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Page 1 of 11 2.0 SYNOPSIS Protocol Number: 1297.8 Document Number: Title of Trial: Pharmacokinetics and safety of in healthy subjects: a randomized, double-blind, single-dose, parallel-arm, active-comparator clinical Phase I study Coordinating Investigator:, MD, New Zealand Trial Sites: Two trial sites in New Zealand and one trial site in Belgium Publication (reference): Data from this trial have not been published Objectives: The primary objective of this trial was to establish three-way pharmacokinetic (PK) similarity of to United States (US)-licensed Humira and European Union (EU)-approved Humira. The secondary objective of this trial was to evaluate the safety and tolerability and other PK parameters of. Methodology: This was a double-blind, randomized, parallel-arm, single-dose, active-comparator trial. This trial consisted of three parallel arms of, or US-licensed Humira or EU-approved Humira.
Page 2 of 11 Protocol Number: 1297.8 Document Number: Number of Subjects (Planned and Analyzed): Planned: Approximately 324 subjects were to be randomized (108 subjects to each treatment group to ensure approximately 100 completed subjects in each treatment group). This was to include an additional 24 subjects to replace early dropouts or subjects with non-evaluable PK data to achieve approximately 300 completed and evaluable subjects. Actual: In total, 327 subjects were randomized (108 subjects to each treatment group). Three subjects did not receive the trial medication; 108 subjects received the trial medication in each treatment group. Overall, 320 subjects completed the trial and 322 subjects were included in the PK analysis set. Diagnosis and Main Criteria for Inclusion: Healthy male subjects aged 18 to 55 years with a body mass index of 18.5 to 29.9 kg/m 2 who provided written informed consent. Test Product, Dose and Mode of Administration, Batch Number: Test product: dose: 40 mg (40 mg/0.8 ml) via single prefilled syringe mode of administration: subcutaneous injection batch number: 306795 Reference Product, Dose and Mode of Administration, Batch Number: Comparator product: US-licensed Humira dose: 40 mg (40 mg/0.8 ml) via single prefilled syringe mode of administration: subcutaneous injection batch number: 241182E
Page 3 of 11 Protocol Number: 1297.8 Document Number: Comparator product: EU-approved Humira dose: 40 mg (40 mg/0.8 ml) via single prefilled syringe mode of administration: subcutaneous injection batch number: 24356XH10 Duration of Treatment: Single administration Criteria for Evaluation: Pharmacokinetics: Primary endpoints: area under the concentration-time curve (AUC) from time zero to infinity (AUC0- ) (predicted), AUC from time zero to the last measurable concentration (AUC0-tz), and maximum observed plasma concentration (Cmax). Secondary endpoints: AUC from time zero to 168 hours postdose (AUC0-168), AUC from time zero to 312 hours postdose (AUC0-312), AUC from time zero to 480 hours postdose (AUC0-480), AUC from time zero to 648 hours postdose (AUC0-648), and AUC from time zero to 1032 hours postdose (AUC0-1032) and area under the concentration-time curve (AUC) from time zero to infinity (AUC0-, obs). Other endpoints: Time from dosing to maximum observed concentration of the analyte in plasma (tmax), apparent terminal phase half-life of the analyte in plasma (t1/2), the apparent terminal rate constant in plasma (λz), apparent volume of distribution after extravascular administration (Vz/F), and apparent clearance of the analyte in the plasma (CL/F).
Page 4 of 11 Protocol Number: 1297.8 Document Number: Safety: The secondary safety endpoint was defined as the number (proportion) of subjects with treatment-related adverse events (AEs) occurring from Day 1 through Day 71. Other safety assessments included physical examination, vital signs (blood pressure, pulse rate, and body temperature), tuberculosis test (interferon-gamma release assay), 12-lead electrocardiogram (ECG), injection site reaction assessment, and laboratory tests. Antibody response and antibody titer were summarized as appropriate (frequency/proportions for anti-drug antibody [ADA] positive samples and descriptive statistics for titer) by scheduled assessments and overall (for ADA positive subjects only). Further, the potential relationship between PK exposure and antibody response, and safety and antibody response was explored where appropriate. Statistical Methods: Descriptive statistics for adalimumab concentrations, PK parameters, and safety (e.g., vital signs, laboratory values, ECG, and AEs) were calculated. The primary assessment of PK similarity of versus US-licensed Humira and EU-approved Humira, and US-licensed Humira versus EU-approved Humira, was assessed employing an analysis of covariance model on the log-transformed primary PK parameters with treatment and trial site as fixed effects, and age and body weight as continuous covariates. The 90% two-sided confidence interval for the ratios of the geometric means for versus US-licensed Humira and EU-approved Humira, and for US-licensed Humira versus EU-approved Humira, were calculated and compared to the boundaries 80.0% to 125.0%. The same type of analysis was performed for all secondary PK parameters. No interim analysis was performed.
