Slide 1: Preliminary results from a 15-month open-label extension study of RG6042 in Huntington's disease
Preliminary results from a 15-month open-label extension (OLE) study investigating RG6042 huntingtin protein (HTT) antisense oligonucleotide (ASO) in adults with manifest Huntington’s disease (HD) Scott A. Schobel MD, MSc Associate Group Medical Director F. Hoffmann-La Roche Ltd, Basel, Switzerland
Slide 2: Disclosures
Disclosures • I am a full-time employee of F. Hoffmann-La Roche Ltd • The data shown in this talk is from preliminary analyses while database lock is ongoing 2
Slide 3: Acknowledgements
Acknowledgements Ionis discovered RG6042 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 Phase I/IIa investigator netwo
Slide 4: RG6042 now has a generic name
RG6042 now has a generic name Tominersen is the international non-proprietary name (generic name) for the investigational molecule most recently referred to as RG6042 Tominersen is an investigational (not approved) medicine that is being studied for the treatment of people with Huntington’s disease.
Slide 5: Today's presentation will focus on preliminary 15-month data from the OLE
Today’s presentation will focus on preliminary 15-month data from the OLE of the tominersen Phase I/IIa study Phase I/IIa OLE of the Phase I/IIa study Ongoing studies CHDI 2018 Today: preliminary 15-month data (N=43 of 46) Future Exploratory fluid PK/PD biomarkers Safety and tolerability Completed O
Slide 6: HTT-lowering therapies may slow or stop clinical progression
HTT-lowering therapies may slow or stop clinical progression MoA schema adapted from Wild and Tabrizi, Lancet Neurology. 2017 HTT-lowering therapies generally target Nucleus DNA upstream pathogenic principles ASO Roche/Ionis ASO suppresses causal pre-mRNA toxic protein (non-allele selective) mRNA RN
Slide 7: In vivo preclinical data were used to define target CSF mHTT reduction
In vivo preclinical data were used to define target CSF mHTT reduction Tissue lowering to Tissue to CSF3 CSF3 efficacy1,2 Cyno tissue/CSF–HTT relationship % CSF % HTT KD in % HTT KD in Target trough human Transgenic mouse models HTT KD cortex caudate CSF mHTT reduction Cortex ~30–80% range: Caudate
Slide 8: 2018 results of the first-in-human Phase I/IIa study presented at CHDI
In 2018, the results of the first-in-human Phase I/IIa study of tominersen (HTT-targeting ASO) were presented at CHDI Photo (top) credit: Gene Veritas. ASO, antisense oligonucleotide; HTT, huntingtin gene. 8
Slide 9: Phase I/IIa: dose-dependent reductions in CSF mHTT
In the Phase I/IIa trial, tominersen treatment produced dose-dependent reductions in CSF mHTT mHTT percentage change from baseline mHTT percentage change over time1 to trough after three or four monthly doses1* 80 NS p=0.01 p=0.02 p<0.01 p<0.01 (% change from baseline) 60 CSF mHTT at endpoint† 60 (%
Slide 10: Tominersen's Clinical Development Programme
Tominersen’s Clinical Development Programme is contributing further data to evaluate the efficacy and safety of the drug Clinical Development Programme Phase I/IIa1 N=46 Open-Label Extension N=462 • First-in-human study • Long-term safety, tolerability, PK and PD • Safety, tolerability, PK and PD ✓
Slide 11: Tominersen's Clinical Development Programme
Tominersen’s Clinical Development Programme is contributing further data to evaluate the efficacy and safety of the drug Clinical Development Programme Phase I/IIa1 N=46 Open-Label Extension N=462 • First-in-human study • Long-term safety, tolerability, PK and PD • Safety, tolerability, PK and PD ✓
Slide 12: Design of the open-label extension of the Phase I/IIa study
Design of the open-label extension (OLE) of the Phase I/IIa study Objective: Replicate and extend understanding of tominersen effects over longer follow-up and gain information earlier than otherwise possible from traditional Phase II study Countries: Canada, Germany, UK (9 sites) Key study features
Slide 13: Baseline characteristics of all patients of the OLE study
Baseline characteristics of all 46 patients of the OLE study Characteristics 120 mg tominersen Q4W Q8W (N=23) (N=23) Age (years) 47.7 (9.3), 30–64 49.5 (11.3), 28–67 mean (SD), range Gender 15/8 13/10 male/female (n) CAG repeats 44.1 (3.1), 40–55 44.4 (3.1), 40–52 mean (SD), range CAP score 477 (66.
