June 2021
Volume 62, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2021
Oral Administration of the Complement Factor D Inhibitor Danicopan (ALXN2040) in Preclinical Studies Demonstrates High and Sustained Drug Concentrations in Posterior Ocular Tissues for the Potential Treatment of Geographic Atrophy
Author Affiliations & Notes
  • David Boyer
    Alexion Pharmaceuticals Inc, Boston, Massachusetts, United States
  • Jose Rivera
    Alexion Pharmaceuticals Inc, Boston, Massachusetts, United States
  • Ya-Ping Ko
    Alexion Pharmaceuticals Inc, Boston, Massachusetts, United States
  • Steven D Podos
    Alexion Pharmaceuticals Inc, Boston, Massachusetts, United States
  • Mark Cartwright
    Alexion Pharmaceuticals Inc, Boston, Massachusetts, United States
  • Xiang Gao
    Alexion Pharmaceuticals Inc, Boston, Massachusetts, United States
  • Jason Wiles
    Alexion Pharmaceuticals Inc, Boston, Massachusetts, United States
  • Mingjun Huang
    Alexion Pharmaceuticals Inc, Boston, Massachusetts, United States
  • Footnotes
    Commercial Relationships   David Boyer, Alexion Pharmaceuticals (E); Jose Rivera, Alexion Pharmaceuticals (E); Ya-Ping Ko, Alexion Pharmaceuticals (E); Steven Podos, Alexion Pharmaceuticals (E); Mark Cartwright, Alexion Pharmaceuticals (E); Xiang Gao, Alexion Pharmaceuticals (E); Jason Wiles, Alexion Pharmaceuticals (E), Alexion Pharmaceuticals (P); Mingjun Huang, Alexion Pharmaceuticals (E)
  • Footnotes
    Support  Alexion Pharmaceuticals Inc
Investigative Ophthalmology & Visual Science June 2021, Vol.62, 187. doi:
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      David Boyer, Jose Rivera, Ya-Ping Ko, Steven D Podos, Mark Cartwright, Xiang Gao, Jason Wiles, Mingjun Huang; Oral Administration of the Complement Factor D Inhibitor Danicopan (ALXN2040) in Preclinical Studies Demonstrates High and Sustained Drug Concentrations in Posterior Ocular Tissues for the Potential Treatment of Geographic Atrophy. Invest. Ophthalmol. Vis. Sci. 2021;62(8):187.

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

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Abstract

Purpose : Danicopan is an investigational first-in-class small-molecule inhibitor of factor D, an essential enzyme of the complement alternative pathway, which, when dysregulated, is implicated in the pathogenesis of age-related macular degeneration (AMD). We explored, in animal models, delivery of PO danicopan to the posterior segment of the eye for the potential treatment of geographic atrophy (GA), an advanced form of AMD.

Methods : Tissue distribution of drug-related radioactivity was studied following PO administration of [14C]danicopan 20 mg/kg to pigmented Long-Evans (LE) and albino Wistar Han (WH) rats. Danicopan binding to natural and synthetic melanin was determined in vitro. Ocular tissue distribution was studied in pigmented Dutch-Belted (DB) and albino New Zealand White (NZW) rabbits following PO danicopan at 15 and 50 mg/kg BID for up to 15 days.

Results : After PO administration to rats, [14C]danicopan-derived radioactivity was absorbed rapidly and distributed widely to tissues. Radioactivity was present 1–8h and became nonquantifiable 24h post-dose in most tissues. In LE, but not WH rats, radioactivity remained quantifiable in the uvea 672h post-dose (t1/2=576h), suggesting danicopan binding to melanin, which was confirmed in vitro (mean KD=8.6µM). Distribution to ocular tissues was also observed following PO administration of danicopan to rabbits: Cmax retina:plasma ratios were 0.5–1 in DB and NZW, demonstrating that danicopan crosses the blood–retinal barrier (BRB); AUC choroid/RPE:plasma ratios were 24 and 0.7, respectively, in DB and NZW after single dosing (15 mg/kg), further supporting danicopan binding to melanin; and AUCs increased 7- and 13-fold in choroid/RPE and retina, respectively, after 15-day dosing (15 mg/kg BID) versus single dosing (15 mg/kg) in DB, suggesting that melanin-bound danicopan in choroid/RPE may serve as a drug depot maintaining high concentrations of danicopan in retina. Danicopan was well tolerated and resulted in no toxicity or ophthalmic abnormalities.

Conclusions : PO danicopan crosses the BRB and binds to melanin, leading to high and sustained drug exposure in posterior ocular tissue. These results support clinical investigation of danicopan for the oral treatment of GA.

This is a 2021 ARVO Annual Meeting abstract.

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