Rainard Fuhr

Efficacy of apolipoprotein B synthesis inhibition in subjects with mild-to-moderate hyperlipidaemia

AIMS Mipomersen, an apolipoprotein (apo) B synthesis inhibitor, has been shown to produce potent reductions in apoB and LDL-cholesterol levels in animal models as well as healthy human volunteers. A randomized, double-blind, placebo-controlled, dose-escalation study was designed to evaluate the efficacy and safety of mipomersen monotherapy with or without dose loading in subjects with mild-to-moderate hyperlipidaemia. METHODS AND RESULTS Fifty subjects with LDL-cholesterol levels between 119 and 266 mg/dL were enrolled into five cohorts at a 4:1 randomization ratio of active to placebo. Two 13-week dose regimens were evaluated at doses ranging from 50 to 400 mg/week. Mipomersen produced dose-dependent reductions in all apoB containing lipoproteins. In the 200 and 300 mg/week dose cohorts, mean reductions from baseline in LDL cholesterol were -45 ± 10% (P= 0.000) and -61 ± 8% (P= 0.000), corresponding to a -46 ± 11% (P= 0.000) and -61 ± 7% (P= 0.000) decrease in apoB levels. Triglyceride levels were also lowered with median reductions up to 53% (P= 0.021). The most common adverse events were injection site reactions. Seven of 40 subjects (18%) showed consecutive transaminase elevations >3× upper limit of normal. Five of these subjects received 400 mg/week, four of whom had apoB levels below the limit of detection. As a consequence, the 400 mg/week cohort was discontinued. CONCLUSIONS Mipomersen administered as monotherapy in subjects with mild-to-moderate hyperlipidaemia produced potent reductions in all apoB-containing lipoproteins. Higher doses were associated with hepatic transaminase increases.

Efficacy of aclidinium bromide 400 μg twice daily compared with placebo and tiotropium in patients with moderate to severe COPD.

BACKGROUND The efficacy and safety of aclidinium bromide bid, a novel, long-acting, muscarinic antagonist, was assessed in patients with moderate to severe COPD. METHODS In this phase IIa randomized, double-blind, double-dummy, crossover trial, patients with moderate to severe COPD received aclidinium 400 μg bid, tiotropium 8 μg once daily, and placebo for 15 days, with a 9- to 15-day washout between treatment periods. Treatments were administered through the Genuair or HandiHaler dry powder inhalers. The primary end point was mean change from baseline in FEV(1) AUC(0-12/12h) (area under the curve where the numbers represent the time period for which data were collected divided by the number of hours over which the data are averaged [eg, 0-12 h postdose divided by 12 h]) on day 15. Secondary end points were changes from baseline in FEV(1) AUC(12-24/12h), FEV(1) AUC(0-24/24h), morning predose FEV(1), peak FEV(1), and COPD symptom scores. RESULTS Thirty patients with COPD were randomized, and 27 completed the study. Mean change from baseline in FEV(1) AUC(0-12/12h) at day 15 was significantly greater for aclidinium and tiotropium over placebo (P < .0001). Mean changes from baseline in FEV(1) AUC(12-24/12h), FEV(1) AUC(0-24/24h), morning predose FEV(1), and peak FEV(1) at day 15 were significantly greater for aclidinium and tiotropium over placebo (P < .0001 for all except P < .001 for FEV(1) AUC(12-24/12h) tiotropium vs placebo). Improvements were significantly greater with aclidinium vs tiotropium on day 1 for all of the normalized AUC values of FEV(1) as well as on day 15 for FEV(1) AUC(12-24/12h) (P < .05 for all). COPD symptoms were significantly improved from baseline with aclidinium vs placebo (P < .05) but not with tiotropium. CONCLUSIONS In patients with COPD, aclidinium 400 μg bid compared with placebo provided clinically meaningful improvements in 24-h bronchodilation that generally were comparable to tiotropium 18 μg daily but with significant differences in favor of aclidinium observed in the average nighttime period. Larger studies with longer treatment duration are ongoing to confirm the efficacy of aclidinium 400 μg bid on bronchodilation and COPD symptoms. TRIAL REGISTRY ClinicalTrials.gov; No.: NCT00868231; URL: www.clinicaltrials.gov.

Exploring the Relationship Between Expression of Cytochrome P450 Enzymes and Gefitinib Pharmacokinetics

Background and objectivesExposure to gefitinib (IRESSA®, ZD1839), an epidermal growth factor receptor-tyrosine kinase inhibitor, is highly variable between subjects. In an attempt to explain this variability, three pharmacokinetic studies were carried out in healthy volunteers to investigate the relationship between exposure to gefitinib and cytochrome P450 (CYP) 3A phenotype (study 1), CYP3A5 genotype (study 2) and CYP2D6 genotype (study 3).MethodsIn study 1 all 15 healthy volunteers received single oral doses of midazolam (7.5mg), as a CYP3A probe, and gefitinib (500mg), separated by an appropriate washout period. Plasma concentrations of midazolam and gefitinib were measured. In study 2, 73 healthy volunteers with previously defined single-dose gefitinib pharmacokinetic profiles were genotyped for CYP3A5. In study 3 a single oral dose of gefitinib (250mg) was administered to poor and extensive CYP2D6 metabolisers (n= 15 in each group). Plasma concentrations of gefitinib and its major metabolite, M523595, were measured. Plasma concentrations of gefitinib, M523595 and midazolam were measured using high-performance liquid chromatography with tandem mass spectrometric detection, and appropriate pharmacokinetic parameters were determined by non-compartmental methods. Genetic analysis of CYP3A5 (study 2) and CYP2D6 (study 3) alleles was carried out using standard methodology.ResultsIn study 1 there was some indication of a correlation between the area under the plasma concentration-time curve from time zero to infinity (AUC∞) values of midazolam and gefitinib, although this did not reach statistical significance (p = 0.062, regression analysis). In study 2 eight of 73 volunteers (11%) were identified as CYP3A5 expressers. No apparent relationship was observed between the occurrence of the CYP3A5 expresser genotype and gefitinib plasma clearance or terminal elimination halflife. In study 3 M523595 was not detected in any plasma samples collected from poor CYP2D6 metabolisers. Gefitinib geometric mean AUC∞ and peak plasma drug concentration were higher in poor CYP2D6 metabolisers compared with extensive metabolisers (AUC∞ 3060 vs 1430 ng · h/mL, p < 0.05, ANOVA), although the range of values was wide with considerable overlap between the groups. Gefitinib was well tolerated in both groups.ConclusionsIndividual differences in CYP3A expression do not explain all the interindividual variability in gefitinib exposure. There is no apparent relationship between CYP3A5 genotype and gefitinib clearance. The lack of measurable levels of M523595 in poor CYP2D6 metabolisers confirms that production of this metabolite is mediated by CYP2D6. Although higher exposure to gefitinib occurs in individuals who are poor CYP2D6 metabolisers, genotyping prior to initiation of therapy and dosage adjustment are not warranted.

A randomized phase l pharmacokinetic study comparing SB4 and etanercept reference product (Enbrel®) in healthy subjects

Aims SB4 has been developed as a biosimilar of etanercept. The primary objective of the present study was to demonstrate the pharmacokinetic (PK) equivalence between SB4 and European Union ‐sourced etanercept (EU‐ETN), SB4 and United States‐sourced etanercept (US‐ETN), and EU‐ETN and US‐ETN. The safety and immunogenicity were also compared between the treatments. Methods This was a single‐blind, three‐part, crossover study in 138 healthy male subjects. In each part, 46 subjects were randomized at a 1:1 ratio to receive a single 50 mg subcutaneous dose of the treatments (part A: SB4 or EU‐ETN; part B: SB4 or US‐ETN; and part C: EU‐ETN or US‐ETN) in period 1, followed by the crossover treatment in period 2 according to their assigned sequences. PK equivalence between the treatments was determined using the standard equivalence margin of 80–125%. Results The geometric least squares means ratios of AUCinf, AUClast and Cmax were 99.04%, 98.62% and 103.71% (part A: SB4 vs. EU‐ETN); 101.09%, 100.96% and 104.36% (part B: SB4 vs. US‐ETN); and 100.51%, 101.27% and 103.29% (part C: EU‐ETN vs. US‐ETN), respectively, and the corresponding 90% confidence intervals were completely contained within the limits of 80–125 %. The incidence of treatment‐emergent adverse events was comparable, and the incidence of the antidrug antibodies was lower in SB4 compared with the reference products. Conclusions The present study demonstrated PK equivalence between SB4 and EU‐ETN, SB4 and US‐ETN, and EU‐ETN and US‐ETN in healthy male subjects. SB4 was well tolerated, with a lower immunogenicity profile and similar safety profile compared with those of the reference products.

Omalizumab Protects against Allergen- Induced Bronchoconstriction in Allergic (Immunoglobulin E-Mediated) Asthma

Background: Omalizumab has been shown to suppress responses to inhaled allergens in allergic asthma patients with pretreatment immunoglobulin E (IgE) ≤700 IU/ml. To extend current dosing tables, we evaluated the potential of high omalizumab doses to block allergen-induced bronchoconstriction in patients with higher IgE levels. Methods: Asthmatic adults (18–65 years; body weight 40–150 kg) were divided into groups according to screening IgE (group 1: 30–300 IU/ml; group 2: 700–2,000 IU/ml) and randomized 2:1 to omalizumab/placebo every 2 or 4 weeks for 12–14 weeks. Allergen bronchoprovocation (ABP) testing was performed before treatment and at weeks 8 and 16. The primary efficacy endpoint, the early-phase allergic response (EAR), was defined as the maximum percentage drop in forced expiratory volume in 1 s during the first 30 min after ABP. Serum free IgE was determined as a pharmacodynamic endpoint, and the exhaled fractional concentration of nitric oxide (FENO) was an exploratory endpoint. Results: Fifty patients were included in the study. Omalizumab improved EAR; at week 8, EAR was 23.1% for placebo, 9.3% in group 1 (p = 0.018 versus placebo) and 5.6% in group 2 (p < 0.001). At week 16, EAR was 20%, 11.8% (p = 0.087) and 5.1% (p < 0.001), respectively. Free IgE decreased in groups 1 and 2 and remained <50 ng/ml in all patients during weeks 6–16. Omalizumab completely suppressed FENO increases after ABP in both groups. Conclusions: Omalizumab blocked early asthmatic responses over a broad range of IgE/body weight combinations. Extending the dosing tables enables omalizumab to benefit a wider range of patients.

A Randomized Phase I Pharmacokinetic Study Comparing Biosimilar Candidate SB3 and Trastuzumab in Healthy Male Subjects

PURPOSE This first-in-human study with SB3 was designed to evaluate the pharmacokinetic (PK) equivalence between SB3 and trastuzumab sourced in the European Union (EU trastuzumab), between SB3 and trastuzumab sourced in the United States (US trastuzumab), and between EU and US trastuzumab (NCT02075073). METHODS In this randomized, double-blind, parallel group, single-dose comparative PK study, 109 healthy male subjects were randomized to receive a single 6-mg/kg IV dose of SB3, EU -trastuzumab, or US trastuzumab. The PK parameters were calculated using noncompartmental methods. The PK equivalence in terms of AUC0--∞), AUC0-last, and Cmax for the pairwise comparisons (SB3 vs EU trastuzumab, SB3 vs US trastuzumab, and EU trastuzumab vs US trastuzumab) were determined using the predefined equivalence margin of 0.8 to 1.25. FINDINGS Baseline demographic characteristics for the randomized subjects were similar across the 3 groups. The 90% CIs for the geometric least square means of the AUC0-∞, AUC0-last, and Cmax were completely contained within the margin of 0.8 to 1.25. The proportions of subjects who experienced adverse events related to the study drug were 36.1%, 44.4%, and 61.1% in the SB3, EU trastuzumab, and US trastuzumab groups, respectively. The most frequently reported adverse events related to the study drug was infusion-related reactions. No subjects had positive results for antidrug antibodies after a single dose of SB3, EU trastuzumab, or US trastuzumab. IMPLICATIONS This study revealed PK equivalence between SB3 and EU trastuzumab, between SB3 and US trastuzumab, and between EU trastuzumab and US trastuzumab. SB3 is well tolerated without tolerability concerns after single-dose administration in healthy male subjects.