Slide 14: Sustained lowering of CSF mHTT in both arms at 15 months
Sustained lowering of CSF mHTT was observed in both arms at 15 months (preliminary analysis) Q4W (N=23) Q8W (N=23) 70% mean trough lowering at 15 months 44% mean trough lowering at 15 months 0 0 Target range -10 Phase I/IIa tominersen 120 mg Q4W1 -10 -20 -20 CSF mHTT change CSF mHTT change from base
Slide 15: Sustained lowering of CSF mHTT in both arms at 15 months
Sustained lowering of CSF mHTT was observed in both arms at 15 months (preliminary analysis) Q4W (N=23) Q8W (N=23) 70% mean trough lowering at 15 months 44% mean trough lowering at 15 months 0 0 Target range -10 Phase I/IIa tominersen 120 mg Q4W1 -10 -20 -20 CSF mHTT change CSF mHTT change from base
Slide 16: Safety and tolerability
Tominersen OLE of the Phase I/IIa study SAFETY AND TOLERABILITY 16
Slide 17: Q8W appears more suitable for chronic dosing than Q4W
Tominersen 120 mg Q8W appears to be more suitable for chronic dosing than Q4W based upon tolerability and safety Q4W (N=23) Q8W (N=23) • 412 AEs in 23 (100%) of patients • 209 AEs in 22 (95.7%) of patients – 86% AEs considered non-drug related – 98% AEs considered non-drug related – 14% AEs consider
Slide 18: No concerning safety laboratory signals with tominersen treatment
No concerning safety laboratory signals with tominersen treatment Potential risk Q4W (N=23) Q8W (N=23) Thrombocytopenia No AEs reported No AEs reported No trend in lab results No trend in lab results Renal toxicity 1 AE of proteinuria, resolved without any dose No AEs reported (i.e. proteinuria, int
Slide 19: CSF WBC elevations less frequent with Q8W vs Q4W
CSF WBC elevations occurred less frequently with tominersen Q8W vs Q4W Q4W (N=23) 70 Q8W (N=23) 70 60 60 CSF leukocytes (/μL) CSF leukocytes (/μL) 50 50 40 40 30 30 20 20 10 10 0 0 0 100 200 300 400 0 100 200 300 400 Visit day Visit day n= 23 23 23 23 23 22 23 22 22 21 20 20 17 20 19 19 23 23 2 23 2
Slide 20: CSF total protein elevation less frequent with Q8W vs Q4W
CSF total protein elevation occurred less frequently with tominersen Q8W vs Q4W 1500 Q4W (N=23) 1500 Q8W (N=23) Total CSF protein (g/L) Total CSF protein (g/L) 1000 1000 500 500 0 0 0 100 200 300 400 0 100 200 300 400 Visit day Visit day n= 23 23 23 23 23 22 23 22 22 21 20 20 17 20 19 19 23 23 2 23
Slide 21: Safety and tolerability summary
Safety and tolerability summary • The Q8W regimen appears better tolerated than the Q4W regimen in terms of number and nature of AEs and SAEs • CSF protein and WBCs are less affected in the Q8W regimen • No evidence for ASO-associated class risks in either regimen • Overall, these findings suggest t
Slide 22: Clinical pharmacology
Tominersen OLE of the Phase I/IIa study CLINICAL PHARMACOLOGY 22
Slide 23: Steady state CSF exposure achieved with Q8W dosing
Tominersen steady state CSF exposure achieved with Q8W dosing Mean (±SD) trough CSF concentration over time 12 Q4W (N=23) 12 Q8W (N=23) Exposure ~5.8 ng/mL Exposure ~1.6 ng/mL 10 10 concentration (ng/mL) concentration (ng/mL) (Initial peak at ~3 ng/mL related to loading regimen) Tominersen CSF Tomin
Slide 24: Similar plasma PK exposure in Q4W and Q8W
Similar plasma PK exposure was observed in both Q4W and Q8W Mean (±SD) trough plasma concentration over time Q4W (N=23) Q8W (N=23) 12 12 Trough expsure ~2.5 ng/mL Trough exposure ~2.4 ng/mL 10 concentration (ng/mL) concentration (ng/mL) 10 Tominersen plasma Tominersen plasma 8 8 6 6 4 4 2 2 0 0 0 58
Slide 25: Population PK/PD model supports shift to less frequent dosing
A clinical population PK/PD model based on Phase I/IIa and OLE data supports programme shift to less frequent dosing Phase I/IIa and OLE data used to develop PK/PD model Simulation of Q8W and Q16W dosing to achieve (120 mg IT Q8W)* pharmacologically relevant effect (120 mg IT) % HTT KD in % CSF HTT