Page 5 of 11 Protocol Number: 1297.8 Document Number: Summary - Conclusions All subjects were male and the majority were White (260 subjects [80.2%]). The age of subjects ranged from 18 to 55 years, in accordance with the inclusion criteria, with a mean age (±standard deviation) of 30 (±11) years in the, 31 (±11) years in the US-licensed Humira group, and 30 (±12) years in the EU-approved Humira group. The mean weight of subjects was 79.4 (±10.4) kg in the group, 78.6 (±10.7) kg in the US-licensed Humira group, and 78.0 (±10.3) kg in the EU-approved Humira group. Pharmacokinetic Results: Mean plasma concentration-time profiles for, US-licensed Humira and EU-approved Humira were comparable over the entire profiling interval. The mean plasma concentration-time curves mostly reflect the course and characteristics of the individual profiles. However, in general, irrespective of treatment multiple secondary absorption maxima were seen in individual graphs. Most of the subjects had measurable concentration levels around 4 hours after administration with a median tmax which was similar between treatment arms and reached after about 4.5 to 5.5 days. The mean estimated t1/2 was 309, 328, and 313 hours for, EU-approved Humira and US-licensed Humira, respectively. For the primary parameters AUC0-, AUC0-tz, and Cmax, a three-fold comparison was conducted to test between and Humira (both US-licensed and EU-approved) as well as between US-licensed Humira and EU-approved Humira. Similar testing was performed for the secondary PK parameters: AUC0-168, AUC0-312, AUC0-480, AUC0-648, and AUC0-1032. Based on the predefined hypothesis test, PK similarity was declared for all comparisons ( versus US-licensed Humira and EU-approved Humira, and US-licensed Humira versus EU-approved Humira ) for all primary and secondary PK parameters (see Table S1). Point estimates for the geometric mean ratios were close to 1. Body weight at baseline was a statistically significant predictor of Cmax and AUC (p<0.0001 for all pairwise analyses) in the primary analysis. Subject age was a statistically significant predictor
Page 6 of 11 Protocol Number: 1297.8 Document Number: of Cmax (p<0.026 for all pairwise analyses) but not for AUC (p>0.149 for all pairwise analyses). Table S1 Pharmacokinetic Similarity Results Primary Analysis (PK Analysis Set) Adjusted Comparison PK Parameter Geometric Mean Geom Comparison [a] Treatment Ratio (%) SE 90% CI AUC (0-inf) (µg*h/ml) versus Humira US 108.62 1.061 (98.50, 119.79) 2649 Humira US 2438 versus Humira EU 101.27 1.057 (92.45, 110.94) 2654 Humira EU 2620 Humira US versus Humira EU 94.02 1.055 (86.01, 102.78) Humira US 2478 Humira EU 2635 AUC (0-tz) (µg*h/ml) versus Humira US 107.32 1.053 (98.49, 116.94) 2449 Humira US 2282 versus Humira EU 99.93 1.050 (92.15, 108.37) 2458 Humira EU 2460 Humira US versus Humira EU 93.66 1.047 (86.76, 101.11) Humira US 2308 Humira EU 2464
Page 7 of 11 Protocol Number: 1297.8 Document Number: Table S1 Pharmacokinetic Similarity Results Primary Analysis (PK Analysis Set) (continued) Adjusted Comparison PK Parameter Geometric Mean Geom Comparison [a] Treatment Ratio (%) SE 90% CI C max (ug/ml) versus Humira US 100.85 1.036 (95.15, 106.88) 3.9202 Humira US 3.8872 versus Humira EU 96.39 1.035 (91.06, 102.03) 3.9485 Humira EU 4.0965 Humira US versus Humira EU 95.93 1.034 (90.83, 101.33) Humira US 3.9363 Humira EU 4.1032 SE = standard error. [a] = (Test); Humira US = Adalimumab (Humira) US-licensed (Reference 1); Humira EU = Adalimumab (Humira) EU-approved (Reference 2) The effect of ADA on levels of adalimumab was treatment independent (also see immunogenicity results). The absence of treatment specific ADA influences was supported by the AUC0- which was comparable between treatments.
Page 8 of 11 Protocol Number: 1297.8 Document Number: Immunogenicity Results: Using a highly sensitive ADA detection method, approximately 90% of all subjects were determined to be ADA positive at the end of the trial (Day 71 after single dose injection). The time course of development of ADA responses, the overall percentage of positive subjects, and the titer of ADA responses were comparable between the three products tested. Approximately 60% of all subjects had developed neutralizing antibody responses at the end of the trial (Day 71 after single dose injection), with comparable proportions of subjects in the, US-licensed Humira, and EU-approved Humira groups. As expected, a clear effect of ADA development on PK exposure was identified, with a similar impact being noted for all three treatment groups. In conclusion, the results of this trial indicate a comparable immunogenicity profile of, US-licensed Humira, and EU-approved Humira.
