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Sensorion Sas — Sensorion — Sensorion KOL Event – GJB2 gene related hearing loss (May 2021)

51 slides from Sensorion Sas's conference presentation, May 10, 2021

1. Slide 1: May 2020

   May 2020 Copyright by Sensorion - 2021 - All Rights Reserved

2. Slide 2: Sensorion KOL Event – GJB2 gene related hearing loss

   Sensorion KOL Event – GJB2 gene related hearing loss DISCLAIMER Q&A PRESENTATION & REPLAY As a reminder, during Today there will also be an The presentation will be today‘s call, we will make opportunity to ask available on Sensorion‘s forward looking statements questions. Please wait website and a

3. Slide 3: Today's agenda

   Today’s agenda Introduction Nawal Ouzren, Chief Executive Officer of Sensorion Clinical aspects, current treatments landscape and unmet medical needs in treating patients with a pediatric onset of GJB2-related hearing loss as well as the role of the GJB2 gene Thomas Lenarz, M.D., Ph.D., Pofessor of

4. Slide 4: GJB2 Gene Related Hearing Loss

   GJB2 Gene Related Hearing Loss Thomas Lenarz Dept Otolaryngology, Hannover Medical School Chair: Thomas Lenarz, MD PhD Sensorion KOL Webinar, May 10, 2021 Version 1.0, November 2017

5. Slide 5: Clinical relevance of hearing loss

   Clinical relevance of hearing loss > 450 Million people Costs for Risk Faktor society 750 for No Medical affected Treatment globally Billion € Dementia 15 % of the population affected, growing with age Children: 2 / 1000 affected www.mhh-hno.de

6. Slide 6: Etiology of Hearing Loss

   Etiology of Hearing Loss • Genetics: Children 50 – 70 %, adults 30 % • Noise • Aging • Ototoxic agents • Infections • Trauma • Unknown www.mhh-hno.de

7. Slide 7: Genetics in Hearing loss

   Genetics in Hearing loss https://www.nature.com/articles/gim200764/figures/2 www.mhh-hno.de

8. Slide 8: Genetics of Hearing Loss

   Genetics of Hearing Loss • Non-syndromic hearing loss follows simple Mendelian laws • autosomal recessive (75-80%) • autosomal dominant (20%) • X-linked (2-5%) • mitochondrial (1%) • Onset and severity also follow simple clinical patterns • autosomal recessive usually prelingual, non-progressive (st

9. Slide 9: Human Genome Project and hearing loss gene discovery

   HUMAN GENOME PRoveCT DRAFT RELEASED. HUMAN GENOME PROJECT 1] COMPLETED: $3 BILLION GIB6(R) GIB3 : GRHL2 A COCH ; MYO3A ; DFNAS i OTOA i MYOISA H USHIC H Sian Gnel POUSE3 H TMCI(D) i anita TECTA (D) H TMCI(R) H MYHI4 POU3F4 SLO26A4 MYHO H TMIE i a : 2000 2001 2002 2003 2004 2005 GJB2(D) GIB6(D) CDH23

10. Slide 10: Genetics in Hearing Loss

    Genetics in Hearing Loss • Loci for genes inherited in an autosomal dominant manner: DFNA • Loci for genes inherited in an autosomal recessiv manner: DFNB • loci for genes inherited in an X-linked manner are referred: DFNX www.mhh-hno.de

11. Slide 11: Genes of Interest: Prevalence in Europe

    Genes of Interest: Prevalence in Europe Gene Locus Percentage Audioprofile GJB2/GJB6 DFNB1 18-41% Late onset possible; progressive TMC1 DFNB7/11 Common in the Late onset with Middle-East progression during first 3 decades possible STRC DFNB16 5.5% in GJB2- Mild to neg population moderate, gentle dow

12. Slide 12: Genetic hearing loss through GJB2 mutations

    Genetic hearing loss through GJB2 mutations Defect Mutation CX26 Gap Resorption Gen GJB2 Junction K+ https://www.researchgate.net/figure/Location -of-connexin-26-GJB2-in-the-potassium- https://www.ncbi.nlm.nih.gov/books/NBK22204 recycling-pathway-of-the- /figure/connexinFig/ cochlea_fig4_5627377

