Preliminary results from a 15-month open-label extension (OLE) study - PowerPoint PPT Presentation

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 M-XX-00000779 To access this presentation go to https://bit.ly/2tK3W0D 1

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

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 network, study participants (present and future) and their families 3

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. Tominersen has not been approved by the Food and Drug 4 Administration (FDA). The efficacy and safety of tominersen are currently being studied. https://www.who.int/medicines/services/inn/innguidance/en (Accessed February 2019).

Today’s presentation will focus on preliminary 15 -month data from the OLE of the tominersen Phase I/IIa study Phase I/IIa Ongoing studies OLE of the Phase I/IIa study CHDI 2018 Future Today : preliminary 15-month data (N=43 of 46) Exploratory fluid biomarkers PK/PD Safety and tolerability Completed OLE HD Natural History Study Phase III GENERATION HD1 I/IIa 5 HD, Huntington's disease; OLE, open-label extension; PD, pharmacodynamics; PK, pharmacokinetics.

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 upstream pathogenic principles DNA Roche/Ionis ASO suppresses causal ASO pre-mRNA toxic protein (non-allele selective) mRNA ASO RNase H-mediated degradation Cause Toxic mHTT* of disease Proteasome Neuronal dysfunction Excitotoxicity Impaired axonal Other current SOC Cellular transport inhibition and death and advanced dysfunction Mitochondrial Caspase/protease Synaptic Transcriptional clinical development dysfunction activation dysfunction deregulation candidates target downstream effects likely addressing few Atrophy Cognitive and behavioural Motor or single domains Clinical • Brain tissue loss • • Psychomotor slowing Coordination • Muscle wasting pathological • • Executive dysfunction Balance/gait • Weight loss • • Apathy Chorea domains • • Irritability Progressive akinesia Speech and swallowing * Toxic mHTT= HTT 36+ CAG repeats. ASO, antisense oligonucleotide; HTT , huntingtin gene; HTT, huntingtin protein; mHTT, mutant HTT; MoA, mechanism of action; SOC, standard of care. Wild EJ, Tabrizi SJ. Lancet Neurol . 2017; 16:837 – 847; Bates GP, et al. Nat Rev Dis Primers . 2015; 1:15005; Ross CA, et al. Nat Rev Neurol . 2014; 10:204 – 216; 6 Roos R. Orphanet J Rare Dis . 2010; 20:5:40; Zuccato C, et al. Physiol Rev . 2010; 90:905 – 981; Zielonka D, et al. Front Physiol . 2014; 5:380.

In vivo preclinical data were used to define target CSF mHTT reduction Tissue to CSF 3 CSF 3 Tissue lowering to efficacy 1,2 Cyno tissue/CSF – HTT relationship % CSF % HTT KD in % HTT KD in Target trough human HTT KD cortex caudate Transgenic mouse models CSF mHTT reduction Cortex ~30 – 80% range: 20 – 30 30 – 55 5 – 20 Caudate ~30% 30 – 40 40 – 70 15 – 35 ~30 – 50% 40 – 50 55 – 80 25 – 45 CSF mHTT lowering of ~20 – 30% at trough meets observed cortical threshold of efficacy in preclinical models of HD; caudate lowering is only covered at higher levels of CSF reduction (e.g. >30%) 1 – 3 Based on preclinical evidence, a CSF mHTT lowering of 30 – 50% is expected to be associated with broad therapeutic benefits 2 See poster 22 “Development of a non -clinical pharmacokinetic/pharmacodynamic model to predict CSF reductions in huntingtin prote in in individuals with Huntington’s disease” for more details. CSF, cerebrospinal fluid; HD, Huntington’s disease; HTT, huntingtin protein; KD, knockdown; mHTT, mutant HTT. 7 1. Kordasiewicz HB, et al. Neuron. 2012; 74:1031 – 1044; 2. Stanek LM, et al. J Huntingtons Dis. 2013; 2:217 – 228; 3. Sanwald Ducray P, et al. Neurology. 2019; 92(15 Suppl):S16.005.

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. 8 ASO, antisense oligonucleotide; HTT , huntingtin gene.

