Slide 1: GENERATION HD2 update and further insights from the tominersen programme
GENERATION HD2 update and further insights from the tominersen programme Peter McColgan, MD, PhD F. Hoffmann-La Roche Ltd, Basel, Switzerland To access this presentation go to: https://bit.ly/3JVO923 Date of preparation: April 2023 M-XX-00013000
Slide 2: Disclosures
Disclosures DisclosuresI am an employee of F. Hoffmann-La Roche Ltd Tominersen is an investigational drug that has not been approved by any health authority. The intent of this presentation is to provide a scientific update on the clinical trial programme of tominersen and the information included s
Slide 3: Outline of today's presentation
Outline of today’s presentation History of the tominersen programme GENERATION HD2 Study design and current status Further insights from GEN-EXTEND CSF NfL, PK and mHTT lowering Further insights from GENERATION HD1 Plasma NfL CSF, cerebrospinal fluid; mHTT, mutant huntingtin protein; NfL, neurofilam
Slide 4: History of the tominersen programme
History of the tominersen programme 4
Slide 5: 10-year tominersen programme history
10-year tominersen programme history Building on science and partnerships 2013 2015–2017 2018–2021 2021 Today/2023 Ionis/Roche Phase I/IIa study GENERATION HD1 Dose-finding OLE of the HD partnership; dosing halted GENERATION HD2 Roche licenses Phase I/IIa study; (Phase II) ongoing investigational in
Slide 6: Overview of the tominersen clinical development programme
Overview of the tominersen clinical development programme Phase I/IIa (CS1), N=461,2 OLE (CS2), N=463–5 GEN-EXTEND, N=23613,14 GENERATION HD2, • 120 mg, Q4W and Q8W • 120 mg Q8W or Q16W N=36015 • First-in-human study • Roll-over study for participants in • Long-term safety, tolerability, PK, PD • 10
Slide 7: GENERATION HD2
GENERATION HD2 Study design and current status 7
Slide 8: GENERATION HD2: Testing a refined hypothesis
GENERATION HD2: Testing a refined hypothesis GENERATION HD1 Focused Lower and less Safety, biomarkers exploratory population frequent dosing and efficacy trends post hoc findings* Potential benefit in GENERATION HD2 will GENERATION HD2 GENERATION HD2 will younger adults with focus on adults with wil
Slide 9: Overview of GENERATION HD2
Overview of GENERATION HD2 A study to evaluate the safety, biomarkers and efficacy trends of two dose levels of tominersen in participants with prodromal (~20-/arm) and early manifest (~100-/arm) HD versus placebo Tominersen 100 mg Q16W N=120 Screening R 1:1:1 Tominersen 60 mg Optional (–4 weeks) (W
Slide 10: "Common close" design
Key aspect of the GENERATION HD2 study: “Common close” design Blinded treatment period (16+ months*) Optional OLE study start† All participants Blinded treatment period (16 months) (except last participant) Last participant • Minimum 16-month treatment period (seven clinic visits with four interim p
Slide 11: Key differences in GENERATION HD2 compared with GENERATION HD1
Key differences in GENERATION HD2 compared with GENERATION HD1 Loading dose (“load”) = tominersen = placebo injection MONTH 0 1 2 3 4 5 6 7 8 GENERATION HD1 120 mg Previous Phase III Q8W What’s different in GENERATION HD2? 120 mg Q16W • Lower doses: 100 or 60 mg vs 120 mg in previous studies PLACEBO
Slide 12: GENERATION HD2: Current status
GENERATION HD2: Current status Open countries CANADA • To date, six countries DENMARK and 15 sites are POLAND open globally UK GERMANY FRANCE • Study planned to run USA AUSTRIA in 15 countries across SPAIN ITALY SWITZERLAND 75 sites* PORTUGAL • Specific study sites will be listed on clinical trial r
Slide 13: Further insights from GEN-EXTEND
Further insights from GEN-EXTEND CSF NfL, PK and mHTT lowering CSF, cerebrospinal fluid; mHTT, mutant huntingtin protein; NfL, neurofilament light protein; PK, pharmacokinetics. 13
