Timothy Wright

A genome-wide study identifies HLA alleles associated with lumiracoxib-related liver injury

Lumiracoxib is a selective cyclooxygenase-2 inhibitor developed for the symptomatic treatment of osteoarthritis and acute pain. Concerns over hepatotoxicity have contributed to the withdrawal or non-approval of lumiracoxib in most major drug markets worldwide. We performed a case-control genome-wide association study on 41 lumiracoxib-treated patients with liver injury (cases) and 176 matched lumiracoxib-treated patients without liver injury (controls). Several SNPs from the MHC class II region showed strong evidence of association (the top SNP was rs9270986 with P = 2.8 × 10−10). These findings were replicated in an independent set of 98 lumiracoxib-treated cases and 405 matched lumiracoxib-treated controls (top SNP rs3129900, P = 4.4 × 10−12). Fine mapping identified a strong association to a common HLA haplotype (HLA-DRB1*1501-HLA-DQB1*0602-HLA-DRB5*0101-HLA-DQA1*0102, most significant allele P = 6.8 × 10−25, allelic odds ratio = 5.0, 95% CI 3.6–7.0). These results offer the potential to improve the safety profile of lumiracoxib by identifying individuals at elevated risk for liver injury and excluding them from lumiracoxib treatment.

Rapid and robust response of biochemical markers of bone formation to teriparatide therapy

Teriparatide, a parathyroid hormone analogue, is a potent anabolic treatment for postmenopausal osteoporosis. Studies have shown that teriparatide induces large increases in biochemical markers of bone formation after 1 month of therapy followed by a delayed increase in bone resorption markers. The aims of this study were to (1) describe changes in bone turnover markers during 28 days of treatment with teriparatide; (2) identify the earliest time point by which most subjects showed a biochemical response to teriparatide; (3) identify potential biomarkers of positive bone response; (4) describe changes in bone turnover markers 4 weeks after stopping teriparatide. We recruited 15 osteopenic postmenopausal women, ages 55-69 (mean 62) years. All received 20 microg teriparatide subcutaneously for 28 days. Serum levels of the bone formation markers type I collagen N-terminal propeptide (PINP), type I collagen C-terminal propeptide (PICP), osteocalcin (OC), bone alkaline phosphatase (bone ALP), and the bone resorption markers crosslinked C-telopeptide of type I collagen (Sbeta-CTX), crosslinked N-telopeptide of type I collagen (S-NTX) and tartrate-resistant acid phosphatase type 5b (TRACP5b) were measured on 11 occasions: three times before dosing (baseline) and on days 3, 7, 10, 14, 19, 24 and 28 and at day 56 (i.e., 28 days after stopping teriparatide ). During the first 2 days of teriparatide treatment, PINP levels increased rapidly, by 8.2% (90% confidence interval (CI) 6.9%, 9.5%) and continued to increase until the end of treatment to 110.8%. PICP and OC showed a similar, but less pronounced, pattern. All three markers increased by at least 75% at day 28. A small, transient decrease in bone resorption markers occurred over the same period. Following cessation of treatment, concentrations of bone formation markers decreased to within 20% of baseline values by day 56. In conclusion, the bone formation markers PINP, PICP and OC show a rapid and robust increase in response to teriparatide, which is noticeable during the first week of therapy. PINP is the most responsive marker. These findings have important implications for monitoring patients treated with teriparatide and may also inform the design of studies of new anabolic agents for osteoporosis.

T-cell assays confirm immunogenicity of tungsten-induced erythropoietin aggregates associated with pure red cell aplasia

Immunogenicity of biotherapeutics and the elicitation of anti-drug antibodies are a key concern for their efficacy, pharmacokinetics, and safety. A particularly severe consequence of immunogenicity of a biotherapeutic is the rare development of antibody-mediated pure red cell aplasia (PRCA) in anemic patients treated with aggregated forms of recombinant human erythropoietin (rhEPO). Here, we investigated in vitro T-cell responses to experimentally heat-induced rhEPO aggregates, and to tungsten-induced rhEPO aggregates in clinical lots associated with rhEPO-neutralizing antibodies and PRCA. Heat-stressed rhEPO elicited T-cell responses only in blood obtained from healthy individuals identified as responders, whereas nonstressed rhEPO overall did not induce reactions neither in responders nor nonresponders. Tungsten-induced rhEPO aggregates in clinical lots associated with rhEPO-neutralizing antibodies and PRCA could induce in vitro T-cell responses in blood obtained from healthy donors, in contrast to rhEPO from low tungsten syringes. Importantly, ex vivo T-cell recall responses of patients treated with rhEPO without PRCA showed no T-cell responses, whereas T cells of a patient who developed PRCA after treatment with a clinical batch with elevated levels of tungsten and rhEPO aggregates showed a clear response to rhEPO from that clinical batch. To our knowledge, this is the first time that T-cell assays confirm the root cause of increased rhEPO immunogenicity associated with PRCA.