June 2021
Volume 62, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2021
Systemic Antisense Oligonucleotide Inhibition of Complement Factor B for Treatment of Geographic Atrophy: Results of a Placebo-controlled Phase 1 Dose-Escalation Study
Author Affiliations & Notes
  • David S Boyer
    Retina-Vitreous Associates Medical Group, Los Angeles, California, United States
  • Jayashree Sahni
    Hoffman-La Roche, Basel, Switzerland
  • Sascha Fauser
    Hoffman-La Roche, Basel, Switzerland
  • Richard Geary
    Ionis Pharmaceuticals Inc, Carlsbad, California, United States
  • Eugene Schneider
    Ionis Pharmaceuticals Inc, Carlsbad, California, United States
  • Michael McCaleb
    Ionis Pharmaceuticals Inc, Carlsbad, California, United States
  • Footnotes
    Commercial Relationships   David Boyer, Adverum Biotechnologies (C), Aerie (C), Alcon (C), Allegro (C), Allergan (C), Apellis Pharmaceuticals (C), AsclepiX Therapeutics (C), Bayer (C), Biogen Inc (C), Boehringer-Ingelheim Pharmaceuticals (C), Chengdu Kanghong Biotechnology (C), Clearside Biomedical (C), EyePoint Pharmaceuticals (C), Genentech (C), GrayBug Vision (C), Iconic Therapeutics (C), Ionis Pharmaceuticals (C), Kala Pharmaceuticals (C), NGMB Pharmaceuticals (C), Novartis Ophthalmics (C), Ocugen, Inc (C), Ocular Therapeutix (C), Ocuphire Pharma (C), Regeneron (C), Regenxbio (C); Jayashree Sahni, Hoffman La Roche (E); Sascha Fauser, Hoffman La Roche (E); Richard Geary, Ionis Pharmaceuticals (E); Eugene Schneider, Ionis Pharmaceuticals (E); Michael McCaleb, Ionis Pharmaceuticals (E), Ionis Pharmaceuticals (P)
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science June 2021, Vol.62, 196. doi:
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      David S Boyer, Jayashree Sahni, Sascha Fauser, Richard Geary, Eugene Schneider, Michael McCaleb; Systemic Antisense Oligonucleotide Inhibition of Complement Factor B for Treatment of Geographic Atrophy: Results of a Placebo-controlled Phase 1 Dose-Escalation Study. Invest. Ophthalmol. Vis. Sci. 2021;62(8):196.

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      © ARVO (1962-2015); The Authors (2016-present)

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Purpose : An over-active alternative complement pathway (ACP) is implicated in geographic atrophy (GA) pathophysiology and ACP end products are present in the choriocapillaris (CC), drusen and Bruch’s membrane of eyes with AMD. In monkeys, a systemic Factor B antisense oligonucleotide (ASO) reduced ocular factor B (FB) protein >99%. We determined clinical safety, pharmacokinetic (PK) and pharmacodynamic (PD) activity of IONIS-FB-LRx, an ASO specifically targeting human complement factor B gene (CFB) and subsequent factor B (FB) production in the liver, as a means to decrease ACP activity in the CC.

Methods : In a phase 1 masked, randomized placebo-controlled single and multiple ascending dose study, healthy volunteers (HV) were randomized to either placebo or IONIS-FB-LRx (ACTRN12616000335493). The drug was administered (8 administrations in 6 wk – twice wk for 2 wk then once wk for 4 wk) at doses of 10 mg or 20 mg in the multiple ascending dose study. Endpoints assessed throughout the study: ocular and systemic safety, pharmacokinetic (PK) and pharmacodynamic (FB and ACP activity (AH50).

Results : 54 HV (age range 27- 65 yrs) were enrolled and all subjects completed study (wk 19). There were no safety signals or clinically-relevant changes in ocular endpoints (BCVA, IOP, comprehensive examination), blood chemistries, hematology or vital signs following IONIS-FB-LRx dosing. The maximum tolerated dose (MTD)was not reached. The systemic PD markers of plasma FB levels reduced in a dose dependent manner by approximately 56% and 72% after multiple administrations of 10 mg and 20 mg, respectively. The mean (+/- SE) % reductions of FB, ACP activity (AH50) and classical complement pathway activity (CH50) levels for the 20 mg dose on Day 43 (7d post last administration) was -72 (+/-3), -62 (+/-5) and -12 (+/-5)%, respectively.

Conclusions : IONIS-FB-LRX, is a novel antisense oligonucleotide drug, administered subcutaneously with a potential for monthly dosing. This first-in-human IONIS-FB-LRx study found the antisense drug to exhibit robust lowering of systemic FB and excellent safety profile. Based on these data, a Phase 2 double-masked, randomized placebo-controlled trial (N=330), the GOLDEN study, is currently underway to determine the potential of systemic IONIS-FB-LRx in reducing progression of GA (NCT03815825).

This is a 2021 ARVO Annual Meeting abstract.


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