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1 S e p t e m b e r 2 0 2 5
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2 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-clinical and clinical trials, the timing of the availability of data from our clinical trials, the timing and sufficiency of patient enrollment and dosing in clinical trials, the timing of expected regulatory filings, and the clinical utility and potential attributes and benefits of ddRNAi and Benitec’s product candidates, and other forward-looking statements. These forward-looking statements are based on the Company’s current expectations and subject to risks and uncertainties that may cause actual results to differ materially, including unanticipated developments in and risks related to: the success of our plans to develop and potentially commercialize our product candidates; the timing of the completion of preclinical studies and clinical trials; the timing and sufficiency of patient enrollment and dosing in any future clinical trials; the timing of the availability of data from our clinical trials; the timing and outcome of regulatory filings and approvals; the development of novel AAV vectors; our potential future out-licenses and collaborations; the plans of licensees of our technology; the clinical utility and potential attributes and benefits of ddRNAi and our product candidates, including the potential duration of treatment effects and the potential for a “one shot” cure; our intellectual property position and the duration of our patent portfolio; expenses, ongoing losses, future revenue, capital needs and needs for additional financing, and our ability to access additional financing given market conditions and other factors, including the length of time over which we expect our cash and cash equivalents to be sufficient to execute on our business plan; unanticipated delays; further research and development and the results of clinical trials possibly being unsuccessful or insufficient to meet applicable regulatory standards or warrant continued development; the ability to enroll sufficient numbers of subjects in clinical trials; determinations made by the FDA and other governmental authorities and other regulatory developments; the Company’s ability to protect and enforce its patents and other intellectual property rights; the Company’s dependence on its relationships with its collaboration partners and other third parties; the efficacy or safety of the Company’s products and the products of the Company’s collaboration partners; the acceptance of the Company’s products and the products of the Company’s collaboration partners in the marketplace; market competition; sales, marketing, manufacturing and distribution requirements; greater than expected expenses; expenses relating to litigation or strategic activities; the impact of, and our ability to remediate the impact of local, regional, and national and international economic conditions and events; and other risks detailed from time to time in the Company’s reports filed with the Securities and Exchange Commission. The Company disclaims any intent or obligation to update these forward-looking statements. This presentation is not a prospectus and is neither an offer to sell nor a solicitation of an offer to buy any securities, and shall not constitute an offer, solicitation or sale in any jurisdiction in which such offer, solicitation or sale is unlawful. Safe Harbor Statement
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3 • Oculopharyn geal Mus c ular Dys trophy (OPMD) is a rare (15,000 patients in North America, Europe, and Israel), autosomal-dominant degenerative muscle disorder, caused by a mutation in the poly(A)-binding protein nuclear 1 (PABPN1) gene • PABPN1 is a ubiquitous protein that controls the length of mRNA poly(A) tails, mRNA export from the nucleus and alternative poly(A) site usage • OPMD has a typical age of onset in the 40s-50s, and patients typically present with: • Ptosis (eyelid drooping) which can be asymmetric at onset • Difficulty swallowing (dysphagia) and choking during meals • Progressive dysphagia impacts 97% of OPMD patients and is a severe, life-threatening complication of OPMD which can lead to chronic choking, malnutrition, aspiration pneumonia and, in severe cases, death • BB-301, a gene therapy designed to treat dysphagia in patients with OPMD, inhibits the production of the disease-causing protein and delivers a new , fully functional version of the protein OPMD is a Debilitating Progressive Disease With No Approved Therapies Design of Lead Candidate BB-301 R estoration of func tional PAB P N1 * c oP AB P N1 is insensitive to shR NA * Strings-Ufombah, et al., Molecular Therapy: Nucleic Acids, Vol. 24, 67-78, June 2021
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4 ddR NAi “S ilence and R eplace” P latform E nables B oth P ermanent S ilencing AND R eplacement of Mutated G enes in the T arget T is sue ADVANT AGES OF THE ddRNAi PLATFORM: • Long-term therapeutic potential from a single administration • Constant, steady-state levels of shRNA expression enables permanent silencing of mutated gene • Provides permanent expression of wildtype gene where activity is necessary for function or viability • Silence a single gene or multiple genes simultaneously LIMIT ATIONS OF CURRENT siRNA TECHNOLOGIES: • Requires repeatedadministration • Enables only transient silencing of mutated gene • Silencing capacity restricted to a single gene