13. Slide 13: Different GJB2 Mutations

    Different GJB2 Mutations • Many mutations are either • biallelic GJB2 mutations • mild to profound • most commonly nonprogressive • Truncating mutations (36) • Homozygous (T/T) • heterozygous (T/NT) • IVS1+1G→A • del(GJB6-D13S1830)

14. Slide 14: Different GJB2 Mutations

    Different GJB2 Mutations • Nontruncating mutations (47) • homozygous nontruncating (NT/NT) • Heterozygous • M34T, Kelsell et al. 1997; • W44C, Denoyelle et al. 1998; • W44S, Gasparini et al. Personal communication; • R75W, Richard et al. 1998a; • D66H, Maestrini et al 1999

15. Slide 15: GJB2 Mutations and Grade of Hearing Loss

    GJB2 Mutations and Grade of Hearing Loss Kochhar, A., Hildebrand, M. & Smith, R. Clinical aspects of hereditary hearing loss. Genet Med 9, 393–408 (2007). https://doi.org/10.1097/GIM.0b013e3180980bd0

16. Slide 16: GJB2 Mutations in MHH Patients

    GJB2 Mutations in MHH Patients Burke WF, Warnecke A, Schöner-Heinisch A, Lesinski-Schiedat A, Maier H, Lenarz T. Prevalence and audiological profiles of GJB2 mutations in a large collective of hearing impaired patients. Hear Res. 2016 Mar;333:77-86. doi: 10.1016/j.heares.2016.01.006. Epub 2016 Jan 1

17. Slide 17: GJB2 Mutations in MHH Patients

    GJB2 Mutations in MHH Patients Burke WF, Warnecke A, Schöner-Heinisch A, Lesinski-Schiedat A, Maier H, Lenarz T. Prevalence and audiological profiles of GJB2 mutations in a large collective of hearing impaired patients. Hear Res. 2016 Mar;333:77-86. doi: 10.1016/j.heares.2016.01.006. Epub 2016 Jan 1

18. Slide 18: GJB2 Mutations in MHH Patients

    GJB2 Mutations in MHH Patients

19. Slide 19: GJB2 Mutations in MHH Patients

    GJB2 Mutations in MHH Patients Burke WF, Warnecke A, Schöner-Heinisch A, Lesinski-Schiedat A, Maier H, Lenarz T. Prevalence and audiological profiles of GJB2 mutations in a large collective of hearing impaired patients. Hear Res. 2016 Mar;333:77-86. doi: 10.1016/j.heares.2016.01.006. Epub 2016 Jan 1

20. Slide 20: Prevalence and audiological profiles of GJB2 mutations

    Burke WF, Warnecke A, Schöner-Heinisch A, Lesinski-Schiedat A, Maier H, Lenarz T. Prevalence and audiological profiles of GJB2 mutations in a large collective of hearing impaired patients. Hear Res. 2016 Mar;333:77-86. doi: 10.1016/j.heares.2016.01.006. Epub 2016 Jan 15. PMID: 26778469.

21. Slide 21: GJB2 Mutations in MHH Patients

    GJB2 Mutations in MHH Patients Burke WF, Warnecke A, Schöner-Heinisch A, Lesinski-Schiedat A, Maier H, Lenarz T. Prevalence and audiological profiles of GJB2 mutations in a large collective of hearing impaired patients. Hear Res. 2016 Mar;333:77-86. doi: 10.1016/j.heares.2016.01.006. Epub 2016 Jan 1

22. Slide 22: GJB2 Mutations in MHH Patients

    GJB2 Mutations in MHH Patients Burke WF, Warnecke A, Schöner-Heinisch A, Lesinski-Schiedat A, Maier H, Lenarz T. Prevalence and audiological profiles of GJB2 mutations in a large collective of hearing impaired patients. Hear Res. 2016 Mar;333:77-86. doi: 10.1016/j.heares.2016.01.006. Epub 2016 Jan 1

23. Slide 23: Treatment for GJB2 Gene Related Hearing Loss

    Treatment for GJB2 Gene Related Hearing Loss • Hearing Devices – Depending on the grade of hearing loss – Hearing Aids – Cochlear Implants • Future – Gene Therapy www.mhh-hno.de