Page 9 of 11 Protocol Number: 1297.8 Document Number: Safety Results: Adverse events by category are summarized in Table S2. Table S2 Overview of Adverse Events (Safety Analysis Set) Humira US Humira EU Total (N = 108) (N = 108) (N = 108) (N = 324) Adverse Event Category n (%) n (%) n (%) n (%) Number of subjects with TEAEs 76 ( 70.4%) 79 ( 73.1%) 77 ( 71.3%) 232 ( 71.6%) Number of subjects with related TEAEs 21 ( 19.4%) 29 ( 26.9%) 28 ( 25.9%) 78 ( 24.1%) Number of subjects with serious TEAEs 3 ( 2.8%) 3 ( 2.8%) 2 ( 1.9%) 8 ( 2.5%) Number of subjects with AESIs 2 ( 1.9%) 2 ( 1.9%) 1 ( 0.9%) 5 ( 1.5%) Number of subjects with TEAEs leading to discontinuation of study drug 0 ( 0.0%) 0 ( 0.0%) 0 ( 0.0%) 0 ( 0.0%) Number of subjects with TEAEs leading death 0 ( 0.0%) 0 ( 0.0%) 0 ( 0.0%) 0 ( 0.0%) Number of subjects with mild TEAEs 68 ( 63.0%) 75 ( 69.4%) 70 ( 64.8%) 213 ( 65.7%) Number of subjects with moderate TEAEs 17 ( 15.7%) 16 ( 14.8%) 17 ( 15.7%) 50 ( 15.4%) Number of subjects with severe TEAEs 4 ( 3.7%) 1 ( 0.9%) 0 ( 0.0%) 5 ( 1.5%) AESI = adverse event of special interest; EU = European Union; TEAE = treatment-emergent adverse events; US = United States Overall, 78 subjects (24.1%) in this trial had at least one investigator reported drug-related treatment-emergent AE (TEAE) reported: 21 subjects (19.4%) in the group, 29 subjects (26.9%) in the US-licensed Humira group, and 28 subjects (25.9%) in the EU-approved Humira group. The proportion of subjects with investigator reported drug-related TEAEs was similar across the treatment groups. The most frequently reported investigator reported drug-related TEAEs were headache, upper respiratory tract infection, and rhinorrhea.
Page 10 of 11 Protocol Number: 1297.8 Document Number: No deaths or AEs leading to premature discontinuation from the trial medication administration were reported. Serious AEs were reported for 3 subjects in the group (1 event of concussion for 1 subject, 1 event of hand fracture and 1 event of ankle fracture for 1 subject due to assault, and 1 event of abdominal pain for 1 subject), for 3 subjects in the US-licensed Humira group (2 events of appendicitis for 2 subjects and 1 event of laceration for 1 subject), and for 2 subjects in the EU-approved Humira group (1 event of nephrolithiasis for 1 subject and 1 event of abdominal pain for 1 subject). The abdominal pain in the group and one of the appendicitis events in the US-licensed Humira group were investigator reported drug-related serious AEs (SAEs). In total, at least one TEAE was reported for 232 of the 324 subjects (71.6%): 76 subjects (70.4%) in the group, 79 subjects (73.1%) in the US-licensed Humira group, and 77 subjects (71.3%) in the EU-approved Humira group. The proportion of subjects with at least one TEAE during treatment was similar across the treatment groups. Most TEAEs were considered to be mild in intensity by the investigator. At least one severe TEAE was reported for 5 subjects (1.5%): 4 subjects (3.7%) in the group (ankle fracture, concussion, joint dislocation [shoulder dislocation following a bicycle fall], and abdominal pain) and 1 subject (0.9%) in the US-licensed Humira group (laceration). Adverse events of special interest were reported for 2 subjects in the group (1 event of injection site hypersensitivity for each of the subjects), for 2 subjects in the US-licensed Humira group (1 event of hypersensitivity for 1 subject and 1 event of urticaria for 1 subject), and for 1 subject in the EU-approved Humira group (1 event of injection site hypersensitivity for 1 subject). All of these events were investigator reported drug-related TEAEs. No notable differences across the treatment groups were observed in injection site reactions.
Page 11 of 11 Protocol Number: 1297.8 Document Number: No positive interferon-gamma release assay test (IGRA-T) results were reported at baseline and the IGRA-T was indeterminate for 11 subjects (3.4%). On Day 71/end of trial, 2 subjects (1.9%) in the US-licensed Humira group and 1 subject (0.9%) in the EU-approved Humira group tested positive. There were no clinically relevant findings with respect to clinical laboratory evaluation, vital signs, ECGs, or injection site reactions. Conclusions: PK similarity has been demonstrated for all comparisons ( versus US-licensed Humira and EU-approved Humira, and US-licensed Humira versus EU-approved Humira ). Point estimates for the geometric mean ratios were close to 1. The results of this trial indicate a comparable immunogenicity profile of, US-licensed Humira, and EU-approved Humira. There is no evidence of a difference in ADA impact on adalimumab levels between, US-licensed Humira and EU-approved Humira treated subjects. The absence of treatment specific ADA influences was supported by the AUC0- which was comparable between all treatment groups. Single subcutaneous doses of 40 mg, US-licensed Humira or EU-approved Humira were generally well tolerated in study participants. There were no notable differences between the three treatment groups in safety and tolerability. Date of the Report: Version 1: 12 June 2015 Revision 1: