Sub-Score SSQ Sub-Score Comments Thin Liquid (Thin 5 mL) Question 2: 46.6 (out of 100) • Prior to BB-301 dosing, Subject 1 reports the least How
Slide 29: Subject 1: SSQ and VFSS Correlate with Pre-Dose TPR Results
Subject 1: Key SSQ Questions and Pre-Dose SSQ Sub-Scores Correlate Directly with Pre-Dose VFSS TPR Results VFSS TPR Correlate Average Pre-Dose VFSS VFSS TPR Comments SSQ Question Average Pre-Dose SSQ SSQ Sub-Score Comments TPR Sub-Score Thin Liquid 4.9% • Prior to BB-301 dosing, the VFSS TPR Questio
Slide 30: Subject 1 Post-Dose Improvements Across All Consistencies
9 Months Post BB-301 Dose: SSQ, VFSS TPR Show Subject 1 Experienced Clinically Meaningful Improvements across all Consistencies Thin liquid SSQ and TPR Thick liquid1 SSQ and TPR TPR SSQ TPR SSQ 24 100 24 89.0 100 77.8 18 63.0 75 18 60.6 75 TPR (%) TPR (%) 46.6 SSQ SSQ 12 50 12 50 26.9 6 25 6 25 0 0
Slide 31: Subject 1 Significant Improvement in 9-Month Average Post-Dose SSQ
Subject 1 Experienced Significant Improvement in 9-Month Avg. Post-Dose Sydney Swallow Questionnaire Scores • The 9-Month Average Post-Dose SSQ Showed a 35% Improvement vs. the Average Pre-Dose SSQ and a 42% Improvement vs. the Final Pre-Dose SSQ Sydney Swallow Questionnaire Total Score 1,300 1,200
Slide 32: Subject 2: SSQ Sub-Scores Correlate with VFSS TPR Assessments
Subject 2: Key SSQ Questions and Pre-Dose SSQ Sub-Scores Correlate Directly with VFSS TPR Assessments VFSS TPR Correlate SSQ Question Average Pre-Dose SSQ Sub-Score SSQ Sub-Score Comments Thin Liquid (Thin 5 mL) Question 2: 26.4 (out of 100) • Prior to BB-301 dosing, Subject 2 reports the least How
Slide 33: Subject 2: SSQ and VFSS Correlate with Pre-Dose TPR Results
Subject 2: Key SSQ Questions and Pre-Dose SSQ Sub-Scores Correlate Directly with Pre-Dose VFSS TPR Results VFSS TPR Correlate Average Pre-Dose VFSS VFSS TPR Comments SSQ Question Average Pre-Dose SSQ SSQ Sub-Score Comments TPR Sub-Score Thin Liquid 1.5% • Prior to BB-301 dosing, the VFSS TPR Questio
Slide 34: Subject 2 Post-Dose Stabilization or Improvement Across Consistencies
6 Months Post BB-301 Dose: SSQ, VFSS TPR Show Subject 2 Experienced Stabilization or Clinically Meaningful Improvement across all Consistencies Thin liquid SSQ and TPR Thick liquid1 SSQ and TPR TPR SSQ TPR SSQ 24 100 24 100 18 75 18 75 54.0 57.0 TPR (%) TPR (%) SSQ SSQ 12 50 12 38.5 50 26.4 6 25 6 2
Slide 35: Significant Reduction in Pathologic Low-Volume Sequential Swallowing
Subject 2 Experienced a Significant Reduction in Pathologic Low-Volume Sequential Swallowing 6 Months Post BB-301 Dose SSQ Question 14: “Do you Ever Need to Swallow More Than SSQ Question 14 Once for Your Food to Go Down?” 100 77.6 For Subject 2, the Average Post-Dose SSQ Sub-Score was 75 SSQ Sub-Sc
Slide 36: Subject 2 Significant 6-Month Post-Dose SSQ Improvement
Subject 2 Experienced a Significant Improvement in Post-Dose Sydney Swallow Questionnaire Scores, Achieving Scores that Represents Clinically Normal Swallowing • The 6-Month Average Post-Dose SSQ Showed an 89% Improvement vs. the Average Pre-Dose SSQ and a 92% Improvement vs. the Final Pre- Dose SSQ
Slide 37: Summary and Conclusions
Summary and Conclusions • Two subjects have received the lowest-dose of BB-301 (1.2e13 vg/subject) with compelling clinical impact • There were no Significant Adverse Events • Both subjects experienced significant levels of clinical benefit per the post-dose SSQ scores • Both subjects experienced si
Slide 38: Summary and Conclusions (continued)
Summary and Conclusions (continued) • The Total SSQ scores represent the most accurate reflection of the subjects’ experiences of their pre-dose and post-dose dysphagic symptoms. • The final pre-dose visit is temporally closest to the subjects’ post-dose experiences • The final pre-dose visit likely
