Nandan Parmanand Koppiker

Enhancing the utility of alanine aminotransferase as a reference standard biomarker for drug-induced liver injury

Drug-induced liver injury (DILI) is the most frequent cause of discontinuation of new chemical entities during development. DILI can either be intrinsic/predictable or an idiosyncratic type. These two forms of DILI are contrasted in their manifestation and diagnosis. Even with regulatory guidance (FDA, 2009), there is still a gap in our ability to identify predictable DILI, both specifically and sensitively. Alanine aminotransferase (ALT) is the principal reference standard biomarker to diagnose DILI, yet its current application in preclinical to clinical translation for decision-making purposes has imperfections: (1) analytical ALT assay uniformity across industry would be aided by common analytical processes; (2) assessment of ALT toxicological performance in a large preclinical analysis would help to establish a true threshold of elevation for predictable DILI and improve translational use across various stages of pharmaceutical development and finally, (3) clinical evaluation of ALT elevations prospectively and retrospectively is recommended to define and manage variations in clinical study subjects including rising body mass index (BMI) range and ALT upper limit of normal (ULN) in the broader population over time. The emergence of new hepatotoxicity biomarkers necessitates a parallel and equivalent assessment to the aminotransferases in a regulatory qualification model.

No clinically important effects on intraocular pressure after short-term administration of sildenafil citrate (Viagra) ☆

PURPOSE To assess the short-term effects of sildenafil citrate on intraocular pressure in healthy male volunteers and participants in clinical trials. METHODS Intraocular pressure and pupil diameter were measured in two placebo-controlled studies. Oral doses of sildenafil citrate (VIAGRA; Pfizer Inc, New York, New York) ranged from 10 mg to 150 mg. RESULTS No major changes in intraocular pressure or pupillometry were detected at any time (1.0-24 hours) after administration of sildenafil. Additionally, of 36 subjects with a medical history of increased intraocular pressure in the sildenafil safety database, none were reported to have a clinically significant increase of their intraocular pressure. During clinical trials, two glaucoma cases were listed as serious adverse events, but were not considered treatment related. CONCLUSION No clinical abnormalities were observed in intraocular pressure or pupil diameter in subjects receiving sildenafil. Currently, no evidence suggests that long-term treatment with sildenafil has an effect on intraocular pressure or is associated with the development or worsening of glaucoma.

Recommendations to qualify biomarker candidates of drug-induced liver injury

Certain compounds that induce liver injury clinically are not readily identified from earlier preclinical studies. Novel biomarkers are being sought to be applied across the pharmaceutical pipeline to fill this knowledge gap and to add increased specificity for detecting drug-induced liver injury in combination with aminotransferases (alanine and aspartate aminotransferase)--the current reference-standard biomarkers used in the clinic. The gaps in the qualification process for novel biomarkers of regulatory decision-making are assessed and compared with aminotransferase activities to guide the determination of safe compound margins for drug delivery to humans where monitoring for potential liver injury is a cause for concern. Histopathologic observations from preclinical studies are considered the principal reference standard to benchmark and assess subtle aminotransferase elevations. This approach correlates quite well for many developmental compounds, yet cases of discordance create dilemmas regarding which standard(s) indicates true injury. Concordance amongst a broader set of biomarker injury signals in a qualification paradigm will increase confidence, leading to accepted and integrated translational biomarker signals during safety assessment processes across the pharmaceutical industry, with academia, in government and in contractor laboratories.

SAT0357 Evaluation of the Nonsteroidal Anti-Inflammatory Drug-Sparing Effect of Etanercept in Axial Spondyloarthritis: Results of the Multicenter Randomized, Double-Blind, Placebo-Controlled SPARSE Trial

Background Nonsteroidal anti-inflammatory drugs (NSAIDs) are first-line pharmacotherapy in axial spondyloarthritis (axSpA) but are recommended for use at the lowest effective dose for the shortest possible time due to safety concerns. Although NSAID discontinuation is common in clinical practice after response to biologic therapy in axSpA patients, its impact has not been evaluated in prospective controlled trials. Objectives The SPARSE trial was conducted to assess the effects of etanercept (ETN) on NSAID intake as measured by the ASAS-NSAID score1 and conventional clinical outcomes in axSpA. Methods In the initial 8-week, double-blind (DB), placebo (PBO)-controlled period, patients with active (mini BASDAI ≥4) axSpA (ASAS criteria) despite optimal NSAID intake were randomised to ETN 50 mg or PBO once weekly for 8 weeks. All patients were advised to taper/stop their NSAID intake (self-reported diary) during the study treatment period. Completers were eligible for ETN 50 mg in the subsequent 8-week open-label (OL) period. ASAS-NSAID scores were calculated according to ASAS recommendations.1 The primary endpoint, the change from baseline (BL) to week 8 in the ASAS-NSAID score, was analysed using an analysis of covariance (ANCOVA). Results In 90 randomised patients at BL, mean age (±SD) was 38.9±11.8 years; disease duration, 5.7±8.1 years; 62% were male; 66% were HLA-B27 positive; and 50% were MRI sacroiliitis positive. Mean ASAS-NSAID scores at BL (ETN vs PBO: 98.2±39.0 vs 93.0±23.4), BASDAI (6.0±1.7 vs 5.9±1.5), and BASFI (5.2±2.1 vs 5.1±2.2) were similar between groups. A between-group difference in changes in ASAS-NSAID scores of -27.3 (P=0.002) favouring ETN was observed at week 8 (table). Significantly more patients in the ETN vs PBO group achieved BASDAI50 and ASAS40 at week 8. Significant reductions in ASAS-NSAID scores were seen in the ETN/ETN group from BL to week 16 and in the PBO/ETN group from week 8 to 16 (table); response rates increased in the ETN/ETN and PBO/ETN groups for most clinical endpoints in the OL period. Conclusions In this population of patients with axSpA, etanercept was associated with clinically relevant NSAID-sparing effects in addition to significant improvements in conventional clinical outcomes. References Dougados M, et al. Ann Rheum Dis 2011;70(2):249-51. Acknowledgements This study was sponsored by Pfizer Inc. Medical writing support was provided by Donna McGuire of Engage Scientific and was funded by Pfizer Inc. Disclosure of Interest M. Dougados Grant/research support: AbbVie, Celgene, Eli Lilly, Novartis, Pfizer, Roche, and Sanofi-Aventis., Consultant for: AbbVie, Celgene, Eli Lilly, Novartis, Pfizer, Roche, and Sanofi-Aventis., E. Wood Consultant for: Full-time employee of Quanticate International, contracted by Pfizer Inc. to provide statistical input to the study and manuscript., B. Combe Grant/research support: Pfizer., Speakers bureau: Merck, Pfizer, UCB., C. Miceli-Richard Grant/research support: AbbVie, Bristol-Myers Squibb, Janssen, and Pfizer., Consultant for: AbbVie, Bristol-Myers Squibb, Janssen, and Pfizer., F. Berenbaum Grant/research support: Boehringer, Merck, Pfizer, Roche, BMS, UCB., Consultant for: AbbVie, UCB, Roche., N. Koppiker Shareholder of: Pfizer., Employee of: Pfizer., A. Dubanchet Shareholder of: Pfizer., Employee of: Pfizer., I. Logeart Shareholder of: Pfizer., Employee of: Pfizer. DOI 10.1136/annrheumdis-2014-eular.1226