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5 B ris s on , J D , Mu s c le & Nerve, 2020 OPMD: Overview of the Clinical Presentation • OP MD typically pres ents with: • P tos is (eyelid drooping) whic h c an be as ym m etric at ons et • Diffic ulty s wallowing (dys phagia) and choking during m eals • A retros pective c hart review was conduc ted at the S aguenay Neurom us cular Clinic (Quebec, Canada) to s creen for and c harac terize their OP MD population • Dysphagia was pres ent in 96.6% of subjec ts • P haryngeal pooling of thickened sec retions was pres ent in 74.1% of s ubjec ts • Dysphagia worsens over time and, as a result, patients can develop malnutrition and aspiration pneumonia which can lead to death
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6 Current Clinical Management Strategies for Dysphagia in OPMD Patients 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/application: – Cricopharyngeal muscle paralysis with botulinum toxin injections – Cricopharyngeal muscle dilation – Cricopharyngeal myotomy • In all cases, the pharyngeal constrictor muscles continue to atrophy, leading to progressive loss of pharyngeal clearance of food and liquid into the esophagus
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7 S wallowing O verview and the R ationale for B B -301 in O P MD OPMD Drives Disordered Swallowing • In OP MD, the pharyngeal cons trictor m us c les are weakened and atrophic and unable to s upport the propuls ion of food or liquid towards the es ophagus • In the c urrent c linic al s tudy, B B -301 is delivered to the pharyngeal c ons tric tor m us cles via direct intram us c ular injection in the operating room • Potential B B -301-derived increas es in m us c le cros s -s ectional area, m us c le m as s , and m us cle force s hould enhance the functional capac ity of the m us c les of OP MD patients , thereby reduc ing dys phagia Anatomical Structures of the Pharynx and BB-301 Injection Sites BB-301
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8 BB-301 Clinical Development Program Dosing (1 Day) Study can enroll up to 30 Subjects S ix S ubjects have been s afely treated with B B-301, an d n o T reatm en t-R elated S erious Advers e E vents were obs erved OPMD Natural History Study (26wk) BB-301 Phase 1b/2a Open-Label Dose Escalation Study (NCT06185673) (52wk)* 23 Subjects enrolled as of Jan 2024 Natural History Study Subjects enroll into the Phase 1b/2a Study Clinical follow-up vis its during which pre- treatm ent bas eline ass es sm ents are carried out for each S ubject Clinical follow-up vis its during which post- treatm ent as ses s m ents are carried out for each S ubject *P rim ary endpoints of safety and tolerability; Incidence of DL T s in P hase 1b, and Incidence of AE s according to NCI C T C AE v5.0 T he clinical and analytical m ethods em ployed exclus ively for the as ses s m ent of S ubject s afety in s tudies B NT C-OP MD-NH-001 and B NTC-OP MD-BB-301-01 repres ent globally- es tablished s tandards of care for hum an s ubjects (e.g., clinical chem is tries, hem atologic ass es sm ents , thyroid function testing, and urinalysis ). Efficacy endpoints (Sydney Swallow Questionnaire or “SSQ” and Videofluoroscopic Swallowing Studies or ”VFSS”) are assessed as the change from Baseline at Day 90, Day 180, Day 270, and Day 360.
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9 The key s ec ondary endpoints of the OPMD Natural His tory S tudy and the B B-301 Phas e 1b/2a C linic al S tudy (NC T06185673) facilitate s erial c haracterization of: • Subject-Reported Oral-Pharyngeal Dysphagia (via use of the 17-question patient reported outcome instrument, SSQ) • The S S Q is employed to s erially evaluate the s everity of dys phag ia as reported by the s ubject at each s ite vis it • Swallowing Efficiency (by assessment of post swallow accumulation of food/liquid material or “Total Pharyngeal Residue” via VFSS) and Swallowing Effectiveness (by assessment of frequency of pathologic sequential swallows via VFSS) • VF S S are employed to s erially analyz e S wallowing E ffic ienc y and S wallowing E ffec tivenes s at eac h clinic vis it, with imaging res ults reviewed and rated via a s tandardiz ed proc es s : • Central review of the respective videofluoroscopic images by multiple independent Speech Language Pathologists is used for all assessments • Individual reviewers are assigned videofluoroscopic studies to review and rate with no knowledge of scores applied by the other raters • The ratings are completed in full by each rater, and any discrepancies are resolved during a consensus meeting • The s tandardized s wallowing tas ks employed during the VF S S are not impac ted by the effort of the s ubjec t, as the autonomic nervous s ys tem c ontrols the involuntary mus c le movements c ompris ing the pharyng eal phas e of s wallowing Key Assessments: Subject-Reported and Videofluoroscopic Endpoints All Study Subjects are blinded to their Total SSQ Scores and VFSS (TPR and Sequential Swallowing) assessment results, and the Central Reader for the VFSS assessments is blinded to the SSQ Scores for all Study Subjects.