24. Slide 24: Cochlear Implant

    Cochlear Implant low high Electrode Auditory Nerve

25. Slide 25: GJB2 Mutations Therapy with CI

    GJB2 Mutations Therapy with CI Sinnathuray, Arasa Raj*†; Toner, Joseph G.*; Clarke-Lyttle, Joanne*; Geddis, Andrea*; Patterson, Christopher C.‡; Hughes, Anne E.† Connexin 26 (GJB2) Gene-Related Deafness and Speech Intelligibility After Cochlear Implantation, Otology & Neurotology: November 2004 - Vo

26. Slide 26: GJB2 Mutations Therapy with CI

    GJB2 Mutations Therapy with CI Sinnathuray, Arasa Raj*†; Toner, Joseph G.*; Clarke-Lyttle, Joanne*; Geddis, Andrea*; Patterson, Christopher C.‡; Hughes, Anne E.† Connexin 26 (GJB2) Gene-Related Deafness and Speech Intelligibility After Cochlear Implantation, Otology & Neurotology: November 2004 - Vo

27. Slide 27: Gene Therapy

    Gene Therapy 1. Gene therapy may be suitable for some of the genetic conditions but not for all 2. Differentiating between recessive and dominant disease is also important when considering gene therapy for GJB2 mutations Bildquelle: MHH HNO www.mhh-hno.de

28. Slide 28: Gene Therapy for Hearing Loss

    Gene Therapy for Hearing Loss • Genetic therapy consists of the delivery of genes into the inner ear • Delivering genes with viral vectors is potentially the most efficient method. • Limitations • potential immune response • lack of access to the scala media • variability in the outcome • lack of sp

29. Slide 29: Gene therapy in Genetic Hearing Loss

    Gene therapy in Genetic Hearing Loss v Preserveation of residual hearing v Protection of spiral ganglion neurons GJB2 SLC26A4 TMPRSS3 CHD7 v Adeno-associated viruses OTOF DDP1/TIMM8a LOXHD1 for cell-specific targeting KCNQ1 CDH23 MYO7A POU3F4 v Identification of patients MYH9 TMC1 suitable for gene

30. Slide 30: Microstructure of the cochlea with cells affected by gene mutations

    Microstructure of the cochlea with cells affected by gene mutations and their incidence

31. Slide 31: Targeted Gene Therapy

    Targeted Gene Therapy Hair cells Stria vascularis Spiral ganglion neurons

32. Slide 32: Application Routes to the Inner Ear

    Application Routes to the Inner Ear Blanc, Fabian; Mondain, Michel; Bemelmans, Alexis-Pierre; Affortit, Corentin; Puel, Jean-Luc; Wang, Jing. 2020. "rAAV- Mediated Cochlear Gene Therapy: Prospects and Challenges for Clinical Application" J. Clin. Med. 9, no. 2: 589. https://doi.org/10.3390/jcm902058

33. Slide 33: Outlook on Gene Therapy for Hearing Loss

    Outlook on Gene Therapy for Hearing Loss • Gene therapeutic approaches will be available for almost all autosomal recessive diseases in the near future • Gene therapy approachs concentrate on adeno-, adenoassociated- and lentiviral vectors • Identification of clinically relevant groups as candidates

34. Slide 34: Thank you for your attention

    Thank you for your attention

35. Slide 35: Sensorion Portfolio: Focus on GJB2 program

    SENSORION PORTFOLIO Focus on GJB2 program Copyright by Sensorion - 2021 - All Rights Reserved

36. Slide 36: Pipeline: Building an attractive pipeline in the hearing space

    Pipeline: Building an attractive pipeline in the hearing space Next Product Indication Discovery In vivo PoC Pre-clinical Phase 1 Phase 2 Phase 3 milestones (estimated timelines) Sudden Phase 2 TREAT Sens-401 sensorineural topline results hearing loss (Q4 2021) Start of natural Cisplatin induced his

37. Slide 37: Connexin 26: A gap-junction protein encoded by GJB2 gene

    Connexin 26: A gap-junction protein encoded by GJB2 gene and responsible for tissue homeostasis Mutation in the gene leads to deafness • GJB2 is the gene encoding for the Connexin 26 protein; one of 20 known connexins in humans and almost endemic to the cochlea (together with Cx30). • Gap Junctions

