Abstract
Purpose :
In a Phase 2 study, a novel topical ocular anti-TNFα antibody fragment, OCS-02, was found to be significantly more effective than vehicle in relieving ocular discomfort associated with severe dry eye disease (DED). An exploratory pharmacogenetics analysis identified genetic factors that may influence the response to OCS-02 in patients with DED.
Methods :
Genomic DNA from consenting patients was extracted from blood samples. Genotyping data were generated using TaqMan® technology. Candidate genes and single nucleotide polymorphisms (SNPs) were selected for pharmacogenomic analysis based on the drug target (TNF-α) or its receptor (TNFRl), or association with Sjogren's syndrome. A total of 8 SNPs were analyzed. A mixed model repeated measures analysis with Bonferroni correction was used to test the association between genotype and the primary efficacy outcome measure (change from baseline in global ocular discomfort score at Day 29). To test the interaction between genotype and treatment, an ANCOVA model was used with baseline global discomfort score, age and race included as covariates. For SNPs found to be associated with the primary endpoint, the percentage of patients with improvement in global ocular discomfort score > 20 (i.e. high responders) was analyzed by genotype using Fisher’s exact test.
Results :
Samples from 86 patients in the per protocol population treated (OCS-02, n = 43, vehicle, n = 43) were utilized for pharmacogenomic analysis. Among the 8 SNPs tested, only one showed a significant effect on the response to OCS-02 after Bonferroni correction (p<0.0001). This effect was only present in patients treated with OCS-02. Genotype-treatment interaction analysis using ANCOVA also found that the identified SNP was significantly associated with response. The proportion of OCS-02 patients with high responder status was significantly greater for the CC genotype (P<0.05, Fisher’s exact test); no significant effect was observed in patients treated with vehicle.
Conclusions :
This pharmacogenetic analysis demonstrated a statistically significant association between response to OCS-02 in patients with DED and a SNP biomarker. The CC genotype was significantly associated with high response to OCS-02. Additional studies are needed to better understand the role of unique SNPs in dry eye disease and susceptibility to anti TNFα therapies.
This is a 2021 ARVO Annual Meeting abstract.