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10 Clinical Utility, Sensitivity, and Specificity of Key Assessment Methods • In the B B -301 P h as e 1b/ 2a C linical T reatm ent S tudy, R adiologis ts an d S peec h L anguage Pathologis ts em ploy s erial VF S S to objectively c haracterize the n ature and s everity of anatom ical and functional abnorm alities pres ent in eac h S ubject du ring th e pre- treatm ent and pos t -treatm ent periods • S erial S S Q as s es s m ents are em ployed to c haracterize the contribution of the videofluoros copic findings to th e total s ymptom bu rden of eac h S ubject, thus , linkin g the VF S S findings to the c hange in S ubject -reported s ymptom bu rden for the pre -treatm ent and pos t - treatm ent periods • The S S Q has been used in c onjunc tion with VF S S in several c ontrolled c linic al studies whic h c ompar ed the results of healthy subjec ts with those of dysphagic patients • T he s tudies dem ons trated s trong correlations between the res ults of VF S S -bas ed as s es s men ts and S S Q-bas ed as s es s men ts and facilitated the iden tification of S S Q cut -off values of 111.0 1 and 118.5 2, below which s wallowing is normal • Au dag, et al. 2 obtained a s en s itivity of 93% and a s pecificity of 82% with the us e of an S S Q cut -off s core of 118.5 • Addition ally, thes e s tudies provide robus t s u pport for the dis crim inant validity of the S S Q whic h is critical to its us e in t he accurate c haracterization of res pons es to treatm ent and the es tablis hm ent of efficacy of a given treatm ent 1Bua, B.A. and Bülow, M., BMC Research Notes (2014) 7:742; 2Audag N., et al., Dysphagia (2019) 34:556-566
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11 Distinct Drivers of Dysphagia Observed in the OPMD Study Population: Inefficient Swallowing and Ineffective Swallowing • OPMD Subjects enrolled into the OPMD Natural History Study and the BB-301 Phase 1b/2a Clinical Treatment Study can be impacted by the post swallow accumulation of food and liquid or “Inefficient Swallowing” • OPMD Subjects enrolled into the OPMD Natural History Study and the BB-301 Phase 1b/2a Clinical Treatment Study can be impacted by pathologic sequential swallows (i.e., rapid involuntary contractions of the pharyngeal muscles without restoration of the resting pharyngeal diameter between pharyngeal contractions occurring during the consumption of small volumes of liquids) or “Ineffective Swallowing”
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12 Post-Swallow Pharyngeal Residue and Dysphagic Symptom Burden • It is not known which of the abnormal consistency post-swallow residue value(s) contribute most to the dysphagic symptom burden in the pre-treatment period • Additionally, it is not clear if there exists a specific magnitude of post-swallow residue for a given consistency or a combination of consistencies which leads to the experience of dysphagic symptoms: • Does post-swallow residue for any consistency need to reach a specific level following treatment with BB- 301 (e.g., TPR for thin liquid must be below 10%) in order for the Subject to experience a reduction in dysphagic symptom burden? • Does post-swallow residue for any consistency need to decline by a specific percentage relative to the post- swallow residue result assessed during the NH Study (i.e., should TPR for thin liquid decline by 20% as compared to the NH Study thin liquid TPR value after the administration of BB-301) in order for the subject to experience a reduction in dysphagic symptom burden?