In the Phase I/IIa trial, tominersen treatment produced dose-dependent reductions in CSF mHTT mHTT percentage change from baseline mHTT percentage change over time 1 to trough after three or four monthly doses 1 * 80 NS p=0.01 p=0.02 p<0.01 p<0.01 (% change from baseline) 60 CSF mHTT at endpoint † 60 (% change from baseline) 40 40 Placebo 20 CSF mHTT ‡ 20 10 mg 30 mg 0 0 60 mg – 20 – 20 90 mg – 40 – 40 120 mg Dose – 60 – 60 – 80 0 29 57 85 113 141 Placebo 10 mg 30 mg 60 mg 90 mg 120 mg Day CSF mHTT lowering of 40 – 60% was observed after four highest doses in the Phase I/IIa study 1 CSF mHTT trendline was still decreasing in the Phase I/IIa study 1 Tominersen was generally well tolerated over 4 monthly doses 1 * Nominal p values from prespecified analysis of key exploratory endpoint. 2 † Endpoint is defined as the later of Day 85 or 113. Day 113 and 141 samples were each performed in randomised subsets of patients, indicated by dotted lines. CSF, cerebrospinal fluid; mHTT; mutant huntingtin protein; NS, not significant. 9 1. Tabrizi SJ, et al . N Engl J Med. 2019; 380:2307 – 2316; 2. Tabrizi SJ, et al. Neurology. 2018; 19(15 Suppl):CT.002.

Tominersen’s Clinical Development Programme is contributing further data to evaluate the efficacy and safety of the drug Clinical Development Programme Phase I/IIa 1 N=46 Open-Label Extension N=46 2 • • First-in-human study ✓ Long-term safety, tolerability, PK and PD ✓ • • Safety, tolerability, PK and PD Early manifest HD patients • • Early manifest HD patients 15 months HD Natural History Study N=95 3 ✓ Complete • Prospective, longitudinal study • Early manifest HD patients ✓ Complete, final analysis ongoing • 15 months GEN-EXTEND 5 Ongoing, recruitment complete GENERATION HD1 N=801 4 (OLE) • Pivotal, long-term efficacy and safety Ongoing, recruiting • Manifest HD patients • 25 months (plus follow-up) Includes digital monitoring platform GEN-PEAK N=12* 6 • PK/PD in CSF and plasma • Manifest HD patients • 7 months including follow-up * An additional 8 patients may be included to allow investigation of additional dose levels and repeat doses if necessary. CSF, cerebrospinal fluid; HD, Huntington's disease; OLE, open-label extension; PD, pharmacodynamics; PK, pharmacokinetics. 1. Tabrizi SJ, et al . N Engl J Med. 2019; 380:2307 – 2316; 2. Clinicaltrials.gov/show/NCT03342053 (Accessed February 2020); 3. Clinicaltrials.gov/show/NCT03664804 (Accessed February 2020); 4. Clinicaltrials.gov/show/NCT03761849 (Accessed February 2020); 10 5. Clinicaltrials.gov/show/NCT03842969 (Accessed February 2020); 6. Clinicaltrials.gov/show/NCT04000594 (Accessed February 2020).

Tominersen’s Clinical Development Programme is contributing further data to evaluate the efficacy and safety of the drug Clinical Development Programme Phase I/IIa 1 N=46 Open-Label Extension N=46 2 • • First-in-human study ✓ Long-term safety, tolerability, PK and PD ✓ • • Safety, tolerability, PK and PD Early manifest HD patients • • Early manifest HD patients 15 months HD Natural History Study N=95 3 ✓ Complete • Prospective, longitudinal study • Early manifest HD patients ✓ Complete, final analysis ongoing • 15 months GEN-EXTEND 5 Ongoing, recruitment complete GENERATION HD1 N=801 4 (OLE) • Pivotal, long-term efficacy and safety Ongoing, recruiting • Manifest HD patients • 25 months (plus follow-up) Includes digital monitoring platform GEN-PEAK N=12* 6 • PK/PD in CSF and plasma • Manifest HD patients • 7 months including follow-up * An additional 8 patients may be included to allow investigation of additional dose levels and repeat doses if necessary. CSF, cerebrospinal fluid; HD, Huntington's disease; OLE, open-label extension; PD, pharmacodynamics; PK, pharmacokinetics. 1. Tabrizi SJ, et al . N Engl J Med. 2019; 380:2307 – 2316; 2. Clinicaltrials.gov/show/NCT03342053 (Accessed February 2020); 3. Clinicaltrials.gov/show/NCT03664804 (Accessed February 2020); 4. Clinicaltrials.gov/show/NCT03761849 (Accessed February 2020); 11 5. Clinicaltrials.gov/show/NCT03842969 (Accessed February 2020); 6. Clinicaltrials.gov/show/NCT04000594 (Accessed February 2020).