SAT0176 A Phase I Pharmacokinetic Study Comparing SB4, An Etanercept Biosimilar, and Etanercept Reference Product (Enbrel®) in Healthy Male Subjects

Background SB4, a biosimilar to etanercept reference product (ETN), has an identical amino acid sequence, similar physicochemical and in vitro functional properties to its reference drug. Objectives The primary objective of this study was to demonstrate pharmacokinetic (PK) equivalence between SB4 and EU sourced ETN (EU-ETN), between SB4 and US sourced ETN (US-ETN), and between EU-ETN and US-ETN. Safety, tolerability, and immunogenicity were investigated as secondary objectives. Methods This study was a randomised, single-blind, three-part (Part A, Part B and Part C), 2-treatment, 2-period cross-over study in 138 healthy male subjects. In each part, 46 subjects were randomised in a 1:1 manner to receive a single 50 mg subcutaneous dose of SB4 or the reference drug (Part A: SB4 or EU-ETN, Part B: SB4 or US-ETN, Part C: EU-ETN or US-ETN) in Period 1 followed by the cross-over treatment in Period 2 according to their assigned treatment sequence. Study treatments were separated by a 28 day washout period. PK assessment was performed 21 days after the treatment in each period. Immunogenicity was assessed at pre-dose and 28 days after the first treatment in Period 1. The primary PK parameters were area under the concentration-time curve from time zero to infinity (AUCinf) and maximum concentration (Cmax). Equivalence for the primary PK parameters was to be concluded if the 90% confidence interval (CI) of the ratio of geometric least squares means (LSMeans) of the groups compared were completely contained within the pre-defined equivalence margin of 0.8 to 1.25 using an analysis of variance (ANOVA). Results The geometric LSMeans ratio of AUCinf and Cmax were 0.990 and 1.037 (Part A), 1.011 and 1.044 (Part B), and 1.005 and 1.033 (Part C), respectively. All 90% CIs for the primary PK parameter comparisons in Part A, B, and C were completely contained within the pre-defined equivalence margin (Table). The proportion of subjects who experienced treatment-emergent adverse events (TEAEs) was comparable between SB4 and EU-ETN (39.1% vs. 34.8%), SB4 and US-ETN (50.0% vs. 43.5%), and between EU-ETN and US-ETN (37.0% vs. 30.4%) in each part. The most frequent TEAEs reported were nasopharyngitis, headache, and injection site reaction. The majority of TEAEs reported was mild or moderate in severity and transient. There were no serious adverse events (SAEs) or deaths reported during the study. Table 1. Comparison of primary PK parameters between the treatments PK parameters Ratio 90% CI Part A: SB4 vs EU-ETN AUCinf (μg·h/mL) 0.990 0.947; 1.036 Cmax (μg/mL) 1.037 0.985; 1.092 Part B: SB4 vs US-ETN AUCinf (μg·h/mL) 1.011 0.958; 1.067 Cmax (μg/mL) 1.044 0.977; 1.114 Part C: EU-ETN vs US-ETN AUCinf (μg·h/mL) 1.005 0.915; 1.104 Cmax (μg/mL) 1.033 0.947; 1.127 Conclusions This study demonstrated PK equivalence of SB4 to EU-ETN, of SB4 to US-ETN, and of EU-ETN to US-ETN in healthy male subjects. All three etanercept products were generally well tolerated with similar safety profiles. Disclosure of Interest Y. J. Lee Employee of: Samsung Bioepis, D. Shin Employee of: Samsung Bioepis, Y. Kim Employee of: Samsung Bioepis, J. W. Kang Employee of: Samsung Bioepis, R. Fuhr Grant/research support from: Samsung Bioepis, A. Gauliard Grant/research support from: Samsung Bioepis

