Roche Holding Ltd · SIX:RO
Roche — AAIC 2024
21 slides from Roche's conference presentation, July 2024
Slide 1: Novel Approaches to Amyloid: Trontinemab and Beyond
Novel Approaches to Amyloid: Trontinemab and Beyond Geoffrey A. Kerchner, MD, PhD Vice President Global Head of Early Development Neuroscience and Rare Diseases Pharma Research and Early Development F. Hoffmann-La Roche, Ltd. 28 July - 1 August | AAIC 2024 1
Slide 2: Disclosures
Disclosures Geoffrey A. Kerchner is a full-time employee of and owns stocks in of F. Hoffmann-La Roche, Ltd. 2
Slide 3: Investigational treatment disclaimer
Investigational treatment disclaimer ■ The information provided may include references to a Roche product or use of a Roche product that the FDA has not approved; because the FDA has not approved such product(s) or use, no conclusions regarding safety or efficacy may be made.Providing this informati
Slide 4: Novel therapeutic approaches to amyloid
Novel therapeutic approaches to amyloid Can we achieve more with anti-amyloid antibody therapy? What about other mechanisms of action? 4
Slide 5: Novel therapeutic approaches to amyloid
Novel therapeutic approaches to amyloid Can we achieve more with anti-amyloid antibody therapy? What about other mechanisms of action? 5
Slide 6: Have we seen the top of the dose-response curve for anti-Aβ therapy?
Have we seen the top of the dose-response curve for anti-Aβ therapy? To date, in any positive trial with >1 dose, the higher dose delivers (numerically) higher efficacy Lecanemab — Phase II1 Aducanumab — Phase III2 (EMERGE) ← CDR-SB → ← ADAS-Cog → 1 Figure from Swanson et al. Alzheimer’s Research &
Slide 7: Blood brain barrier (BBB)
Blood brain barrier (BBB) A major challenge for the delivery of large therapeutic molecules to the brain The blood brain barrier phenomenon1 Only 1 of 3300 IgG molecules enters the brain2 200000 Cynomolgus monkey 150000 Concentration (ng/l) 100000 50000 1000 0.03% 500 0 n a ai m Br as Pl 1 From Saun
Slide 8: Trontinemab - a novel Brainshuttle antibody targeting Aβ
Trontinemab - a novel BrainshuttleTM antibody targeting Aβ Active transport across the BBB significantly increases brain penetration and target engagement Trontinemab BBB Brain resident Microglia Anti-Aβ binder IgG1 Fc domain Transferrin Receptor 1 BrainshuttleTM (TfR1) module Aggregated Aβ Transfer
Slide 9: Brainshuttle technology enables higher brain exposure and broader CNS biodistribution
BrainshuttleTM technology enables a higher brain exposure and broader CNS biodistribution of therapeutic antibodies Standard IgG2 BrainshuttleTM IgG2 Direct endothelial cell-mediated transport fundamentally alters the point of brain entry CNS, central nervous system; IV, intravenous. 1 Kulic et al.,
Slide 10: Trontinemab has shown substantially improved CNS penetration
Trontinemab has shown substantially improved CNS penetration Both in non-human primates and human healthy volunteers 6-17-fold higher brain exposure (AUC) in nonhuman primates 8-fold increase in CSF/plasma (trontinemab compared with gantenerumab)1,2 ratio in healthy volunteers1,3 Hippocampus CNS, ce
Slide 11: Brainshuttle AD is a Phase Ib/IIa dose escalation study of trontinemab
BrainshuttleTM AD is a Phase Ib/IIa dose escalation study of trontinemab Staggered, parallel-group, adaptive study design with 4 initial sequential cohorts Screening Double-blind treatment period Follow-up Continuous 28 weeks (7 IV doses) 28 weeks Dose escalation: Cohort 4: 3.6 mg/kg or Pbo IV Q4W C
