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Pre-clinical data demonstrate a pivotal role for interleukin (IL)-13 in the development and maintenance of asthma. This study assessed the effects of tralokinumab, an investigational human IL-13-neutralising immunoglobulin G4 monoclonal antibody, in adults with moderate-to-severe uncontrolled asthma despite controller therapies.194 subjects were randomised to receive tralokinumab (150, 300 or 600 mg) or placebo subcutaneously every 2 weeks. Primary end-point was change from baseline in mean Asthma Control Questionnaire score (ACQ-6; ACQ mean of six individual item scores) at week 13 comparing placebo and combined tralokinumab dose groups. Secondary end-points included pre-bronchodilator lung function, rescue β2-agonist use and safety. Numerical end-points are reported as mean±sd.At week 13, change from baseline in ACQ-6 was -0.76±1.04 for tralokinumab versus -0.61±0.90 for placebo (p=0.375). Increases from baseline in forced expiratory volume in 1 s (FEV1) were 0.21±0.38 L versus 0.06±0.48 L (p=0.072), with a dose-response observed across the tralokinumab doses tested. β2-agonist use (puffs per day) was decreased for tralokinumab -0.68±1.45 versus placebo -0.10±1.49 (p=0.020). The increase in FEV1 following tralokinumab treatment remained evident 12 weeks after the final dose. Safety profile was acceptable with no serious adverse events related to tralokinumab.No improvement in ACQ-6 was observed, although tralokinumab treatment was associated with improved lung function.

AstraZeneca.

Background-Lapaquistat acetate is a squalene synthase inhibitor investigated for the treatment of hypercholesterolemia. Methods and Results-This report summarizes the phase 2 and 3 results from the lapaquistat clinical program, which was halted at an advanced stage as a result of potential hepatic safety issues. Efficacy and safety data were pooled from 12 studies (nϭ6151). These were 6-to 96-week randomized, double-blind, parallel, placebo-or active-controlled trials with lapaquistat monotherapy or coadministration with other lipid-altering drugs in dyslipidemic patients, including a large (nϭ2121) 96-week safety study. All studies included lapaquistat 100 mg daily; 5 included 50 mg; and 1 included 25 mg. The main outcome measures were the percent change in low-density lipoprotein cholesterol, secondary lipid/metabolic parameters, and overall safety. Lapaquistat 100 mg significantly decreased low-density lipoprotein cholesterol by 21.6% in monotherapy and by 18.0% in combination with a statin. It also reduced other cardiovascular risk markers, such as C-reactive protein. Total adverse events were higher for lapaquistat than placebo, although individual events were generally similar. At 100 mg, there was an increase in alanine aminotransferase value Ն3 times the upper limit of normal on Ն2 consecutive visits (2.0% versus 0.3% for placebo in the pooled efficacy studies; 2.7% versus 0.7% for low-dose atorvastatin in the long-term study). Two patients receiving lapaquistat 100 mg met the Hy Law criteria of alanine aminotransferase elevation plus increased total bilirubin. Conclusions-Squalene synthase inhibition with lapaquistat acetate, alone or in combination with statins, effectively lowered low-density lipoprotein cholesterol in a dose-dependent manner. Elevations in alanine aminotransferase, combined with a rare increase in bilirubin, presented potential hepatic safety issues, resulting in termination of development. The lapaquistat experience illustrates the current challenges in lipid-altering drug development.

AIMSTralokinumab, an investigational human immunoglobulin G4 monoclonal antibody, potently and specifically neutralizes interleukin-13, a central mediator of asthma. Tralokinumab has shown improvements in clinical endpoints in adults with uncontrolled asthma. The present study explored the pharmacokinetics (PK) and safety of a single tralokinumab dose, and utilized a population PK modelling and simulation approach to evaluate the optimal dosing strategy for adolescents. METHODSAdolescent subjects with asthma, using daily controller medication, received a single subcutaneous dose of tralokinumab 300 mg. Safety, immunogenicity and PK data were collected during a 57-day follow-up. A population PK model was developed using data from the present study and prior studies in adults. Simulations were performed to evaluate dose adjustment requirements for adolescents. RESULTSTwenty adolescents (12-17 years) were enrolled; all completed the study. No clinically relevant safety findings or antidrug antibodies were detected. PK parameters were similar to those observed in adults. PK modelling showed that body weight was a minor predictor of tralokinumab PK; after incorporating body weight into the PK model, a 15% (nonparametric 95% confidence interval 5%, 26%) lower clearance was found in adolescents compared with adults [173 (151, 209) vs. 204 (191, 229) Simulations showed no therapeutically relevant differences in exposures between adolescent and adult populations, and similar PK profiles for weight-based (4 mg kg -1 ) and fixed (300 mg) fortnightly subcutaneous doses of tralokinumab. CONCLUSIONSingle-dose administration of tralokinumab 300 mg in adolescents was well tolerated, with a PK profile similar to that in adults. Exposure predictions suggest that dose adjustment is not required for adolescents.

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No abstract

Tralokinumab is a human monoclonal antibody in clinical development for asthma and atopic dermatitis that specifically neutralizes interleukin-13. This phase I, single-blind, randomized, placebo-controlled, single ascending-dose study assessed the safety, tolerability, pharmacokinetics (PK), and immunogenicity of subcutaneous tralokinumab (150, 300, or 600 mg) in thirty healthy Japanese adults. The most frequent treatment-emergent adverse event (TEAE) in all treatment groups was injection-site pain. The frequency and severity of TEAEs was similar across tralokinumab doses. C, AUC, and AUC increased in a dose-proportional manner, and mean t ranged from 20 to 25 days. No anti-drug antibodies were detected. A post-hoc pooled population PK modeling analysis, incorporating PK data from this study, demonstrated that Japanese individuals had greater systemic exposure to tralokinumab than non-Japanese individuals. This difference was not clinically relevant and was primarily due to differences in body weight, with lower body weight associated with greater PK exposure. Japanese ethnicity was not a significant predictor of tralokinumab PK. This study indicates that single-dose subcutaneous administration of tralokinumab 150-600 mg was well tolerated in Japanese healthy volunteers, and supports the 300 mg dose selection for Japanese patients with asthma in ongoing clinical trials.