38. Slide 38: GJB2 related hearing loss affects ~300,000 patients in the US and EU

    We estimate that GJB2 related hearing loss affects ~ 300,000 patients in the US and EU We have identified 3 forms of hearing loss associated with GJB2 gene mutations (Connexin 26). Prevalence of Congenital and Childhood onset forms estimated to be around 200k patients and around 50% of autosomal rec

39. Slide 39: Cx26 is a good candidate for gene therapy

    Cx26 is a good candidate for gene therapy Why CX26 is a good candidate? Key parameters to consider More than 100 recessive mutations origin Cx26 Age of mice: Use conditional-inducible Cx26-/- mice to truncation/ deletion leading to nonsyndromic hearing better mimic the intended intervention into hum

40. Slide 40: Value proposition for restoring natural hearing with gene therapy

    Value proposition for restoring natural hearing with gene therapy • Acoustic hearing: High frequency resolution (20-20.000 Hz) allowing to enjoy music and complex sounds. • Cochlear implants: Use 8-22 electrodes resulting in artificially distorted signal. • Spatial hearing: Humans can identify the d

41. Slide 41: Next steps

    Next steps Aim: Restoration/reversion, at minima safely stop disease progression 1. Natural History Study in collaboration with the research and innovation center of Necker Hospital: Study patient phenotypes to deepen the knowledge of the patients’ profile (genetics, phenotype, disease progression)

42. Slide 42: Sensorion Capabilities

    SENSORION CAPABILITIES Copyright by Sensorion - 2021 - All Rights Reserved

43. Slide 43: Sensorion HQ in Montpellier

    Sensorion HQ in Montpellier • Sensorion was founded in 2009 as a Spin-Off from INSERM. • Moved to SANOFI Campus in 2015: • SANOFI R&D Center was built in 1972. • Hosting >1000 employees. • Fully integrated development site for small molecules and biologics. • Spare capacity is rented out to 10 exter

44. Slide 44: We are continuously strengthening our in vitro / in vivo platforms

    We are continuously strengthening our in vitro / in vivo platforms Ganglion Spiral ligament neurons fibrocytes Primary culture Cellular Assays of the main cochlear cell types, live imagin ex vivo cochlear Tissular Assays explant cultures, Design of live imaging biological Assay Invitro systems and l

45. Slide 45: Gene Therapy screening platform to select the best candidate

    We use our Gene Therapy screening platform to select the best candidate for expression specificity Promoter Design • Inner ear cell-specific • Transcription Factor Binding promoters design Motif In Silico Promoters • Plasmids design and Plasmids Design • Enhancers, silencers • Optimal expression • P

46. Slide 46: Our in-vivo gene therapy platform enables us to test different techniques

    Our in-vivo gene therapy platform enables us to test different techniques Round window (RW) injection Canalostomy of the posterior Optimization of the Microsurgery semi-circular canal (PSCC) inner ear gene delivery of the inner ear techniques in rodents and Round window membrane disease models injec

47. Slide 47: Understanding deeply the manufacturing process is critical

    Understanding deeply the manufacturing process is critical CF5 – CF10 2L – 10L 50L 50L 200L PROCESS NON-GMP & GMP RESEARC DEVELOPMENT MANUFACTURIN AND SCALE UP G H Process adjustment • GRADE Vector Genome titer (VG) DoE at small scale for optimizing conditions Master cell banks (or working CB) • SDS

48. Slide 48: Developing internally AAV quantification assays

    We are developing internally the AAV quantification assays to measure our key product attributes Accurate Specific to each & precise vector Vector Genome titer Vector Genome titer (qPCR / ddPCR) (qPCR / ddPCR) DOSE INFECTIVITY Used to determine Used to determine the therapeutic dose the therapeutic

49. Slide 49: The platforms developed within Sensorion are critical

    The platforms developed within Sensorion are critical for the successful development of our programs Preclinical GT facilities • AAV Screening platform: Design and select the best drug candidate according to the target indication • In vivo gene therapy platform: From the PoC to the dose-finding stud

50. Slide 50: Sensorion is continuously improving its capabilities

    Sensorion is continuously improving its capabilities to become a leading gene therapy player Experienced management team with broad expertise in gene therapy. Established canalostonomy and RWI techniques enable efficient and safe delivery with potent transduction of inner ear cells. Proprietary AAV

51. Slide 51: Thank You

    THANK YOU Copyright by Sensorion - 2021 - All Rights Reserved

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