Establishing clinical equivalence

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PHASE l PHARMACOKLNETIC STUDY OF IMRALDI™ LOW-VOLUME CITRATE-FREE

STUDY DESlGN1

N=188 healthy male subjects

Baseline to 57 days

Single-blind, two-arm, parallel group, and single-dose study in which subjects were randomised (1:1) to receive, via SC injection, a single dose of the low volume Imraldi™ (adalimumab) formulation (SB5-HC, 40 mg/0.4 mL) or the original formulation (SB5-LC, 40 mg/0.8 mL). Patents were observed for 57 days following the injection (Day 1) during which the PK, safety profile, and immunogenicity were evaluated.

Primary endpoints were the area under the concentration–time curve from time zero to infinity (AUCinf) and maximum serum concentration (Cmax). Secondary PK endpoints included area under the concentration–time curve from time zero to the last quantifiable concentration (AUClast), time to Cmax (Tmax), apparent volume of distribution during the terminal phase (Vz/F), terminal rate constant (kz), terminal half-life (t1/2), apparent total body clearance (CL/F), and percentage of AUCinf due to extrapolation from time of last measurable concentration (Tlast) to infinity (%AUCextrap). The safety endpoints were adverse events (AEs) and serious AEs (SAEs), clinical laboratory values, 12-lead ECG, vital signs, physical examination, and injection site assessment. Immunogenicity endpoints were the incidence of ADAs and neutralizing antibodies (NAbs) to ADL.

Adapted from: Ahn S, et al. 2022

 

Abbreviations: ADA, anti-drug antibodies; ADL, adalimumab; AEs, adverse events; Cmax, maximum observed concentration; EOS, end of study; IP, investigational product; NAbs, neutralising antibodies; PK, pharmacokinetic; SAE, serious adverse events; SC, subcutaneous.


a 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 treatment groups compared were completely contained within the pre-defined equivalence margin of 0.80 to 1.25 using an analysis of variance.

REFERENCES

The new Imraldi™ (adalimumab) formulation demonstrated PK bioequivalence with the original lmraldi™1

The primary PK endpoints were all within the pre-defined equivalence margins1

  • The geometric LSMeans ratios for the comparison of the Imraldi™ (adalimumab) new and original formulation groups for AUCinf and Cmax were 0.920 and 0.984, respectively, and the corresponding 90% CIs were within the pre-defined equivalence margin of 0.80 to 1.25
  • In addition, the mean values of PK parameters (AUClast, Tmax, Vz/F, λz, t1/2, CL/F, and %AUCextrap) were comparable between two treatment formulations
PK
Parrameter 		Imraldi™
(adalimumab)
treatment 		n Geometric
LSMean 		Ratio 90% CI
AUCinf
(h-µg/mL)		 New formulation 93 2616.1 0.920 0.8262;1.0239
Original formulation 93 2616.1
Cmax
(µg/mL)		 New formulation 93 4.1 0.984 0.9126;1.0604
Original formulation 94 4.1
AUClast
(h-µg/mL)		 New formulation 93 2317.5 0.942 0.8604;1.0310
Original formulation 94 2460.6

Adapted from: Ahn S, et al. 2022.

Abbreviations: AUC, area under concentration-time curve; Cmax, maximum observed concentration; LSMeans, geometric least squares means; PK, pharmacokinetic.

The pharmacokinetic profiles between treatment groups were superimposable1

Mean (+/- SD) serum SB5-HC and SB5-LC concentration-time-profiles for PC
analysis set; linear (upper graph) and semi-logarithmic (lower graph) scales.

Adapted from: Ahn S, et al. 2022.

The new and original lmraldi™ (adalimumab) formulations had comparable safety profile and immunogenicity1

  • The proportion of subjects who experienced TEAEs in the Imraldi™ (adalimumab) new and original formulations were 44.7% and 51.1% respectively with all being mild to moderate in severity
  • There were no deaths, serious AEs or discontinuation of the study due to TEAEs during the study
  • The overall incidence of subjects with post-dose ADAs to ADL was comparable between the two formulation groups: 93.6% of subjects in the new formulation group and 94.7% of those receiving the original formulation
  • The overall incidence of subjects with post-dose NAbs to ADL among those with a positive ADA result, was similar between the new (75.0%) and original (67.4%) Imraldi™ (adalimumab) formulations
  • For full safety information, please refer to the Imraldi™ (adalimumab) Summary of Product Characteristics here
Imraldi™
(adalimumab)
New formulation 		Imraldi™
(adalimumab)
Original
formulation 		Total
N=94
n (%)		 N=94
n (%)		 N=188
n (%)
Any TEAE 42 (44.7) 48 (51.1) 90 (47.9)
Related TEAE 17 (18.1) 28 (29.8) 45 (23.9)
Any SAE 0 0 0
Any TEAE leading to disconuation 0 0 0
TEAEs occurring in >5% of subjects in any group
Headache 10 (10.6) 12 (12.8) 22 (11.7)
Injection site reaction 4 (4.3) 10 (10.6) 14 (7.4)
Back pain 1 (1.1) 5 (5.3) 6 (3.2)
Nausea 0 (0.0) 5 (5.3) 5 (2.7)

Adapted from: Ahn S, et al. 2022.

Abbreviations: ADA, anti-drug antibodies; ADL, adalimumab; NAbs, neutralising antibodies; SAE, serious adverse event; TEAE, treatment-emergent adverse event.