Slide 12: Baseline characteristics are consistent across cohorts
Baseline characteristics are consistent across cohorts Interim analysis1 included data from 15 participants in cohort 4 (3.6 mg/kg) at BL2 12-week interim analysis Cohort 1 Cohort 2 Cohort 3 Cohort 41 Baseline demographic and disease 0.2 mg/kg or Pbo 0.6 mg/kg or Pbo 1.8 mg/kg or Pbo 3.6 mg/kg or Pb
Slide 13: Dose-dependent amyloid lowering with trontinemab (cohorts 1 to 4)
Dose-dependent amyloid lowering with trontinemab (cohorts 1 to 4) Mean amyloid PET change from baseline1 Placebo n = 12 n=5 n=9 0.2 mg/kg n = 11 - n = 10 0.6 mg/kg n = 11 - n = 10 1.8 mg/kg n = 13 n = 11 n=8 3.6 mg/kg n = 12 n=8 - 1 Snapshot date: 23 October 2023. Mean values ±SE (standard errors) o
Slide 14: Majority of participants at 3.6 mg/kg amyloid negative at 12 weeks
Majority of participants at 3.6 mg/kg amyloid negative at 12 weeks 5 out of 8 participants below the amyloid positivity at interim analysis1 Mean amyloid value in CL at visit (% amyloid negative (≤24.0 CL)) Visit 0.2 0.6 1.8 3.6 Pbo mg/kg mg/kg mg/kg mg/kg 98 CL 91 CL 88 CL 100 CL 119 CL BL (0%) (0%
Slide 15: Relevant AEs and MRI findings: IRR, anemia and ARIA
Relevant AEs and MRI findings: IRR, anemia and ARIA1 Lower IRR incidence with premedication; one mild anemia; no ARIA-E / ARIA-H in cohort 4 to date 12-week interim analysis Cohort 1 Cohort 2 Cohort 3 Cohort 4 Total number of participants with at least one 0.2 mg/kg or Pbo 0.6 mg/kg or Pbo 1.8 mg/kg
Slide 16: Novel therapeutic approaches to amyloid
Novel therapeutic approaches to amyloid Can we achieve more with anti-amyloid antibody therapy? What about other mechanisms of action? 16
Slide 17: γ-secretase modulation is a promising therapeutic approach in AD
γ-secretase modulation is a promising therapeutic approach in AD Increasing production of Aβ 37 and Aβ38 and reducing Aβ42 and Aβ40 APP processing ■ γ-secretase modulators (GSMs) selectively target the processing of APP and leave the other substrates (e.g. Notch) unchanged. Gamma-secretase ■ GSMs re
Slide 18: γ-secretase modulators target the amyloid cascade at its origin
Ph1a in HV n≈80 γ-secretase modulators target the amyloid cascade at its origin, reducing production and aggregation inhibition of amyloid ■ The MoA of GSMs is distinctly different Aβ42,40 ti on from that of anti-amyloid mAbs which GSM g a g re are plaques/ aggregate-removers. Aβ37,38 ag ced e du R
Slide 19: RG6289 Entry-in-Human study: modulation of γ-secretase
RG6289 Entry-in-Human study: modulation of γ-secretase Dose-dependent effect of RG6289 on Aβ monomers in CSF1 RG6289 Pharmacodynamics in Healthy Volunteers1 ■ In young and elderly healthy volunteers: Placebo (N=4) Dose-dependent Mean change from Mean change from Low dose (N=3) ▫ baseline (%) baselin
Slide 20: Summary
Summary Clinical efficacy from anti-amyloid antibody therapy may depend upon brain exposure. The blood-brain barrier presents a formidable obstacle to conventional IgG penetration. Trontinemab, using BrainshuttleTM technology to drive higher exposure in the cerebral cortex, aims to optimize the bene
Slide 21: Acknowledgements
Acknowledgements We thank all the study participants and their families, the investigators, and site staff for their time and commitment to the mentioned Roche studies 21