Slide 1: SENS-501 Gene Therapy for Autosomal Recessive Non-Syndromic Deafness 9 (DFNB9)
SENS-501 Gene Therapy for Autosomal Recessive Non-Syndromic Deafness 9 (DFNB9) Laurent DESIRE, PhD ARO 2024
Slide 2: Disclaimer
DISCLAIMER • This document has been prepared by Sensorion (the “Company”) and is provided for • This document contains certain forward-looking statements. These statements are not information purposes only. This document does not purport to contain comprehensive guarantees of the Company’s future pe
Slide 3: Sensorion's Gene Therapy Programs Target Rare Auditory Diseases
Sensorion’s Gene Therapy Programs Target Rare Auditory Diseases FIRST PROGRAMS RESULTING FROM THE INSTITUT PASTEUR COLLABORATION OTOFERLIN DEFICIENCY GJB2-RELATED HEARING LOSS • Patients with mutations in OTOF suffer from severe to profound Three forms of hearing loss are associated with GJB2 gene s
Slide 4: OTOF Gene Encodes Otoferlin, A Key Ca2+ Sensor Protein
OTOF Gene Encodes Otoferlin, A Key Ca2+ Sensor Protein Iow Ca2+ Increase in Ca2+ SNARE Proteins VAMP Ca2+ Ca2+ Ca2+ Ca2+ Vesicle Ca2+-Channel Otoferlin Pre-synaptic membrane neurotransmitters release restricted SNARE interaction Otoferlin SNARE interaction SNARE-complex binding primed vesicle contai
Slide 5: Rationale for OTOF Mutation-associated Hearing Loss Gene Therapy
Rationale for OTOF Mutation-associated Hearing Loss Gene Therapy SENS-501 (OTOF-GT) to restore physiological hearing • Pilot program demonstrating that GT is a relevant • Well understood biology and pathology of the otoferlin medical approach for the inner ear deficiency • Establish understanding of
Slide 6: Current strategies for OTOF gene therapies
Current strategies for OTOF gene therapies Dual AAV - Different serotypes and promoters1-5 Dual AAV - Protein trans-splicing of N- and C-terminal otoferlin6 AAV8 ANC80 RNA Base conversion (correction of Q829X stop mutation)7 AAV1 Shanghai Refreshgene Therapeutics AAV1 Suzhou Otovia Therapeutics AAV
Slide 7: Development Strategy
Development Strategy CRITERIA SENSORION AAV capsid selected for high-level of target cells specificity GT product showing high level of target cells transduction Limited off-target tissue biodistribution Surgical approach developed and mastered by ENTs surgeons Natural History Study preparing execut
Slide 8: SENS-501 Is a Dual AAV8 Containing The Coding Sequence Of Human Otoferlin
SENS-501 Is a Dual AAV8 Containing The Coding Sequence Of Human Otoferlin, Allowing Expression Of Full-length Otoferlin Schematic hybrid dual AAV8 In vitro expression of full length Otoferlin protein SENS-501 Nter SENS-501 Cter ITR ITR ITR ITR prom HR * • Highly efficient recombination (e.g. full le
Slide 9: SENS-501 Is a Dual AAV8 Containing The Coding Sequence Of Human Otoferlin
SENS-501 Is a Dual AAV8 Containing The Coding Sequence Of Human Otoferlin, Allowing Expression Of Full-length Otoferlin Schematic hybrid dual AAV8 In vivo expression of full length Otoferlin protein SENS-501 Nter SENS-501 Cter ITR ITR ITR ITR prom HR Cter Flag Cter Flag Cter specific antibody ITR: I
Slide 10: SENS-501 Is a Dual AAV8 Containing The Coding Sequence Of Human Otoferlin
SENS-501 Is a Dual AAV8 Containing The Coding Sequence Of Human Otoferlin, Allowing Expression Of Full-length Otoferlin Schematic hybrid dual AAV8 No deleterious impact on cochlear histology and ABR at high dose in WT mice SENS-501 Nter SENS-501 Cter ITR ITR ITR ITR prom HR ITR: Inverted Terminal Re
Slide 11: SENS-501 Efficacy is Supported by multiple In Vivo Studies
SENS-501 Efficacy is Supported by multiple In Vivo Studies Conducted in a Translational Model of Otoferlin Deficiency Dual vector Treatment Duration Main results2 OTOF -/- mice1 • Stable & long-term restoration AAV8 – murine OTOF Before hearing onset 1 year as early as 4w post injection (P10) • No a
Slide 12: SENS-501 Leads To Long-term Hearing Recovery In OTOF-/- Mice
