Slide 1: The anti-amyloid beta Brainshuttle antibody trontinemab rapidly reduces amyloid plaques in Alzheimer's disease
THE ANTI-AMYLOID BETA BRAINSHUTTLETM ANTIBODY TRONTINEMAB RAPIDLY REDUCES AMYLOID PLAQUES IN PARTICIPANTS WITH ALZHEIMER’S DISEASE Luka Kulic1, Fabien Alcaraz1, Annamarie Vogt1, Carsten Hofmann4, Philip Barrington3, Maddalena Marchesi6, Jakub Wojtowicz6, Gregory Klein1, Ruth Croney7, David Agnew7, D
Slide 2: Affiliations
Affiliations 1. Neuroscience and Rare Diseases, Roche Pharma Early Research and Development, F. Hoffmann-La Roche Ltd, Basel, Switzerland 2. Roche Diagnostics GmbH, Deutschland 3. TranScrip group, UK 4. Pharmaceutical Sciences, Roche Pharma Research and Early Development, F. Hoffmann-La Roche Ltd, B
Slide 3: Disclosures
Disclosures ▪ Luka Kulic, Fabien Alcaraz, Annamarie Vogt, and Carsten Hofmann, Maddalena Marchesi, Jakub Wojtowicz, Gregory Klein, Ruth Croney, David Agnew, Denise Sickert, Niels Janssen, João A. Abrantes, Paul Delmar, and Iris Wiesel are full-time employees and own stock in F. Hoffmann- La Roche Lt
Slide 4: Trontinemab - a novel Brainshuttle antibody targeting Aβ
Trontinemab - a novel BrainshuttleTM antibody targeting Aβ Active transport across the BBB may enable superior brain penetration and target engagement Trontinemab BBB Brain resident Microglia Anti-Aβ binder (Gantenerumab) IgG1 Fc domain Transferrin Receptor 1 BrainshuttleTM (TfR1) module Aggregated
Slide 5: Substantially higher CNS exposure due to shuttling
Substantially higher CNS exposure due to shuttling Evidence from nonhuman primates and the First-in-Human study of trontinemab 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 Hippocamp
Slide 6: Brainshuttle AD is a Phase Ib/IIa study assessing safety, tolerability, PK and PD
BrainshuttleTM AD is a Phase Ib/IIa study assessing the safety, tolerability, PK and PD of trontinemab in participants with AD Primary Study Population Endpoints Objective Nature, frequency, severity, and timing MCI due to AD or mild-to-moderate AD (NIA-AA criteria) Safety and of AEs, including labs
Slide 7: Brainshuttle AD study design
BrainshuttleTM AD study design 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 Cohort Expansion: ▪ ≥10 study ▪ Expansion o
Slide 8: Brainshuttle AD study design
BrainshuttleTM AD study design 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 Cohort Expansion: ▪ ≥10 study ▪ Expansion o
Slide 9: Baseline characteristics at interim analysis
Baseline characteristics at interim analysis Analysis included 44 participants enrolled in dose escalation cohorts 1 to 3 Cohort 1 Cohort 2 Cohort 3 Baseline demographic and disease All Participants 0.2 mg/kg or Pbo 0.6 mg/kg or Pbo 1.8 mg/kg or Pbo characteristics (n = 44) (n = 14) (n = 14) (n = 16
Slide 10: Plasma PK and ADAs
Plasma PK and ADAs Impact of ADAs on exposure was dose-dependent and less pronounced at higher dose PK after 1st dose was in line with PK results from previous SAD study in healthy volunteers. ADAs developed in a majority of participants 2-3 months after start of the treatment. The effect of ADAs on
Slide 11: Dose-dependent amyloid plaque lowering with trontinemab