Slide 14: In GENERATION HD1, transient increases in CSF NfL were observed in Q8W dosing
In GENERATION HD1 (with loading dose), transient increases in CSF NfL were observed in the Q8W dosing regimen • Q8W: NfL increases from 50 Percentage change from baseline at all time 40 baseline in CSF NfL points, with the greatest increases 30 at Week 21; 20 trending towards baseline by 10 Week 69
Slide 15: Exposure–response relationship of biomarkers in GENERATION HD1
Exposure–response relationship of biomarkers in GENERATION HD1 showed that CSF NfL increases can be avoided at lower exposures • Increases in CSF Data pooled across 120 mg Q8W and Q16W dosing regimens with loading dose (n=791) NfL and CSF Lowest exposure Highest exposure protein were quartile quarti
Slide 16: In GEN-EXTEND, CSF NfL levels remained below baseline in Q16W no-load dosing
In GEN-EXTEND, CSF NfL levels remained below baseline in the Q16W no-load dosing regimen Percentage mean change (95% CI) 40 Tominersen 120 mg Q16W (without loading) • No CSF NfL from baseline in CSF NfL increase above baseline observed 20 in the GEN-EXTEND Q16W no-load 0 group -0.05 -3.42 -1.49 -3.7
Slide 17: Observed CSF tominersen concentrations and mHTT reductions within predicted ranges
Observed CSF tominersen concentrations and mHTT reductions were within predicted ranges after Q16W no-load dosing in GEN-EXTEND PK – tominersen PD – CSF mHTT Regimen Regimen 1 120 mg Q16W without loading (model) 40 120 mg Q16W without loading (model) GEN-EXTEND Q16W without loading GEN-EXTEND Q16W w
Slide 18: Simulation of CSF tominersen PK profiles in GENERATION HD2 population
Simulation of CSF tominersen PK profiles in a typical target GENERATION HD2 population in comparison with simulations in GEN-EXTEND population 0.6 CSF PK prediction at trough median +50% PI Regimen CSF PK (ng/mL) 0.4 GEN-EXTEND 120 mg Q16W without loading GENERATION HD2 0.2 100 mg Q16W without loadi
Slide 19: Simulation of CSF mHTT profiles in GENERATION HD2 population
Simulation of CSF mHTT profiles in a typical target GENERATION HD2 population in comparison with simulations in GEN-EXTEND population 0 CSF mHTT model prediction median +50% PI change from baseline (%) -10 CSF mHTT percentage Regimen -20 GEN-EXTEND 120 mg Q16W without loading -30 GENERATION HD2 100
Slide 20: Further insights from GENERATION HD1
Further insights from GENERATION HD1 Plasma NfL NfL, neurofilament light protein. 20
Slide 21: GENERATION HD1: Q16W plasma NfL trends below placebo beyond Week 21
GENERATION HD1: In the Q16W group, plasma NfL showed trends below placebo beyond Week 21 20 Q16W–placebo Q8W–placebo Placebo • Q8W: Plasma NfL Difference in percentage change greater than Dosing stopped 15 placebo at all time points on 12.1 10 treatment, below from baseline placebo at 5.8 5 2.9 Week
Slide 22: Summary
Summary GENERATION HD2 will test two lower dose regimens of tominersen (100 mg and 60 mg Q16W) in prodromal and early manifest HD, evaluating safety, biomarker and efficacy trends GENERATION HD2 is planned to run in 15 countries across approximately 75 sites New GENERATION HD1 and GEN-EXTEND data su
Slide 23: More data on tominersen
More data on tominersen GENERATION HD1 manuscript under review 23
Slide 24: Acknowledgements
Acknowledgements Ionis discovered tominersen and is partnered with Roche for its development Special thanks to Frank Bennett, Holly Kordasiewicz, Eric Swayze, Roger Lane and Anne Smith Special thanks for sharing data and for ongoing collaboration Deepest gratitude to the investigator network, person
Slide 25: THANK YOU
THANK YOU A big THANK YOU to the HD community for their ongoing collaboration, especially to all study participants, their families, investigators and site staff, and the tominersen steering committee Your ongoing contributions to the programme are inspirational HD, Huntington’s disease