A randomized phase I comparative pharmacokinetic study comparing SB5 with reference adalimumab in healthy volunteers

SB5 is a biosimilar to the reference adalimumab (ADL) currently in development. The primary study objective was to demonstrate pharmacokinetic (PK) equivalence of SB5 to European Union‐sourced adalimumab (EU‐ADL), and United States‐sourced adalimumab (US‐ADL) in healthy subjects. Safety, tolerability and immunogenicity were also assessed as secondary objectives.

FRI0110 A Phase I Pharmacokinetic Study Comparing SB5, An Adalimumab Biosimilar, And Adalimumab Reference Product (Humira®) in Healthy Subjects

Background SB5, a biosimilar to adalimumab reference product (ADL), has an identical amino acid sequence, similar physicochemical and in vitro functional properties to its reference drug. Objectives The primary objective of this study was to demonstrate pharmacokinetic (PK) equivalence between SB5 and EU sourced ADL (EU-ADL), SB5 and US sourced ADL (US-ADL), and between EU-ADL and US-ADL. Safety, tolerability, and immunogenicity were investigated as secondary objectives. Methods This study was a randomised, single-blind, 3-arm, parallel group study in 189 healthy subjects. In each arm, all subjects received a single 40 mg dose of SB5, EU-ADL, or US-ADL by subcutaneous injection on Day 1 and then were observed for 71 days during which the PK, safety, tolerability, and immunogenicity measurements were made. The serum concentration of adalimumab was measured using an enzyme-linked immunosorbent assay (ELISA). The primary PK parameters were area under the concentration-time curve from time zero to infinity (AUCinf), area under the concentration-time curve from time zero to the last quantifiable concentration (AUClast), and maximum concentration (Cmax). Equivalence for the primary PK parameters was to be concluded if the 90% confidence intervals (CIs) for the ratio of geometric least squares means (LSMeans) of the groups compared were completely contained within the pre-defined equivalence margin of 0.8 to 1.25 using an analysis of variance (ANOVA). Results All of the 90% CIs for the geometric LSMeans ratios of primary PK parameters for SB5 and EU-ADL comparison, SB5 and US-ADL comparison, and EU-ADL and US-ADL comparison were within the pre-defined equivalence margin of 0.8 to 1.25 (Table). The proportion of subjects who experienced treatment-emergent adverse events (TEAEs) was comparable between the SB5, EU-ADL, and US-ADL groups. The most frequent TEAEs were nasopharyngitis and headache. The majority of TEAEs were mild to moderate in severity. Two serious adverse events (SAEs) were reported. Both SAEs were assessed not to be related to the study drugs. There were no statistically significant differences in the incidence of post-dose anti-drug antibodies between the three groups. Table 1. Comparison of primary PK parameters between the treatments Comparison PK parameters Ratio 90% CI SB5 vs EU-ADL AUCinf (μg·h/mL) 0.990 0.885; 1.108 AUClast (μg·h/mL) 1.027 0.915; 1.153 Cmax (μg/mL) 0.957 0.870; 1.054 SB5 vs US-ADL AUCinf (μg·h/mL) 1.001 0.890; 1.126 AUClast (μg·h/mL) 1.025 0.911; 1.153 Cmax (μg/mL) 0.972 0.881; 1.073 EU-ADL vs US-ADL AUCinf (μg·h/mL) 1.011 0.904; 1.131 AUClast (μg·h/mL) 0.998 0.887; 1.122 Cmax (μg/mL) 1.016 0.920; 1.121 Conclusions This study demonstrated PK equivalence between SB5 and EU-ADL, SB5 and US-ADL, and between EU-ADL and US-ADL in healthy subjects. All three adalimumab products were generally well tolerated with similar safety profiles. Disclosure of Interest D. Shin Employee of: Samsung Bioepis, Y. Kim Employee of: Samsung Bioepis, H. S. Kim Employee of: Samsung Bioepis, R. Fuhr Grant/research support from: Samsung Bioepis, T. Körnicke Grant/research support from: Samsung Bioepis

