September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
A novel oral small molecule Factor D inhibitor blocks complement activation in the blood and ocular tissues
Author Affiliations & Notes
  • Karen Anderson
    Ophthalmology, Novartis, Cambridge, Massachusetts, United States
  • Sha-Mei Liao
    Ophthalmology, Novartis, Cambridge, Massachusetts, United States
  • Juergen Maibaum
    GDC, Novartis, Basel, Switzerland
  • Frederic Cumin
    CPC, Novartis, Basel, Switzerland
  • Omar Delgado
    Ophthalmology, Novartis, Cambridge, Massachusetts, United States
  • Andrea De Erkenez
    Ophthalmology, Novartis, Cambridge, Massachusetts, United States
  • Fang Liu
    Ophthalmology, Novartis, Cambridge, Massachusetts, United States
  • Upendra Argikar
    MAP, Novartis, Cambridge, Massachusetts, United States
  • Ron Newton
    PCS, Novartis, Cambridge, Massachusetts, United States
  • Bruce D Jaffee
    Ophthalmology, Novartis, Cambridge, Massachusetts, United States
  • Footnotes
    Commercial Relationships   Karen Anderson, NIBR (E); Sha-Mei Liao, Novartis (E); Juergen Maibaum, Novartis (E); Frederic Cumin, Novartis (E); Omar Delgado, Novartis (E); Andrea De Erkenez, Novartis (E); Fang Liu, Novartis (E); Upendra Argikar, Novartis (E); Ron Newton, Novartis (E); Bruce Jaffee, Novartis (E)
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science September 2016, Vol.57, 4440. doi:
  • Views
  • Share
  • Tools
    • Alerts
      ×
      This feature is available to authenticated users only.
      Sign In or Create an Account ×
    • Get Citation

      Karen Anderson, Sha-Mei Liao, Juergen Maibaum, Frederic Cumin, Omar Delgado, Andrea De Erkenez, Fang Liu, Upendra Argikar, Ron Newton, Bruce D Jaffee; A novel oral small molecule Factor D inhibitor blocks complement activation in the blood and ocular tissues
      . Invest. Ophthalmol. Vis. Sci. 2016;57(12):4440.

      Download citation file:


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

      ×
  • Supplements
Abstract

Purpose : Strong genetic associations in humans have implicated complement alternative pathway (AP) activation in age-related macular degeneration (AMD). Factor D (FD) inhibition is proposed as an attractive mechanism to reduce alternative pathway overactivity at the first and rate-limiting step of the AP.

Methods : First-in-class, reversible, non-covalent Factor D inhibitors were identified using structure-based drug design, employing a tailored chemical library and in silico docking. Potency was assessed initially in a biochemical enzymatic assay, followed by serum- and whole blood-based in vitro functional assays using zymosan to activate the AP and measuring deposition of membrane attack complex (MAC). Compound 6 was investigated in vivo using a humanized FD knock-in mouse pharmacodynamic (PD) model. In this model, intraperitoneal lipopolysaccharide (LPS) was used to activate complement, and AP breakdown products were monitored in the blood and the eye tissue. We also evaluated the inhibitor’s ability to block ex vivo serum complement activation after oral administration of the compound to cynomolgus monkeys.

Results : The FD inhibitor 6 was very potent in 50% human whole blood with a half-maximal inhibitory value (IC50) of 71 nM. The compound dose-dependently inhibited LPS-induced generation of Ba and iC3b/C3d in blood and eye after oral gavage in mice, with complete suppression of the AP in both compartments at 100 mg/kg PO. Dose dependent inhibition of ex vivo complement activation in serum was also demonstrated after oral administration to monkeys, with an IC50 value of 3.6 µM.

Conclusions : Compound 6 represents a first-in-class reversible, selective, and potent small molecule FD inhibitor that is orally efficacious in a humanized mouse model and in a monkey ex vivo PD assay. Systemic dysregulation of the AP underlies a number of human diseases with apparent local manifestations, like age-related macular degeneration. Fully effective treatment of these diseases will likely require inhibition at the systemic level. Our findings support continued efforts aimed at developing oral AP-targeting therapies for complement-mediated diseases.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.

×
×

This PDF is available to Subscribers Only

Sign in or purchase a subscription to access this content. ×

You must be signed into an individual account to use this feature.

×