The Tumor necrosis factor (TNF)-Related Apoptosis Inducing Ligand, TRAIL, has gained much attention due to its specific anti-tumor potential without toxic side effects. TRAIL binds to a complex receptor system. In humans there are two death-inducing receptors for TRAIL while only one is present in mice. The signaling induced by these receptors leads to apoptosis but might also result in activation of survival signals. To assess the safety and possible side effects of TRAIL-based cancer therapy it is necessary to understand the physiological role of the TRAIL/TRAIL-R system. This has been addressed in mice deficient either for TRAIL or for its only murine apoptosis-inducing receptor, TRAIL-R (MK/mDR5). In this review we will discuss their phenotypes and the results of recent studies on the role of TRAIL in the homeostasis of the immune system, the influence of the TRAIL/TRAIL-R system on infection and autoimmune diseases and the still controversial role of TRAIL in tumorigenesis. Clinical trials with TRAIL and other TRAIL receptor agonists are now under way. It will be exciting to determine which TRAIL-R agonists, either alone or in combination with other anti-cancer therapeutics, will result in better outcome of cancer treatment in the future.
Purpose: NOV03 has a unique dual mode of action to address dry eye disease (DED) associated with meibomian gland dysfunction. SEECASE evaluated the efficacy, safety, and tolerability of NOV03 at 2 dosing regimens compared with a saline comparator in patients with DED. Methods: SEECASE was a prospective, multicenter, randomized, double-masked, saline-controlled clinical study. A total of 336 DED patients [tear film breakup time ≤5 seconds, abnormal meibum secretion, total corneal fluorescein staining (tCFS) score of 4 ≤ X ≤ 11 (National Eye Institute scale), Schirmer of ≥5 mm] were randomized in a 2:2:1:1 manner to NOV03 4 times daily (QID), NOV03 twice daily (BID), saline BID, and saline QID, respectively. The primary efficacy endpoint was tCFS staining at 8 weeks for both regimens. Secondary endpoints included visual analog scales and the Ocular Surface Disease Index questionnaire for symptom assessment. Results: The study met its primary endpoint, change from baseline of tCFS over control, for both dosing regimens QID and BID ( P < 0.001 and P = 0.009, respectively). NOV03 also showed pronounced improvement in various symptoms. For the Eye Dryness Score, changes from baseline were statistically significant compared with those of the control at week 8 [ P < 0.001 (QID) and P = 0.002 (BID)]. Benefits on tCFS and symptoms started at 2 weeks after start of treatment and were maintained over the study duration. The effects were dosing schedule dependent. NOV03 was well tolerated with instillation site reactions below 3% in both treatment regimes. Conclusions: The SEECASE study demonstrated that NOV03 improves signs and symptoms in patients with highly symptomatic evaporative dry eye disease.
Background and Objective Atacicept is an inhibitor of the B lymphocyte stimulator (BLyS) and a proliferation-inducing ligand (APRIL), and is being studied in relation to immunological disease. Currently, limited data on atacicept are available in non-Caucasian subjects. Pharmacokinetic data from earlier studies of atacicept were derived using an enzyme-linked immunosorbent assay (ELISA), which was subsequently found to have inadequacies. Hence, a new bioanalytical ELISA for total atacicept was developed and validated. We conducted this randomized, double-blind, placebo-controlled phase I study to compare the safety, tolerability, pharmacokinetics, and pharmacodynamics of atacicept in healthy Japanese and Caucasian subjects while generating pharmacokinetic data using the new ELISA. Methods Japanese subjects aged ≥ 18 to ≤ 55 years (n = 24) were randomized (1:1:1:1) to a single subcutaneous dose of atacicept 25, 75, or 150 mg or placebo. Caucasian subjects were then enrolled to match the Japanese subjects' gender, body weight (± 20%), and height (± 15%). Results Atacicept was well tolerated and there were no clinically significant differences in treatment-emergent adverse events (TEAEs), vital signs, or laboratory parameters between the Japanese and Caucasian subjects. Most (90%) TEAEs were mild; no severe or serious TEAEs or deaths occurred. Weight-adjusted atacicept exposure was comparable between ethnicities and across doses: the Japanese/Caucasian ratio of the area under the serum concentration-time curve from time zero to the last sampling point (AUC 0-t) was 107.21% (90% CI 93.42-123.02%) and the Japanese/Caucasian ratio of maximum serum concentration (C max) was 95.74% (90% CI 74.26-123.43%; ANCOVA). Median time to reach C max (t max) was 20-60 h across all subjects. Dose-exposure relationships were comparable for the two ethnicities, with dose-normalized AUC 0-t decreasing with increasing dose, indicating nonlinear pharmacokinetics for the doses examined. There were no statistically significant differences between ethnicities in the pharmacokinetics-dose relationship. Some transient dose-related decreases in mean serum immunoglobulin (Ig)A and IgM, but not IgG, were observed after atacicept administration. There were small transient increases in peripheral B cell numbers in the first 4 days after dosing that were larger with atacicept than with placebo, with no apparent dose relationship. No anti-atacicept antibodies were detected. Conclusion The safety, pharmacokinetic, and pharmacodynamic profiles of atacicept in healthy Japanese subjects were comparable to those in healthy Caucasian subjects. EudraCT-ID: 2013-002703-34.