SAT0144 A Phase I Pharmacokinetic Study Comparing SB2, An Infliximab Biosimilar, And Infliximab Reference Product (Remicade®) in Healthy Subjects

Background SB2, a biosimilar to infliximab reference product (INF), has an identical amino acid sequence and similar physicochemical and in vitro functional properties to its reference drug. Objectives The primary objective of this study was to demonstrate pharmacokinetic (PK) equivalence between SB2 and EU sourced INF (EU-INF), SB2 and US sourced INF (US-INF), and between EU-INF and US-INF. Safety, tolerability, and immunogenicity were investigated as secondary objectives. Methods This study was a randomised, single-blind, 3-arm, parallel group study in 159 healthy subjects. In each arm, all subjects received a single 5 mg/kg dose of SB2, EU-INF, or US-INF by intravenous infusion on Day 1 and then were observed for 71 days during which the PK, safety, tolerability, and immunogenicity measurements were made. The serum concentration of infliximab was measured using an enzyme-linked immunosorbent assay (ELISA). The primary PK parameters were area under the concentration-time curve from time zero to infinity (AUCinf), area under the concentration-time curve from time zero to the last quantifiable concentration (AUClast), and maximum concentration (Cmax). Equivalence for the primary PK parameters was to be concluded if the 90% confidence intervals (CIs) for the ratio of geometric least squares means (LSMeans) of the groups compared were completely contained within the pre-defined equivalence margin of 0.8 to 1.25 using an analysis of variance (ANOVA). Results All of the 90% CIs for the geometric LSMeans ratios of primary PK parameters for SB2 and EU-INF comparison, SB2 and US-INF comparison, and EU-INF and US-INF comparison were within the pre-defined equivalence margin of 0.8 to 1.25 (Table). The proportion of subjects who experienced treatment-emergent adverse events (TEAEs) was comparable between the SB2, EU-INF, and US-INF groups. The most frequent TEAEs were nasopharyngitis and headache. The majority of TEAEs were mild to moderate in severity. Three serious adverse events (SAEs) were reported in two subjects from SB2 group where one SAE was assessed to be related to the study drug: one subject had a Borrelia infection which resolved without sequelae. There were no statistically significant differences in the incidence of post-dose anti-drug antibodies between the three groups. Table 1. Comparison of primary PK parameters between the treatments Comparison PK parameters Ratio 90% CI SB2 vs EU-INF AUCinf (μg·h/mL) 0.986 0.897; 1.083 AUClast (μg·h/mL) 0.994 0.915; 1.079 Cmax (μg/mL) 1.007 0.964; 1.052 SB2 vs US-INF AUCinf (μg·h/mL) 0.979 0.894; 1.072 AUClast (μg·h/mL) 0.981 0.904; 1.064 Cmax (μg/mL) 0.985 0.942; 1.030 EU-INF vs US-INF AUCinf (μg·h/mL) 0.993 0.908; 1.086 AUClast (μg·h/mL) 0.987 0.913; 1.067 Cmax (μg/mL) 0.978 0.935; 1.024 Conclusions This study demonstrated PK equivalence between SB2 and EU-INF, SB2 and US-INF, and between EU-INF and US-INF in healthy subjects. All three infliximab products were generally well tolerated with similar safety profiles. Disclosure of Interest D. Shin Employee of: Samsung Bioepis, Y. Kim Employee of: Samsung Bioepis, Y. S. Kim Employee of: Samsung Bioepis, R. Fuhr Grant/research support from: Samsung Bioepis, T. Körnicke Grant/research support from: Samsung Bioepis