Dose-dependent amyloid plaque lowering with trontinemab Mean amyloid PET change from baseline1 BL Week 12 (D78) Week 28 (D196) Placebo n=9 n=3 n=9 1 Mean values ±SE (standard errors) of available PET results at the different visit time points are plotted. CL, Centiloid units. Florbetapir or florbeta
Slide 12: Dose-dependent amyloid plaque lowering with trontinemab
Dose-dependent amyloid plaque lowering with trontinemab Mean amyloid PET change from baseline1 BL Week 12 (D78) Week 28 (D196) Placebo n=9 n=3 n=9 0.2 mg/kg n = 11 - n = 10 1 Mean values ±SE (standard errors) of available PET results at the different visit time points are plotted. CL, Centiloid unit
Slide 13: Dose-dependent amyloid plaque lowering with trontinemab
Dose-dependent amyloid plaque lowering with trontinemab Mean amyloid PET change from baseline1 BL Week 12 (D78) Week 28 (D196) Placebo n=9 n=3 n=9 0.2 mg/kg n = 11 - n = 10 0.6 mg/kg n = 11 - n = 10 1 Mean values ±SE (standard errors) of available PET results at the different visit time points are p
Slide 14: Dose-dependent amyloid plaque lowering with trontinemab
Dose-dependent amyloid plaque lowering with trontinemab Mean amyloid PET change from baseline1 Baseline (BL) Week 12 (-70 CL) Week 28 (-83 CL) BL Week 12 (D78) Week 28 (D196) Placebo n=9 n=3 n=9 Longitudinal amyloid PET images 0.2 mg/kg n = 11 - n = 10 in a participant who was treated 0.6 mg/kg n =
Slide 15: Rapid amyloid depletion at 1.8 mg/kg
Rapid amyloid depletion at 1.8 mg/kg 4/11 (36% of participants) below the amyloid positivity threshold at week 12, 6/8 (75%) at week 281 Mean amyloid value in CL at visit (% amyloid negative (<24.1 CL)) Visit 0.2 0.6 1.8 Placebo mg/kg mg/kg mg/kg BL 95 (0) 91 (0) 88 (0) 100 (0) Week 12 128 (0) - - 4
Slide 16: Blinded safety profile
Blinded safety profile1 Number of participants with safety events or early discontinuations Cohort 1 Cohort 2 Cohort 3 Total Participants, n (%) 0.2 mg/kg or Pbo 0.6 mg/kg or Pbo 1.8 mg/kg or Pbo (n = 44) (n = 14) (n = 14) (n = 16) Participants with ≥1 AE 12 (85.7%) 14 (100%) 16 (100%) 42 (95.5%) De
Slide 17: IRRs and transient mild anemia were more common AEs in cohort 3
IRRs and a transient mild anemia were more common AEs in cohort 3 Most IRRs occurred without premedication (after dose 1) and were mild or moderate in severity Frequent blood draw contributed to a mild decrease in hematological parameters in all groups Cohort 1 Cohort 2 Cohort 3 Common treatment-eme
Slide 18: Low incidence of ARIA despite robust amyloid lowering at 1.8 mg/kg
Low incidence of ARIA despite robust amyloid lowering at 1.8 mg/kg One ARIA-E and one ARIA-H case occurred in cohort 3 (at 1.8 mg/kg trontinemab or Pbo)1 Cohort 1 Cohort 2 Cohort 3 Total number of participants [events per All Participants 0.2 mg/kg or Pbo 0.6 mg/kg or Pbo 1.8 mg/kg or Pbo participan
Slide 19: Summary
Summary Trontinemab is a novel BrainshuttleTM Aβ antibody that crosses the blood brain barrier via active TfR1 mediated transcytosis at the capillary level. In people with AD, trontinemab demonstrated rapid and robust amyloid plaque reduction at relatively low doses (1.8 mg/kg Q4W), compared with st
Slide 20: Acknowledgements
Acknowledgements We thank all the study participants and their families, the investigators, and site staff for their time and commitment to the BrainshuttleTM AD study 20
Slide 21: Doing now what patients need next
Doing now what patients need next