A randomized, double-blind, three-arm, parallel group, single-dose phase I study to evaluate the pharmacokinetic similarity between SB12 (a proposed eculizumab biosimilar) and eculizumab (Soliris) in healthy subjects.

OBJECTIVES: To compare the pharmacokinetics (PK), pharmacodynamics (PD), safety, and immunogenicity between SB12 (a proposed eculizumab biosimilar) and the reference product (RP) eculizumab (i.e., European Union (EU)-sourced Soliris and United States (US)-sourced Soliris). MATERIALS AND METHODS: In this phase I study, healthy adult subjects were randomized to receive a 300-mg dose of SB12 or RP eculizumab via intravenous infusion. The PK endpoints were area under the serum concentration-time curve from time zero to infinity and to the last quantifiable concentration, and maximum serum concentration. Bioequivalence for the PK endpoints was determined if the 90% confidence intervals (CIs) for the ratio of geometric least squared means (Lsmeans) were within the pre-defined bioequivalence margins of 80.00 - 125.00%. PD, safety, and immunogenicity were also investigated. RESULTS: The 90% CIs of the geometric Lsmeans ratios of the PK endpoints were fully contained within the pre-defined bioequivalence margin. PD profiles and incidence of treatment-emergent adverse events across treatment groups were comparable. Incidence of anti-drug antibodies was also comparable between all groups, and a positive result for neutralizing antibodies was not detected. CONCLUSION: This study demonstrated PK bioequivalence and similar PD, safety, and immunogenicity profiles of SB12 to both reference eculizumab products.

SB5 shows cross-immunogenicity to adalimumab but not infliximab: results in patients with inflammatory bowel disease or rheumatoid arthritis.

BACKGROUND: The primary objective of this study was to analyze the cross-reactivity of antidrug antibodies to reference adalimumab (ADL) and SB5 (adalimumab biosimilar) in patients with inflammatory bowel disease (IBD) or rheumatoid arthritis (RA). METHODS: Sera from patients with IBD and RA with or without antibodies to adalimumab (ATA+ or ATA-, respectively) were tested for cross-reactivity with SB5 and ADL. Functional inhibition of tumor necrosis factor-α binding was measured. Sera from patients with antibodies to reference infliximab (ATI+) were examined for cross-reactivity to SB5. Sera were tested by enzyme-linked immunosorbent assay. RESULTS: All 30 anti-ADL ATA+ sera from patients with IBD and all 4 anti-SB5 ATA+ sera from patients with RA were cross-reactive with ADL and SB5 (range of mean concentrations: IBD, 20.99-21.31 µg/ml; RA, 16.46-17.48 µg/ml). In general, there was no significant difference between mean ATA titers. A strong correlation was detected in all ATA+ samples (rho = 0.997 to >0.999; p < 0.001 each). However, ATA- sera were not reactive to either ADL or SB5. anti-ADL ATA+ sera similarly neutralized functional activity of ADL and SB5; no functional inhibition was observed with ATA- sera. ATI+ sera did not cross-react with SB5. CONCLUSIONS: ADL and SB5 show cross-immunogenicity in sera from patients with IBD or RA, supporting shared immune-dominant epitopes. ATI+ sera did not cross-react with SB5, suggesting different immunogenic epitopes between infliximab and SB5.

Comparative pharmacokinetics of an adalimumab biosimilar SB5 administered via autoinjector or prefilled syringe in healthy subjects.