SENS-501 Leads To Long-term Hearing Recovery In OTOF-/- Mice Long-term hearing restoration Hearing restoration correlates with de novo OTOF expression AAV-mOTOF injected in mice before hearing onset SENS-501 injected in mice after hearing onset O/IHC: Outer/Inner Hair Cells • Long term (up to 10 mon
Slide 13: SENS-501 Leads To Restoration Of The Startle Reflex In OTOF-/- Mice
SENS-501 Leads To Restoration Of The Startle Reflex In OTOF-/- Mice Startle platform Behavior test based on hearing recovery implemented in P14 Otof-/- mice White noise pulse (2-20 kHz, 115 dB) Wild type Non-injected Otof ko/ko Restored Otof ko/ko • Restoration of the startle reflex in Otof-/- mice,
Slide 14: Dedicated Surgical Approach For Gene Therapy
Dedicated Surgical Approach For Gene Therapy Non-Human Primates injected through the round window membrane (RWI) with or without stapedotomy (stap) with AAV8 GFP 1 Fenestration Surgical approach Used for cochlear implant • Surgical procedure mastered by ENTs surgeons • Overpressure • Limited volume
Slide 15: Dedicated Surgical Approach For Gene Therapy
Dedicated Surgical Approach For Gene Therapy Non-Human Primates injected through the round window membrane (RWI) with or without stapedotomy (stap) with AAV8 GFP Efficient transduction in NHP Comparable transducibility No impact of anti-AAV8 immunity from base to apex mouse vs NHP on transgene expre
Slide 16: 3-month GLP Toxicology and Biodistribution Studies In NHP
3-month GLP Toxicology and Biodistribution Studies In NHP Study design Toxicology • 2 doses, vehicle group • SENS-501 is well tolerated and did not No local findings in the inner ear or • M/F, n=3/sex/group induce any macroscopic/organ weight vestibular system, the auditory nerve • Juvenile at surg
Slide 17: 3-month GLP Toxicology and Biodistribution Studies In NHP
3-month GLP Toxicology and Biodistribution Studies In NHP Study design Biodistribution and shedding • 2 doses, vehicle group • The vast majority of the vectors remains in the injected ear, no dissemination was • M/F, n=3/sex/group observed in gonads, main organs and brain • Juvenile at surgery • Ou
Slide 18: SENS-501 Preclinical Development Status
SENS-501 Preclinical Development Status - A 3-month single dose toxicology study aiming to assess toxicology, biodistribution, local tolerance and immunogenicity of intracochlear administration of SENS-501 in NHP (study SENS1100-TX-413). - A 6-month single dose toxicology study aiming to assess toxi
Slide 19: Phase 1/2 Audiogene Study (SENS-501) Approved in France
Phase 1/2 Audiogene Study (SENS-501) Approved in France First Patient Communication Anticipated in H2 2024 Audiogene, a Phase 1/2 clinical trial in children aged 6 to 31 months to assess safety, tolerability, and efficacy of SENS-501 following unilateral injection into the cochlea Audiogene Study De
Slide 20: Otoferlin Audinnove Consortium and ongoing Natural History Studies
Otoferlin “Audinnove” Consortium and ongoing Natural History Studies Provide Privileged Access To Patients And Surgeons Audinnove consortium received Hospital-University Research (RHU) prize: • The consortium is eligible to receive up to €9.7m to develop a Gene Therapy program addressing otoferlin d
Slide 21: SENS-501 (OTOF) Gene Therapy Program Status – Progressing
SENS-501 (OTOF) Gene Therapy Program Status – Progressing Injection device system Preclinical package completed development completed GMP Drug product manufactured CTA Approval in France European Natural History Study First Patient Communication OTOCONEX H2 2024 Copyright by Sensorion - 2023 - All R
Slide 22: Acknowledgements
Acknowledgements Arnaud Giese Christine Le Bec Jerome Nevoux Natalie Loundon Guillaume Olivier Emilie Bousquet Ghizlene Lahlou Christophe Tran Van Ba Geraldine Honnet Marie-José Lecomte Lise Barrot Lionel Hofsepian Saaid Safieddine Rafik Boudra Laetitia Zara Baptiste Plion Julie Duron Dos Reis Valer