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13 Interim Cohort 1 Phase 1b Clinical Data Demonstrate Clinically Meaningful Improvements in Swallowing Function for the Two Discrete Causes of Dysphagia
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14 4.9 15.1 14.1 3.1 10.7 11.6 0 5 10 15 20 25 30 Thin Liquid Thick Liquid* Solid T otal Pharyngeal Residue Pre-dose average Post-dose average 12-Months Post BB-301 Treatment: VFSS TPR Assessments Demonstrate Significant, Clinically Meaningful Reductions of Post Swallow Residue Across all Consistencies for Subject 1 *Thick liquid represents average of moderately and extremely thick liquid on VFSS 37% improvement vs. Pre-dose Average TPR 18% improvement vs. Pre-dose Average TPR 29% improvement vs. Pre-dose Average TPR Total Pharyngeal Residue (%)
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15 1136 667 0 100 200 300 400 500 600 700 800 900 1,000 1,100 1,200 1,300 Average SSQ (Pre-Dose) 12-Month Average SSQ-Phase 1b (Post-Dose) SSQ Score Sydney Swallow Questionnaire Total Score 12-Months Post BB-301 Treatment: Total SSQ Scores Demonstrate Significant, Clinically Meaningful Reductions in the Total Dysphagic Symptom Burden Experienced by Subject 1 469-Point Decline • The 12-Month Average Post-Dose SSQ Score Showed a 41% Improvement vs. the Average Pre-Dose SSQ Score
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16 *Thick liquid represents average of moderately and extremely thick liquid on VFSS 12-Months Post BB-301 Treatment: VFSS TPR Assessments Demonstrate Stabilization of Post Swallow Residue for Thin Liquid and Reduction of Post Swallow Residue for Solid Food for Subject 2 1.5 2.6 5.3 1.6 9.1 4.7 0 5 10 15 20 25 30 Thin Liquid Thick Liquid* Solid T otal Pharyngeal Residue Pre-dose average Post-dose average 6.5-point increase vs. Pre-dose Average TPR Stabilization of TPR 11% improvement vs. Pre-Dose Average TPR Total Pharyngeal Residue (%)
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17 12 2 0 5 10 15 Pre-dose Post-dose Number of Tasks Eliciting Sequential Swallows VFSS Thin Liquid Tasks Demonstrating Pathologic Sequential Swallows 12-Months Post BB-301 Treatment: VFSS Assessments Demonstrate Significant, Clinically Meaningful Reductions in the Frequency of Pathologic Sequential Swallows for Subject 2 For Subject 2, pathologic sequential swallows for Thin Liquid were observed: • during 12 of the 15 swallowing tasks (frequency of 80%) carried out for Thin Liquid during the pre -dose site visits • during 2 of the 12 swallowing tasks (frequency of 17%) carried out for Thin Liquid during the post -dose site visits 12-months post BB-301 administration Subject 2 experienced an 83% reduction in the occurrence of pathologic sequential swallows The magnitude of reduction in frequency of pathologic sequential swallows for Thin Liquid noted at the 6 -month post-treatment interim clinical update in October 2024 (frequency of 17%) was maintained at month 12 The significant post-dose reduction in the frequency of pathologic sequential swallows drove a clinically meaningful reduction i n total dysphagic symptom burden for Subject 2 as demonstrated by VFSS assessments and Total SSQ Score.
