Eplontersen: NEURO-TTRansform Week 85 Topline Results July 10, 2023 Nasdaq:
IONS
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registered trademark of Ionis Pharmaceuticals, Inc. 2
NEURO-TTRansform Study Designed to Demonstrate Benefit in Patients with
ATTRv-PN A multicenter, open-label study in 168 patients with hereditary TTR amyloid polyneuropathy (ATTRv-PN) 1Benson et al, N Engl J Med (2018) 379:22-3 1. Figure adapted from Coelho et al, Neurol Ther (2021) 10:375-89. Randomization
6:1 0 Study timeline (weeks) 35 Interim analysis 85 EOT analysis Patients with ATTRv - PN Screening Eplontersen (N=144) NEURO-TTR external placebo control1 (N=60) Inotersen (N=24) Eplontersen Final
analysis 105 Open-label Extension (up to 3 years) Co-Primary Efficacy Endpoints or 20-week post-treatment evaluation Serum TTR: % change from baseline mNIS+7: Change from baseline Norfolk QoL-DN: Change from baseline Co-Primary
Efficacy Endpoints Serum TTR: % change from baseline mNIS+7: Change from baseline Key Secondary Efficacy Endpoint Norfolk QoL-DN: Change from baseline Key Exploratory Endpoints Serum TTR: % change from baseline mNIS+7: Change from
baseline Norfolk QoL-DN: Change from baseline 66 66 3
Eplontersen Treatment Resulted in Substantial and Sustained Reductions in Serum
TTR Concentration Compared to Baseline LSM: Least Square Mean; LSMD: Least Square Mean Difference Week 35:Mean = -11.1% (LSM = -14.5%) Week 81Last dose Mean (SE) % Change From Baseline in Serum TTR Concentration Week 35:Mean =
-82.1% (LSM = -81.1%) Week 65:Mean = -83.0% (LSM = -81.7%) Week 65:Mean = -6.0% (LSM = -11.2%) Week 85:Mean = -81.8% LSMD (95% CI) = -70.4% (-75.2, -65.7) p<0.0001
−100 −80 −60 −40 −20 0 0 5 8 13 25 35 49 57 65 73 81 85 W eek Eplontersen Placebo 4
Eplontersen Continued to Halt Neuropathy Progression at Week 85 Substantial
number of patients showed improvement in neuropathy impairment through 19 months of treatment mNIS+7 Composite Score Worse Better Mean (SE) Change From Baseline in mNIS+7 Composite Score Week 35:Mean = 9.8 (LSM = 10.0) Week 35:Mean =
-0.04 (LSM = 0.7) Week 66:Mean = 23.9 (LSM = 25.1) Week 66:Mean = -0.2 (LSM = 0.3) Week 85:Mean = -2.9 LSM: Least Square Mean; LSMD: Least Square Mean Difference LSMD (95% CI) = -24.8 (-31.0, -18.6) p<0.0001 5
Eplontersen Continued to Improve Quality of Life at Week 85 Norfolk QoL-DN Total
Score Worse Better Mean (SE) Change From Baseline in Norfolk QoL-DN Total Score Week 35:Mean = 5.5 (LSM = 8.2) Week 35:Mean = -4.8 (LSM = -3.6) Week 66:Mean = 10.8 (LSM = 14.2) Week 66:Mean = -7.2 (LSM = -5.5) Week 85:Mean =
-6.2 Substantial number of patients showed improvement in quality of life through 19 months of treatment LSM: Least Square Mean; LSMD: Least Square Mean Difference LSMD (95% CI) = -19.7 (-25.6, -13.8) p<0.0001 6
Eplontersen Continued to Demonstrate a Favorable Safety and Tolerability Profile
at 85 Weeks1 At 85 weeks, TEAEs incidence remains consistent with week 66 No TEAEs of special interest led to study drug discontinuation No imbalance of ocular events excluding vitamin A decrease or deficiency No SAEs were related to study
drug 3 non-drug related deaths in the eplontersen group, all related to known sequelae of ATTR amyloidosis2-6 1External placebo concluded at week 66 while eplontersen patients remained on treatment and could accrue additional events;
2Cavallaro et al, Neurology (2016) 87:750-1; 3Yamada et al, Prog Mol Biol Transl Sci (2012) 107:41-78; 4Yamashita et al, Neurology (2008) 70:123-28; 5Ellie et al, Neurology (2001) 57:135-7; 6Porcari et al, Cardiovasc Res (2023)
118:3517-35. Incidence, n (%) Placebo Eplontersen Week 66 Eplontersen Week 85 N 60 144 144 Any TEAE 60 (100) 140 (97.2) 141 (97.9) Related to study drug 23 (38.3) 53 (36.8) 55 (38.2) Leading to study drug discontinuation 2
(3.3) 6 (4.2) 8 (5.6) TEAE of special interest 14 (23.3) 41 (28.5) 43 (29.9) Ocular events potentially related to Vit A deficiency 12 (20.0) 39 (27.1) 41 (28.5) Ocular events excluding lab TEAEs of Vit A decrease or deficiency 9
(15.0) 24 (16.7) 26 (18.1) Thrombocytopenia 1 (1.7) 3 (2.1) 3 (2.1) Glomerulonephritis 2 (3.3) 0 0 Other TEAE of interest 48 (80.0) 87 (60.4) 93 (64.6) Any serious TEAE 13 (21.7) 21 (14.6) 27 (18.8) Related to study drug 1
(1.7) 0 0 Fatal TEAE 0 2 (1.4) 3 (2.1) Related to study drug 0 0 0 7
