Pharma Update

ASO factor B in GA: Targeting hyperactive alternative complement pathway via SC delivery ASO factor B Gene mRNA Transcription Small molecule drugs Inhibitors or agonists of proteins Disease-causing protein Translation Disease-causing Translation protein Antisense oligonucleotide (ASO) Preclinical and Ph I data Preclinical results in monkeys¹ Roche Systemic (A) and ocular (B) ASO FB protein knockdown achieved with RG6299 SC 1501 Ph I: Significant dose-dependent reductions in plasma FB levels² 20 Placebo 696844 10 mg 696844 20 mg A Biologics Plasma FB Protein (% of BL) 93kD 100- 50- Saline ION-588548 20 40 60 Study Day 80 100 Saline FB ION-588548 FB Mean (+/- SEM) %Change from Baseline FBL (mcg/mL) -20 -40 -60 I -80 BL 8 15 22 29 36 43 -5 57 14 71 个个个个 ↑ ↑ ↑ IONIS-FB-LRX Injection Number of Subjects Visit (day) - 59 85 H T 106 127 • Complement Factor B (CFB): key component of alternative complement pathway; associated with complement hyperactivity seen in GA • Inhibits CFB gene expression & reduces the production of factor B protein B 50kD Advantages of ASO factor B: Placebo: 6 a Tubulin 696844 10 mg 696844 20 mg 12 12 2622 12 12 1622 129 622 622 622 12 12 12 622 122 622 622 Potential for systemic Q4W SC administration, simultaneous treatment of bilateral GA and self-administration at home More suitable option for treatment of early stage disease (e.g. ¡AMD) Ph II GOLDEN ongoing* with data expected 2024; pivotal study in planning stage *Managed by IONIS; 1. Grossman et al., Mol Vis 2017; 2. Guymer RG, et al. Presented at EURETINA 2020; ASO=antisense oligonucleotide; FB-Factor B; GA=geographic atrophy; CFB-Complement factor B; ¡AMD-intermediate age related macular degeneration; SC=Subcutaneous; Q4W-Every 4 weeks; SEM-Standard error of the mean; ASO factor B in-licenced from IONIS pharmaceuticals 128

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