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18 766 68 0 100 200 300 400 500 600 700 800 900 1,000 1,100 1,200 1,300 Average SSQ (Pre-Dose) 12-Month Average SSQ-Phase 1b (Post-Dose) SSQ Score Sydney Swallow Questionnaire Total Score 12-Months Post BB-301 Treatment: Total SSQ Scores Demonstrate Significant, Clinically Meaningful Reductions in the Total Dysphagic Symptom Burden Experienced by Subject 2, with Subject 2 Achieving Scores Representing Clinically Normal Swallowing The 12-month post-dose average SSQ value of 68 units for Subject 2 represents a clinically normal swallowing profile. 698-Point Decline • The 12-Month Average Post-Dose SSQ Score Showed a 91% Improvement vs. the Average Pre-Dose SSQ Score 82 82 82 82 SSQ Cut-Off Score for Normal Swallowing1,2 1Bua, B.A. and Bülow, M., BMC Research Notes (2014) 7:742; 2Audag N., et al., Dysphagia (2019) 34:556-566
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19 7.4 22.6 16.2 11.1 18.1 15.2 0 5 10 15 20 25 30 Thin Liquid Thick Liquid* Solid T otal Pharyngeal Residue Pre-dose average 3-months Post-dose 20% improvement vs. Pre-dose Average TPR *Thick liquid represents average of moderately and extremely thick liquid on VFSS 3-Months Post BB-301 Treatment: VFSS TPR Assessments Demonstrate Significant, Clinically Meaningful Reductions of Post Swallow Residue for Thick Liquid and Stabilization of Post Swallow Residue for Solid Food for Subject 3 3.7-point increase vs. Pre-dose Average TPR Stabilization of TPR Total Pharyngeal Residue (%)
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20 3-Months Post BB-301 Treatment: VFSS Assessments Demonstrate Significant, Clinically Meaningful Reductions in the Frequency of Pathologic Sequential Swallows for Subject 3 For Subject 3, pathologic sequential swallows for Thin and Thick liquids were observed: • during 21 of the 25 swallowing tasks (frequency of 84%) carried out for Thin and Thick Liquids during the pre -dose site visits • during 0 of the 5 swallowing tasks (frequency of 0%) carried out for Thin and Thick Liquids during the first post -dose clinical site visit at Month 3 3-months post BB-301 administration Subject 3 experienced a complete resolution of pathologic sequential swallows for Thin and Thick Liquids The complete resolution of pathologic sequential swallows for thin and thick liquid drove a clinically meaningful reduction in total dysphagic symptom burden for Subject 3 as demonstrated by VFSS assessments and Total SSQ Score. 21 0 0 5 10 15 20 25 Pre-dose Post-dose Number of Tasks Eliciting Sequential Swallows VFSS Thin Liquid Tasks and Thick Liquid Tasks Demonstrating Pathologic Sequential Swallows
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21 221 70 0 100 200 300 400 500 600 700 800 900 1,000 1,100 1,200 1,300 Average SSQ (Pre-Dose) 3-Month Post-Dose SSQ SSQ Score Sydney Swallow Questionnaire Total Score 3-Months Post BB-301 Treatment: Total SSQ Scores Demonstrate Significant, Clinically Meaningful Reductions in the Total Dysphagic Symptom Burden Experienced by Subject 3, with Subject 3 Achieving Scores Representing Clinically Normal Swallowing The 3-month post-dose SSQ value of 70 units for Subject 3 represents a clinically normal swallowing profile. 151-Point Decline • The 3-Month Post-Dose SSQ Score Showed a 68% Improvement vs. the Average Pre-Dose SSQ Score 82 82 SSQ Cut-Off Score for Normal Swallowing1,2 1Bua, B.A. and Bülow, M., BMC Research Notes (2014) 7:742; 2Audag N., et al., Dysphagia (2019) 34:556-566
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22 • Three Subjects with distinct causes of their respective total dysphagic symptom burdens were safely treated with BB-301 (1.2e13 vg/Subject) and experienced significant, clinically meaningful improvements in swallowing function • There were no Treatment-Related Severe Adverse Events • All three Subjects experienced significant reductions in their total dysphagic symptom burdens • Subject 1, plagued by Inefficient Swallowing, experienced clinically meaningful reductions in post swallow accumulation of foods and liquids per the VFSS TPR results and achieved a corresponding reduction in total dysphagic symptom burden per the Total SSQ Scores 12-months post-BB-301 administration. This Subject has completed the statistical follow-up period of the BB-301 Phase 1b/2a Treatment Study. • Subject 2, plagued by Ineffective Swallowing, experienced an almost complete resolution of Pathologic Sequential Swallows per the VFSS results and achieved a corresponding reduction in total dysphagic symptom burden per the Total SSQ Scores, achieving an SSQ score indicative of clinically normal swallowing 12-months post-BB-301 administration. This Subject has completed the statistical follow-up period of the BB-301 Phase 1b/2a Treatment Study. • Subject 3, plagued by Ineffective Swallowing, experienced complete resolution of Pathologic Sequential Swallows per the VFSS results and achieved a corresponding reduction in total dysphagic symptom burden per the Total SSQ Scores, achieving an SSQ score indicative of clinically normal swallowing at 3-months post BB-301 administration. Summary and Conclusions