BackgroundAtacicept is a recombinant TACI/IgG1-Fc fusion protein that binds and antagonizes the biological activity of the B lymphocyte stimulating factor (BLyS) and a proliferation inducing ligand (APRIL). BLyS and APRIL appear to play a role in the pathogenesis of systemic lupus erythematosus (SLE).ObjectivesThe aim of the analysis was to develop a semi-mechanistic binding population pharmacokinetic (PK) model of atacicept in healthy volunteers (HV) and SLE patients, to characterize the influence of covariates on the PK of atacicept.Methods37 subjects from a Phase I study in Caucasian and Japanese HV where single doses of 25, 75 or 150 mg were administered and 301 subjects from a Phase II study in SLE where 75 or 150 mg doses of atacicept were administered weekly for 52 weeks (bi-weekly during the first four weeks of treatment) contributed 2261 measurements of atacicept in serum. The population PK analysis was conducted with NONMEM software. A Quasi-Steady-State (QSS) approximation [1] of the target-mediated drug disposition (TMDD) [2] model was used to describe drug concentrations. The analyzed covariates were weight, age, gender, race, creatinine clearance, serum BLyS and APRIL at baseline, dose, and SLE vs HV population. Model based exposure metrics (e.g. area under the concentration curve, AUC) were derived.ResultsA two-compartment QSS TMDD binding model with first-order absorption described atacicept concentrations of the two trials adequately capturing the central tendency and variability in the data. The model provided precise (relative standard errors <20%) estimates of all parameters, including binding (Kss=14.5 ng/mL), target turnover (Rmax=617 ng/mL; Kdeg=0.00431 h-1), and drug-target complex elimination (Kint=0.00066 h-1) parameters. The typical estimate of linear apparent clearances and volumes of distribution of the drug were: CL=0.334 L/h, Vc=32.2 L, Q=0.125 L/h and Vp=37.6 L. Residual variability was moderate, slightly higher in the phase II/III study (CV=25%) than in the phase I study (CV=20%). Drug CL and central volume Vc significantly increased with body weight following allometric relationships (exponents of 0.75 and 1.00 respectively) while absorption rate slightly decreased with age (as Ka ∼ (Age/29)-0.689). No significant differences in PK between HV and SLE patients or ethnicities were detected.ConclusionsThe developed population PK model allowed the description of the complete atacicept concentration time profile in SLE patients, a first step in the identification of relevance to the indication exposure-response relationships for PD/clinical/safety endpoints that can inform on future study design.ReferencesGibiansky L, Gibiansky E, Kakkar T, Ma P. Approximations of the target-mediated drug disposition model and identifiability of model parameters. J Pharmacokinet Pharmacodyn, 2008; 35(5):573-591.Mager DE, Jusko WJ. General pharmacokinetic model for drugs exhibiting target-mediated drug disposition. J. Pharmacokinet Pharmacodyn, 2001; 28:507-532.Disclosure of InterestO. Papasouliotis Emp...
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