Nonclinical Safety Assessment of Anti-Factor D: Key Strategies and Challenges for the Nonclinical Development of Intravitreal Biologics.

Abstract

PURPOSE:

The nonclinical toxicology program described here was designed to characterize the safety profile of anti-factor D (AFD; FCFD4514S, lampalizumab) to support intravitreal (ITV) administration in patients with geographic atrophy (GA).

METHODS:

The toxicity of AFD was assessed in a single-dose and 6-month repeat-dose study in monkeys at doses up to 10 mg/eye. Toxicity was assessed by clinical ophthalmic examinations, intraocular pressure measurements, ocular photography, electroretinography, fluorescein angiography, optical coherence tomography, and anatomic pathology.

RESULTS:

Systemic exposure to AFD generally increased with the increase in dose level. The increases in mean maximal concentration and area under the curve values were roughly dose proportional. No accumulation of AFD was observed following 10 doses, and drug exposures were not affected by anti-drug antibodies. AFD was locally and systemically well tolerated in monkeys following ITV doses of up to 10 mg/eye. Ocular effects associated with AFD were limited to transient, reversible, dose-related, aqueous cell responses and injection-related, mild, vitreal cell responses. In the 6-month repeat-dose study, 2 monkeys had a nonspecific immune response to AFD that resulted in severe ocular inflammation, attributed to administration of a heterologous (humanized) protein.

CONCLUSIONS:

The comprehensive toxicology program in monkeys described here was designed to evaluate the safety profile of AFD and to support multiple ITV injections in the clinic. Administration of a heterologous (humanized) protein presents a challenge, and immunogenicity in nonclinical species is not predictive of immunogenicity in humans. Taken together, the results of the nonclinical program described here support the use of AFD in patients with GA.

• Authors: Vladimir Bantseev, Rebecca Erickson, Douglas Leipold, Caroline Amaya, Paul E Miller, Helen Booler, Evan A Thackaberry
• Journal: Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics (J Ocul Pharmacol Ther) 2018 Jan/Feb Vol. 34 Issue 1-2 Pg. 204-213 ISSN: 1557-7732 [Electronic] United States
• PMID: 29148965 (Publication Type: Journal Article)

Chemical References

• Immunoglobulin Fab Fragments
• Ophthalmic Solutions
• lampalizumab

Topics

• Animals
• Female
• Fluorescein Angiography
• Haplorhini
• Immunoglobulin Fab Fragments (administration & dosage, blood, pharmacology)
• Intraocular Pressure (drug effects)
• Intravitreal Injections
• Male
• Ophthalmic Solutions (administration & dosage, pharmacology)
• Tomography, Optical Coherence