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Financial Summary 23 Nasdaq Listed: BNTC • Exclusively Nasdaq listed; re- domiciled in April 2020 Shares Outstanding • 26,250,469 as of 8/31/25 Cash & Cash Equivalents • $96.25mm as of 8/31/25
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24 Appendix
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25 • 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 binding protein nuclear 1 (P ABPN1) gene • OP MD has been diagnos ed in at leas t 33 countries , and currently im pacts an es tim ated 15,000 patients in North Am erica E urope, and Is rael • L arge patient cohorts exis t globally as verified by the literature and s pecific patient/ population databas es OPMD: A Debilitating, Progressive Disease With No Approved Therapies Wildtype: ATG (GCG)6 -------------(GCA)3 GCG GGG GCT GCG… OPMD Mutant: ATG (GCG)6 (GCN)1-7 (GCA)3 GCG GGG GCT GCG… Estimated OPMD Estimated OPMD Country/Province/Region Population Prevalence Estimate Patient Population United States 333,000,000 0.00001 3,330 Quebec 8,500,000 0.001 8,500 Europe 742,000,000 0.00001 7,420
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26 Banerjee, A, FEBS J., 2013 Models for OPMD Pathogenesis • PABPN1 is a ubiquitous protein that controls the length of mRNA poly(A) tails, mRNA export from the nucleus and alternative poly(A) site usage • Currently two general models are used to explain how alanine-expanded PABPN1 confers muscle pathology in autosomal dominant OPMD where patients have one normal and one mutant allele of PABPN1 • One model suggests that nuclear aggregates cause disease (right column, outlined in red) • A second model suggests that loss of PABPN1 function (bottom row, outlined in blue) underlies pathology
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27 Szczesniak, M., et al, Dysphagia, 2014 S ubject-R eported O ral-P haryngeal Dysphagia: S ydney S wallow Questionnaire (S S Q) S coring Subject-reported oral-pharyngeal dysphagia as assessed by the SSQ: • The SSQ is a 17-item self-report inventory assessing subjective symptoms of oral-pharyngeal dysphagia • The questionnaire uses a 100-mm long visual analogue scale for all but 1 question • Possible scores range from 0 to 1700, with higher scores indicating greater swallowing difficulty • The SSQ has demonstrated strong content, construct, discriminant, and predictive validity and test-retest reliability in a range of patient populations • The SSQ evaluates a range of domains, including: difficulty swallowing specific food types/consistencies, frequency of choking during ingestion of specific food types/consistencies, and the requirement for multiple swallows during ingestion of food and liquid SSQ Example Questions
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28 Steele, C., et al. ASHA 2019 Convention Session on the ASPEKT C Method of Videofluoroscopy Analysis Swallowing Inefficiency: As Measured by Post Swallow Total Pharyngeal Residue • C2-C4 length serves as an anatomical scalar • Total Pharyngeal Residue measurement comprises the amount of food or liquid material remaining in the pharynx after the first swallow of the bolus • Measurement (yellow, green, and blue) occurs on the first frame showing pyriform sinuses at lowest position • Normal Total Pharyngeal Residue values should be close to zero