Slide 26: Dosing regimen changes make Phase III participation less demanding
Changes to the dosing regimens have made participation in the Phase III study less demanding = Tominersen 120 mg = Placebo injection = Lumbar puncture only MONTH 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Q4W ORIGINAL Q8W PLACEBO U P D AT E D Q8W Q16W PLACEBO Q4W, every mont
Slide 27: Effect on exploratory CSF fluid biomarkers: NfL and Tau
Tominersen OLE of the Phase I/IIa study EFFECT ON EXPLORATORY CSF FLUID BIOMARKERS: NfL AND TAU 27
Slide 28: The plausible role of NfL in HD and other CNS diseases
The plausible role of NfL in HD and other CNS diseases • NfL increases are associated with disease status and Association of elevated plasma NfL with HD stage5 severity, and have prognostic value across a range of diseases – HD, AD, ALS, FTD, MS, CJD, stroke, TBI,1 cardiac arrest,2 HIV-associated de
Slide 29: CSF NfL increases in both arms then decreases on continued treatment
CSF NfL increases in both arms at Day 141 and then decreases on continued treatment Q4W (N=23) Q8W (N=23) 53% mean increase in NfL at 15 months 10% mean increase in NfL at 15 months 400 400 350 350 from baseline (%) from baseline (%) 300 300 CSF NfL change CSF NfL change 250 250 200 200 150 150 100
Slide 30: CSF NfL in Q8W arm decreases to natural history range at 15 months
CSF NfL levels in the Q8W arm decrease to within expected natural history range at 15 months CSF NfL change in the Q8W arm compared with untreated early HD patients in HD-CSF 150 130 Tominersen Q8W (N=23) 110 Untreated patients from baseline (%) CSF NfL change 90 (HD-CSF; N=28)* 70 50 30 10 -10 -30
Slide 31: CSF NfL and Tau associated at baseline and over time
CSF NfL and Tau are associated at baseline and over time during tominersen treatment Baseline Day 141 Day 253 Day 421 Spearman correlation=0.44 Spearman correlation=0.84 Spearman correlation=0.5 Spearman correlation=0.38 2.0 Change in CSF NfL (log) 8.4 Change in CSF NfL (log) Change in CSF NfL (log)
Slide 32: CSF Tau in Q8W arm decreases to natural history range at 15 months
CSF Tau levels in the Q8W arm decrease to within expected natural history range at 15 months CSF Tau change in the Q8W arm compared with untreated early HD patients in HD-CSF 70 Tominersen Q8W (N=23) 60 50 Untreated patients from baseline (%) (HD-CSF; N=28)* CSF Tau change 40 30 20 10 0 -10 -20 BL 8
Slide 33: Exploratory fluid biomarker summary
Exploratory fluid biomarker summary • Based on published literature, NfL appears relevant in HD and NfL and Tau levels are expected to increase in untreated HD1,2 • NfL levels increase then decrease on continued treatment, with Tau following the same trend • No associations were observed between NfL
Slide 34: Exploring potential mechanisms underlying the observed NfL changes
Exploring potential mechanisms underlying the observed NfL changes • Neurofilaments appear in aggregates in HD and may be Progressive loss of neurofilament staining in mis-localised in HD neurons1,2 the human cortex immunostained with SMI-351 • Neurofilament is under negative transcriptional regulat
Slide 35: Tominersen's Clinical Development Programme for HD
Tominersen’s Clinical Development Programme for HD Longer-term follow-up will ultimately inform clinical outcomes of tominersen and the potential prognostic and predictive value of the candidate markers in the context of tominersen treatment of HD * An additional 8 patients may be included to allow
Slide 36: Overall summary of tominersen clinical development
Overall summary of tominersen clinical development • Preliminary data from the 15-month OLE study has been used to further inform the tominersen Clinical Development Programme – The strength of the 120 mg tominersen effect on CSF mHTT allowed for amendment of GENERATION HD1 for testing less frequent