Pharmacogenetic investigation of efficacy response to mepolizumab in eosinophilic granulomatosis with polyangiitis.

Treatment of patients with the rare disease eosinophilic granulomatosis with polyangiitis (EGPA) with mepolizumab, a monoclonal antibody to interleukin-5 (IL-5) that reduces blood eosinophil counts, as an add-on therapy to glucocorticoid treatment, results in more accrued weeks in remission, reductions in glucocorticoid use and reductions in relapse rate. However, treatment response varies across a continuum. Therefore, to investigate if large genetic effects could identify responders, the impact of genetic variants on efficacy in EGPA subjects taking mepolizumab and glucocorticoids was assessed in this post hoc study. Using linear regression and a negative binomial model, genetic variant association with three endpoints (accrued duration of remission, average oral glucocorticoid dose, and frequency of relapse) was tested in 61 EGPA subjects dosed with mepolizumab from MIRRA, a phase 3 trial. Candidate gene and genome-wide approaches were used. The candidate gene analysis was designed to investigate drug target effects with eight gene regions selected that were focused on the intersection of the glucocorticoid response (steroidal response) and IL-5 response mechanisms and recognizing potential overlap between EGPA and severe eosinophilic asthma diseases for which mepolizumab is used. The sample size was insufficient to enable testing of rare variants for effects. No genetic variant from either the candidate gene analysis or the GWAS associated with any endpoint. Thresholds to declare significance were p < 0.0008 (candidate variant) and p < 2.5 × 10-8 (genome-wide) analyses. Large genetic effects on mepolizumab-treatment response were not identified which could help differentiate responders from non-responders.

A Randomized Phase 2 Study of an Anti-Amyloid ß Monoclonal Antibody in Geographic Atrophy Secondary to Age-Related Macular Degeneration.

PURPOSE: To investigate the efficacy of intravenous GSK933776, a humanized monoclonal antibody directed against the N-terminal amino acids of amyloid ß, for the treatment of geographic atrophy (GA) in age-related macular degeneration (AMD). DESIGN: Prospective, randomized, placebo-controlled, double-masked, multicenter phase 2 clinical trial. PARTICIPANTS: Patients with GA secondary to AMD, a visual acuity score of at least 35 letters, and GA with a total area of 1.9 to 17 mm2 were enrolled. METHODS: Participants were monitored monthly for 4 months during an observation period to determine the rate of GA enlargement in the study eye. After the observation period, randomization was performed into 1 of 4 treatment arms (GSK933776 at 3, 6, and 15 mg/kg/month and placebo). At each monthly visit over 18 months, participants underwent visual acuity testing under normal luminance and low-luminance conditions. Ocular imaging included color fundus photography, fundus autofluorescence, fluorescein angiography, and spectral-domain OCT. MAIN OUTCOME MEASURE: Enlargement in the area of GA measured from color fundus photographs with reference to fundus autofluorescence images. RESULTS: A total of 191 participants were randomized into the study, with 139 (73%) fulfilling the efficacy population criteria. Over 18 months, GSK933776 did not reduce the rate of GA enlargement relative to placebo. Overall, there were no consistent meaningful differences relative to placebo in any of the visual function measures. There was a correlation between the low-luminance visual acuity (LLVA) deficit at baseline and the rate of GA enlargement. Genetic variations in complement factor I (CFI) gene did not correlate with GA progression. No ocular serious adverse events considered related to the GSK933776 treatment were identified, and a similar number of nonocular serious adverse events were reported across all treatment groups. CONCLUSIONS: Intravenous amyloid ß inhibition with GSK933776 did not slow the rate of GA enlargement compared with placebo, and no clinically meaningful differences relative to placebo were observed in visual function testing over 18 months. The LLVA deficit was associated with faster GA enlargement; however, no correlation was shown between genetic variations in the CFI gene and the rate of GA enlargement.

Rash in lapatinib-treated patients is not associated with human leukocyte antigen polymorphisms.

Rash is a common side effect of lapatinib treatment. Since human leukocyte antigen (HLA) alleles have been implicated in multiple drug-induced cutaneous reactions, this study investigated the association of HLA alleles with lapatinib-induced rash. 1191 participants from a large lapatinib monotherapy trial underwent HLA genotyping, and allele carriage frequencies between rash cases and controls were compared. This analysis had adequate power to detect an association of common HLA alleles with rash, similar to those reported previously. No HLA alleles were significantly associated with lapatinib-induced rash, including the previously identified lapatinib hepatotoxicity biomarker HLA-DRB1*07:01 (p = 0.87). The present study is consistent with the view that lapatinib-induced rash is not the consequence of HLA-restricted, immune-mediated mechanisms.

Prospective validation of HLA-DRB1*07:01 allele carriage as a predictive risk factor for lapatinib-induced liver injury.

PURPOSE: Liver injury is a serious adverse event leading to permanent discontinuation of lapatinib in affected patients. This study aimed to validate previously associated major histocompatibility complex (MHC) variants as predictors of risk of liver injury by using a large, randomized, placebo-controlled trial of lapatinib in human epidermal growth factor receptor 2-positive, early-stage breast cancer (Tykerb Evaluation After Chemotherapy [TEACH]: Lapatinib Versus Placebo In Women With Early-Stage Breast Cancer). PATIENTS AND METHODS: The frequency of ALT elevation cases was compared among four MHC variants in 1,194 patients randomly assigned to lapatinib. Cumulative ALT elevation time courses during treatment were also compared between carriers and noncarriers of specified MHC variants. RESULTS: In lapatinib-treated patients, there was a significant difference in ALT case incidence between HLA carriers and noncarriers. The highly correlated alleles HLA-DRB1*07:01 and HLA-DQA1*02:01 (study frequency, 22.4%) were associated with ALT elevation (odds ratio, 14) between cases (n = 37) and controls (n = 1,071). These associations strengthened at higher ALT elevation thresholds and in Hy's Law cases. In lapatinib-treated patients, the overall risk for National Cancer Institute-Common Terminology Criteria for Adverse Events grade 3 ALT elevation (> 5× upper limit of normal) was 2.1%; HLA allele carriers had an increased risk of 7.7%; in noncarriers, risk was reduced to 0.5%, comparable to ALT elevation for all patients receiving placebo. The increase in ALT case incidence in the lapatinib arm showed no evidence of plateau during 1 year of lapatinib treatment. CONCLUSION: These results validate HLA-DRB1*07:01 allele carriage as a predictor of increased risk of lapatinib-induced liver injury and implicate an immune pathology. The HLA association could support clinical management of patients experiencing hepatotoxicity during lapatinib treatment.