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29 Swallowing Ineffectiveness: As Measured by the Frequency of Pathologic Sequential Swallows • Sequential swallowing is defined as the completion of two or more consecutive swallows in rapid succession where the hyolaryn geal complex (HLC) does not return to rest and the pharynx lacks complete patency between swallows 1 • Under normal physiologic conditions, sequential swallowing occurs during continuous drinking of large volumes ( 90 mL or greater) of thin liquids via straw, cup, or bottle (for reference, one can of a soft drink has a volume of approximately 355 mL of thin liquid) • For the BB-301 Phase 1b/2a Study, the return of the HLC to its resting position (i.e., achievement of pharyngeal muscle relaxati on) between swallows is characterized on VFSS via the identification of the the “Swallow Rest Frame” • Swallow Rest is the terminal event of each discrete swallow, and the Swallow Rest Frame is identified as the first VFSS frame showing the pyriform sinuses at their lowest position, relative to the spine, prior to any hyoid burst or laryngeal elevation for a subsequent subswallow2 • In dysphagic disorders (e.g., OPMD), during the consumption of small volumes of liquids ( e.g., less than 15 mL, as employed in the BB-301 Phase 1b/2a Study ), pharyngeal muscle relaxation may not be achieved consistently between swallows (i.e., the HLC does not return to rest and the pharynx lacks complete patency); instead, a Subject may experience pathologic sequential swallows when consuming small volumes of liquids • Pathologic sequential swallows occur during the consumption of small volumes of liquid and are detected during VFSS as a series of rapid involuntary contractions of the pharyngeal muscles without restoration of the resting pharyngeal diameter between contractions 1Ambrocio, K. R., et al., Dysphagia (2023) 38:1497–1510; 2Steele, C., et al., Journal of Speech, Language, and Hearing Research, Vol. 62, 1338–1363, May 2019
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30 IND-Enabling Studies for BB-301 • 8-week study to confirm the transduction efficiency of BB-301 following direct intramuscular injection into the pharyngeal muscles via the use of an open surgical approach • The pharyngeal muscles injected with BB-301 in Beagle dogs (Hypopharyngeal muscles and Thyropharyngeal muscles) correspond to the dosing targets for human OPMD subjects (Middle Pharyngeal Constrictor muscles and Inferior Pharyngeal Constrictor muscles) 12-week GLP Toxicology and Biodistribution study in Beagle dogs Pilot Dosing Study in Beagle Dogs Toxicology Study in Beagle Dogs
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31 Dose-Dependent BB-301 Tissue Transduction Observed 8 Weeks Following Direct Intramuscular Injection in Beagle Dogs 1.52 3.15 5.12 2.06 2.70 5.66 Copies of BB-301 (average copies per cell) BB-301 Dose (vg/mL) Hypopharyngeal Muscle Thyropharyngeal Muscle 3.00 x 1013 vg/ml High Volume 5.12 5.66 3.00 x 1013 vg/ml Low Volume 3.15 2.70 1.00 x 1013 vg/ml 1.52 2.06 Biologically significant, dose-dependent delivery of the multi-functional genetic construct was achieved in the target pharyngeal muscles of Beagle dogs
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32 Dose-Dependent Expression of coPABPN1 Observed 8 Weeks Following Direct Intramuscular Injection of BB-301 in Beagle Dogs 1.52 3.15 5.12 2.06 2.70 5.66 Copies of coPABPN1 (average copies per cell) BB-301 Dose (vg/mL) Hypopharyngeal Muscle Thyropharyngeal Muscle 3.00 x 1013 vg/ml High Volume 61.69 77.26 3.00 x 1013 vg/ml Low Volume 27.43 62.89 1.00 x 1013 vg/ml 17.54 30.84 Dose-dependent expression of the replacement wildtype PABPN1 genetic construct was achieved in the target pharyngeal muscle cells of Beagle dogs
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33 Dose-Dependent Expression of siRNA13, siRNA17 Observed 8 Weeks Following Direct Intramuscular Injection of BB-301 in Beagle Dogs 1.52 3.15 5.12 2.06 2.70 5.66 siRNA13 siRNA17 Hypopharyngeal Muscle Thyropharyngeal Muscle Hypopharyngeal Muscle Thyropharyngeal Muscle BB-301 Dose (vg/mL) average copies per cell average copies per cell average copies per cell average copies per cell 3.00 x 1013 vg/ml High Volume 340,613 518,329 64,393 112,783 3.00 x 1013 vg/ml Low Volume 221,663 303,516 41,787 59,723 1.00 x 1013 vg/ml 83,168 136,812 17,321 30,253 Dose-dependent expression of the silencing moieties of the multi-functional genetic construct was achieved in the target pharyngeal muscle cells of Beagle dogs
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34 Dose-Dependent Inhibition of PABPN1 Observed 8 Weeks Following Direct Intramuscular Injection of BB-301 in Beagle Dogs 1.52 3.15 5.12 2.06 2.70 5.66 Average Reported % Inhibition of wtPABPN1 BB-301 Dose (vg/mL) Hypopharyngeal Muscle Thyropharyngeal Muscle 3.00 x 1013 vg/ml High Volume 83% 82% 3.00 x 1013 vg/ml Low Volume 74% 64% 1.00 x 1013 vg/ml 60% 69% 8 weeks following administration of BB -301 , an average wtPABPN1 inhibition level of 72% was achieved in the target pharyngeal muscle cells of Beagle dogs