Slide 39: Q&A: Videofluoroscopic Swallowing Studies and Subject-Reported Outcome Measures
Q&A: Videofluoroscopic Swallowing Studies and Subject-Reported Outcome Measures Professor Emily Plowman, PhD, CCC-SLP, FASHA 39
Slide 40: Appendix
Appendix 40
Slide 41: OPMD: A Chronic, Progressive Disease With No Approved Therapeutics
OPMD: A Chronic, Progressive Disease With No Approved Therapeutics • Oculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant, chronic, myopathic disorder characterized by ptosis (drooping of the upper eyelid) and progressive dysphagia (loss of the ability to swallow) due to impairment of
Slide 42: Models for OPMD Pathogenesis
Models for OPMD Pathogenesis • PABPN1 is a ubiquitous protein that controls the length of mRNA poly(A) tails, mRNA export from the nucleus & alternative poly(A) site usage • Currently two general models are used to explain how alanine-expanded PABPN1 confers muscle pathology in autosomal dominant OP
Slide 43: BB-301 Inhibits the Production of the Key Disease-Causing Protein in OPMD
BB-301 Inhibits the Production of the key Disease-Causing Protein in OPMD and Delivers a New, Fully-Functional Version of the Protein • BB-301 is a gene therapy designed by Benitec Biopharma Inc. to accomplish two goals: Design of Lead Candidate * BB-301 • Reduce the production of the mutant (harmfu
Slide 44: IND-Enabling Studies for BB-301
IND-Enabling Studies for BB-301 Pilot Dosing Study in Beagle Dogs Toxicology Study in Beagle Dogs • 8-week study to confirm the transduction 12-week GLP Toxicology and Biodistribution efficiency of BB-301 following direct study in Beagle dogs intramuscular injection into the pharyngeal muscles via t
Slide 45: Dose-Dependent BB-301 Tissue Transduction in Beagle Dogs
Dose-Dependent BB-301 Tissue Transduction Observed 8 Weeks Following Direct Intramuscular Injection in Beagle Dogs Copies of BB-301 (average copies per cell) BB-301 Dose Hypopharyngeal Thyropharyngeal 5.66 (vg/mL) Muscle 5.12 Muscle 3.00 x 1013 vg/ml 5.12 5.66 High Volume 3.00 x 1013 vg/ml 3.15 2.70
Slide 46: Dose-Dependent Expression of coPABPN1 in Beagle Dogs
Dose-Dependent Expression of coPABPN1 Observed 8 Weeks Following Direct Intramuscular Injection of BB-301 in Beagle Dogs Copies of coPABPN1 (average copies per cell) BB-301 Dose Hypopharyngeal Thyropharyngeal 5.66 (vg/mL) Muscle 5.12 Muscle 3.00 x 1013 vg/ml 61.69 77.26 High Volume 3.00 x 1013 vg/ml
Slide 47: Dose-Dependent Expression of siRNA13, siRNA17 in Beagle Dogs
Dose-Dependent Expression of siRNA13, siRNA17 Observed 8 Weeks Following Direct Intramuscular Injection of BB-301 in Beagle Dogs siRNA13 siRNA17 Hypopharyngeal Thyropharyngeal Hypopharyngeal Thyropharyngeal Muscle Muscle Muscle Muscle BB-301 Dose average copies per 5.66 average copies per cell avera
Slide 48: Dose-Dependent Inhibition of PABPN1 in Beagle Dogs
Dose-Dependent Inhibition of PABPN1 Observed 8 Weeks Following Direct Intramuscular Injection of BB-301 in Beagle Dogs Average Reported % Inhibition of wtPABPN1 BB-301 Dose Hypopharyngeal Thyropharyngeal 5.66 (vg/mL) Muscle Muscle 5.12 3.00 x 1013 vg/ml 83% 82% High Volume 3.00 x 1013 vg/ml 74% 64%
Slide 49: Swallowing Overview and The Rationale for BB-301 in OPMD
Swallowing Overview and The Rationale for BB-301 in OPMD Normal vs. Disordered Swallowing Anatomical Structures of the Pharynx and BB-301 Injection Sites • Under normal conditions, a food bolus leaves the oral cavity and is able to traverse the length of the pharynx, en route to the esophagus, via t
Slide 50: Primary Source Data Verification
Primary Source Data Verification • All safety data are confirmed via a process of Source Data Verification (SDV) approximately monthly • The SDV process entails a clinical representative of the Clinical Research Organization (CRO) visiting the clinical site and reviewing all primary medical data ent