June 2020
Volume 61, Issue 7
Open Access
ARVO Annual Meeting Abstract  |   June 2020
Ocular Pharmacokinetics and Safety of Suprachoroidal A01017, Small Molecule Complement Inhibitor, Injectable Suspension in Rabbits
Author Affiliations & Notes
  • Shelley E Hancock
    Clearside Biomedical, Inc., Alpharetta, United States, Georgia
  • Avinash Phadke
    Achillion Pharmaceuticals, Connecticut, United States
  • Viral Kansara
    Clearside Biomedical, Inc., Alpharetta, United States, Georgia
  • David Boyer
    Achillion Pharmaceuticals, Connecticut, United States
  • Jose Rivera
    Achillion Pharmaceuticals, Connecticut, United States
  • Christopher Marlor
    Achillion Pharmaceuticals, Connecticut, United States
  • Steven Podos
    Achillion Pharmaceuticals, Connecticut, United States
  • Jason Wiles
    Achillion Pharmaceuticals, Connecticut, United States
  • Rick McElheny
    Clearside Biomedical, Inc., Alpharetta, United States, Georgia
  • Thomas A Ciulla
    Clearside Biomedical, Inc., Alpharetta, United States, Georgia
    Indiana University School of Medicine, Indiana, United States
  • Mingjun Huang
    Achillion Pharmaceuticals, Connecticut, United States
  • Mark Cartwright
    Achillion Pharmaceuticals, Connecticut, United States
  • Footnotes
    Commercial Relationships   Shelley Hancock, Clearside Biomedical, Inc. (E), Clearside Biomedical, Inc. (I); Avinash Phadke, Achillion Pharmaceuticals (E), Achillion Pharmaceuticals (P), Achillion Pharmaceuticals (I); Viral Kansara, Clearside Biomedical, Inc. (E), Clearside Biomedical, Inc. (I); David Boyer, Achillion Pharmaceuticals (E), Achillion Pharmaceuticals (P), Achillion Pharmaceuticals (I); Jose Rivera, Achillion Pharmaceuticals (E), Achillion Pharmaceuticals (P), Achillion Pharmaceuticals (I); Christopher Marlor, Achillion Pharmaceuticals (E), Achillion Pharmaceuticals (P), Achillion Pharmaceuticals (I); Steven Podos, Achillion Pharmaceuticals (E), Achillion Pharmaceuticals (P), Achillion Pharmaceuticals (I); Jason Wiles, Achillion Pharmaceuticals (E), Achillion Pharmaceuticals (P), Achillion Pharmaceuticals (I); Rick McElheny, Clearside Biomedical, Inc. (E), Clearside Biomedical, Inc. (I); Thomas Ciulla, Clearside Biomedical, Inc. (E), Clearside Biomedical, Inc. (I); Mingjun Huang, Achillion Pharmaceuticals (E), Achillion Pharmaceuticals (P), Achillion Pharmaceuticals (I); Mark Cartwright, Achillion Pharmaceuticals (E), Achillion Pharmaceuticals (P), Achillion Pharmaceuticals (I)
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science June 2020, Vol.61, 3694. doi:
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      Shelley E Hancock, Avinash Phadke, Viral Kansara, David Boyer, Jose Rivera, Christopher Marlor, Steven Podos, Jason Wiles, Rick McElheny, Thomas A Ciulla, Mingjun Huang, Mark Cartwright; Ocular Pharmacokinetics and Safety of Suprachoroidal A01017, Small Molecule Complement Inhibitor, Injectable Suspension in Rabbits. Invest. Ophthalmol. Vis. Sci. 2020;61(7):3694.

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

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  • Supplements
Abstract

Purpose : Complement alternative pathway (AP) activation has been implicated via genetic association in dry age-related macular degeneration (AMD). Inhibition of complement components using therapeutics delivered systemically or via intermittent intravitreal injection has yielded varying clinical trial success. Alternative delivery methods could yield more sustained high levels of inhibition and consequently improved clinical benefits. Given the bioavailability and durability potential of suprachoroidal (SC) small molecule suspensions, this preclinical study assessed the safety and pharmacokinetics (PK) of SC A01017, a highly potent complement factor D inhibitor that blocks AP activity.

Methods : A single bilateral suprachoroidal injection (100 µL) of A01017 suspension was administered to male Dutch-Belted (DB) pigmented rabbits (N=2-3 rabbits/timepoint) to assess toxicity and PK. Toxicity was assessed at 0 (vehicle control), 0.03, 0.1, 0.3, and 1 mg/eye based on mortality, clinical observations, ophthalmic observations, intraocular pressure measurement, electroretinography, and pathology. Ocular PK was assessed at 0.03, 0.1, 0.3 mg/eye. Retinal pigment epithelium-choroid-sclera (RCS), neural retina, vitreous, aqueous humor and blood collected on days 15, 29, 43, 57, 71, and 92 were analyzed for drug content via LC-MS-MS.

Results : SC A01017 was well tolerated in DB rabbits. Minimal, non-adverse drug-related toxicity was observed in this study. Sustained high exposure of A01017 was observed in RCS and retina throughout the 92-day study at all three doses. Elimination of A01017 from RCS was roughly first-order, with an estimated half-life (T1/2) of 66, 66, and 76 days at 0.03, 0.1, and 0.3 mg/eye level, respectively. Mean RCS levels on day 92 (Clast) were 13400, 81500, and 409000 ng/mL at dose levels 0.03, 0.1, and 0.3 mg/eye, respectively, that are 3-5 orders of magnitude higher than the in-vitro (AP hemolysis assay) IC90 value. Mean retina levels (AUC0-92) were 76.8, 606, and 5040 day*μg/mL for dose level 0.03, 0.1, and 0.3 mg/eye, respectively. Low or no quantifiable A01017 was detected in vitreous, aqueous humor or plasma.

Conclusions : SC delivery of A01017 suspension provided well tolerated, sustained high drug levels in the posterior segment in rabbits, and merits further studies in the development of long-acting small molecule complement inhibitors for dry AMD.

This is a 2020 ARVO Annual Meeting abstract.

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