PURPOSE: The objective of this study was to demonstrate comparable pharmacokinetic (PK), safety, and tolerability parameters of the adalimumab biosimilar SB5 administered via autoinjector (AI) pen or prefilled syringe (PFS). PATIENTS AND METHODS: In this phase 1, randomized, open-label, single-dose, parallel-group study, healthy subjects aged 18-55 years were randomized 1:1 to a single dose of 40 mg SB5 delivered subcutaneously via AI or PFS. PK parameters, safety, and tolerability were assessed for 57 days post-dose. The primary endpoint was area under the curve (AUC) of the concentration-time curve from zero to infinity (AUCinf) and from zero to last quantifiable concentration (AUClast) and maximum serum concentration (Cmax). Equivalence was determined using predefined margins of 0.80-1.25 for the 90% CI for the ratio of SB5 AI to SB5 PFS. RESULTS: Ninety-five subjects were randomized to each group. Mean serum concentration-time profiles were superimposable between groups. Mean values for AUCinf, AUClast, and Cmax were similar between the SB5 AI and SB5 PFS groups. For the primary endpoints, the 90% CIs for the ratio of geometric least squares means for SB5 AI to SB5 PFS ranged between 0.9503 and 1.2240, which were all within the equivalence margin of 0.80-1.25. Incidence of treatment-emergent adverse events and injection site reactions was similar between groups. CONCLUSION: In healthy subjects receiving a single dose of SB5 via AI or PFS, PK parameters and corresponding 90% CIs were within the predefined margins, showing bioequivalence between the two delivery methods. Safety and tolerability assessments were also similar between groups. CLINICALTRIALSGOV IDENTIFIER: NCT02326233. EUDRACT NUMBER: 2014-005178-12.

ZBTB2 increases PDK4 expression by transcriptional repression of RelA/p65.

The NF-κB is found in almost all animal cell types and is involved in a myriad of cellular responses. Aberrant expression of NF-κB has been linked to cancer, inflammatory diseases and improper development. Little is known about transcriptional regulation of the NF-κB family member gene RelA/p65. Sp1 plays a key role in the expression of the RelA/p65 gene. ZBTB2 represses transcription of the gene by inhibiting Sp1 binding to a Sp1-binding GC-box in the RelA/p65 proximal promoter (bp, -31 to -21). Moreover, recent studies revealed that RelA/p65 directly binds to the peroxisome proliferator-activated receptor-γ coactivator1α (PGC1α) to decrease transcriptional activation of the PGC1α target gene PDK4, whose gene product inhibits pyruvate dehydrogenase (PDH), a key regulator of TCA cycle flux. Accordingly, we observed that RelA/p65 repression by ZBTB2 indirectly results in increased PDK4 expression, which inhibits PDH. Consequently, in cells with ectopic ZBTB2, the concentrations of pyruvate and lactate were higher than those in normal cells, indicating changes in glucose metabolism flux favoring glycolysis over the TCA cycle. Knockdown of ZBTB2 in mouse xenografts decreased tumor growth. ZBTB2 may increase cell proliferation by reprogramming glucose metabolic pathways to favor glycolysis by upregulating PDK4 expression via repression of RelA/p65 expression.

Lipin1 regulates PPARγ transcriptional activity.

PPARγ (peroxisome-proliferator-activated receptor γ) is a master transcription factor involved in adipogenesis through regulating adipocyte-specific gene expression. Recently, lipin1 was found to act as a key factor for adipocyte maturation and maintenance by modulating the C/EBPα (CCAAT/enhancer-binding protein α) and PPARγ network; however, the precise mechanism by which lipin1 affects the transcriptional activity of PPARγ is largely unknown. The results of the present study show that lipin1 activates PPARγ by releasing co-repressors, NCoR1 (nuclear receptor co-repressor 1) and SMRT (silencing mediator of retinoid and thyroid hormone receptor), from PPARγ in the absence of the ligand rosiglitazone. We also identified a novel lipin1 TAD (transcriptional activation domain), between residues 217 and 399, which is critical for the activation of PPARγ, but not PPARα. Furthermore, this TAD is unique to lipin1 since this region does not show any homology with the other lipin isoforms, lipin2 and lipin3. The activity of the lipin1 TAD is enhanced by p300 and SRC-1 (steroid receptor co-activator 1), but not by PCAF (p300/CBP-associated factor) and PGC-1α (PPAR co-activator 1α). The physical interaction between lipin1 and PPARγ occurs at the lipin1 C-terminal region from residues 825 to 926, and the VXXLL motif at residue 885 is critical for binding with and the activation of PPARγ. The action of lipin1 as a co-activator of PPARγ enhanced adipocyte differentiation; the TAD and VXXLL motif played critical roles, but the catalytic activity of lipin1 was not directly involved. Collectively, these data suggest that lipin1 functions as a key regulator of PPARγ activity through its ability to release co-repressors and recruit co-activators via a mechanism other than PPARα activation.