Purpose: An overactive alternative complement pathway has been implicated in the pathophysiology of geographic atrophy secondary to age related macular degeneration (AMD). We determined clinical safety, pharmacokinetic (PK) and pharmacodynamic (PD) activity of IONIS-FB-LRx, an ribonucleic acid therapeutic specifically targeting human complement factor B gene and subsequent factor B (FB) production in the liver, as a means to decrease alternative complement pathway activity in the cho-riocapillaris and retina. Methods: Healthy volunteers (N = 54; ages 25-65 years; 69 M) enrolled in subcutaneously administered, single ascending dose or multiple ascending dose (MAD), randomised (1:3 or 1:4, respectively) to placebo or IONIS-FB-LRx at 10, 20 or 40 mg and 10 or 20 mg (MAD: 8 administrations in 6 weeks). Endpoints assessed throughout the study: ocular and systemic safety, PK and PD. All subjects completed study (week 19) (ACTRN12616000335493). Results: No safety signals or clinically-relevant changes in ocular endpoints (best-corrected visual acuity, intraocular pressure, comprehensive examination), blood chemistries, hematology or vital signs following IONIS-FB-LRxdosing. Systemic PD: reduction of FB levels at the 20 mg dose (MAD) achieved lower alternative complement activity (AH50) without classical pathway (CH50) change (mean ± SE reductions on day 43 of -72 ± 3, -62 ± 5 and -12 ± 5, for FB, AH50 CH50, respectively). PK: 3-4 week half-life supports monthly dosing. Conclusions: This first-in-human study found the ribonucleic acid therapeutic, IONIS-FB-LRx, to exhibit robust lowering of systemic FB and excellent safety profile, leading to initiation of the phase 2 study determine the potential of systemic IONIS-FB-LRx in reducing progression of geographic atrophy (GOLDEN study; NCT03815825).
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