Assessing the Interchangeability of AVT02 and Humira® in Participants with Moderate‑to‑Severe Chronic Plaque Psoriasis: Pharmacokinetics, Efficacy, Safety, and Immunogenicity Results from a Multicenter, Double-Blind, Randomized, Parallel-Group Study

2.1 Study Design and Participant Population

This was a multicenter, randomized, double-blind, parallel-group study conducted at 23 study centers across five countries (Georgia, Iceland, Poland, Russia, and Ukraine). Eligible participants had moderate-to-severe chronic plaque psoriasis with involved body surface area ≥ 10% (Palm Method), a Psoriasis Area and Severity Index (PASI) score ≥ 12, a static Physician’s Global Assessment (sPGA) ≥ 3 (moderate to severe) at screening and at baseline (week 1/day 1), and naïve to adalimumab therapy. A negative QuantiFERON test for tuberculosis was required during screening. Exclusion criteria included: participants diagnosed with erythrodermic psoriasis; pustular psoriasis; guttate psoriasis; medication-induced psoriasis; other skin conditions (e.g., eczema); or other systemic autoimmune disorder inflammatory diseases. The study design comprised: a lead-in period during weeks 1–12 (open‑label treatment), a module with switching arm (three switching periods) and a non-switching arm during weeks 12–28 (double‑blind treatment), followed by an optional open-label phase extension during weeks 28–52 (open‑label treatment if completed the lead-in period and switching period) (Fig. 1).

Fig. 1figure 1

Study design. EOW every other week, PASI Psoriasis Area and Severity Index, PK pharmacokinetics, PsP plaque psoriasis, RP reference product, SC subcutaneous, W week

During scheduled clinic visits, participants underwent several evaluations and assessments including vital signs, electrocardiograms, clinical laboratory tests, body surface area, PASI, sPGA, Dermatology Life Quality Index (DLQI), immunogenicity, PK analysis, and assessment of adverse events (AEs). Participants provided written informed consent before participation in this study. The study was conducted in accordance with the Declaration of Helsinki, the International Council for Harmonisation Good Clinical Practice (ICH-GCP) guidelines and the appropriate regulatory requirements in the countries in which the study was conducted.

2.2 Study Treatment

During the lead-in period (open label; treatment given from week 1 to 12), participants initially received 80 mg of reference product [2 × 40 mg subcutaneous (SC) injections] on week 1/day 1. This was followed by a single 40 mg SC injection of reference product every other week (EOW) from week 2 to 12 with doses given at weeks 2, 4, 6, 8, and 10) (Fig. 1). Study treatment was administered by the site investigator at each study visit during the lead-in period. At the end of the lead-in period, participants with a clinical response of ≥ 75% improvement in the Psoriasis Area and Severity Index (PASI75) were permitted to enter the switching module and randomly assigned (1:1) to one of two treatment groups. In group 1 for the first switching period, participants received a single 40 mg SC injection of AVT02 EOW (i.e., doses at weeks 12 and 14); for the second switching period, participants received a single 40 mg SC injection of reference product EOW (i.e., doses at weeks 16 and 18); for the third switching period, participants received a single 40 mg SC injection of AVT02 EOW (i.e., doses at weeks 20, 22, 24, and 26). For treatment group 2, participants received a single 40 mg SC injection of reference product EOW from week 12 to 26 (i.e., doses at weeks 12, 14, 16, 18, 20, 22, 24, and 26). During the switching module (weeks 12–28), study treatment was administered at each study visit by the site investigator (i.e., weeks 12, 16, 20, and 26); the participant/caregiver administered the study treatment at home, with optional administration on site if required on weeks 14, 18, 22, and 24. At week 28, participants with a clinical response (PASI50) were offered the possibility of continuing in the optional extension phase of the study (weeks 28–52). In the extension phase, a single 40 mg SC injection of AVT02 was administered EOW starting from week 28, ending with the final study treatment administration at week 50 (i.e., doses at weeks 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, and 50). Except for doses at weeks 28 and 42, when study treatment was administered at the study visit by the site investigator, the participant/caregiver administered remaining doses at home (i.e., doses at weeks 30, 32, 34, 36, 38, 40, 44, 46, 48, and 50). The end of study visit was at week 52.

Patients were encouraged not to miss study drug doses, and a window of ± 3 days was allowed for the dosing schedule. Patients/caregivers were instructed to inject study drug at approximately the same time and day every other week. Study drug was dispensed in single-use, prefilled syringes. Subjects/caregivers were instructed for handling of the study drug and trained to utilize an eDiary to collect information about the injections and any possible injection site reactions (ISRs). The study staff helped the subject/caregiver register into the eDiary system at the time of the first dosing visit. Study staff and subjects were notified if the subject/caregiver did not enter information into the eDiary system ± 3 days of the expected date/time of a dose. The subject/caregiver received a telephone call from the study site to enquire whether the dose of study drug was given and/or any AEs have occurred. At each visit, study staff reviewed the eDiary entries with the subject/caregiver and provided re-training, as necessary. Study drug compliance per protocol in this study was assessed by the investigator and study staff on the basis of the study drug usage recorded by the subject/caregiver in the eDiary. For participants for whom there were compliance issues, participants/caregivers were re-educated by the investigator or study staff on the importance of administering study drug per protocol.

In this study, AVT02 and reference product were administered per the approved dosing regimen for moderate-to-severe chronic plaque psoriasis (40 mg/mL). Blinding during the switching module (double blind) was achieved by masking devices to conceal the syringes. During the lead-in period, all participants received the reference product. At week 12, if participants met the PASI75 qualification for the switching module, the site contacted the interactive response technology to randomize the participant to the treatment arms. Participants were assigned to the study drug in accordance with the randomization schedule generated using permuted block randomization by an independent statistician. Participant randomization was stratified by body mass index (BMI) (< 30 kg/m2 or ≥ 30 kg/m2), and age (< 65 years or ≥ 65 years).

2.3 Primary Outcomes

The primary objective of this study was to evaluate the PK in participants receiving only reference product compared with the PK in participants undergoing repeated switches between reference product and AVT02 using the endpoints: area under the concentration–time curve over the dosing interval (AUCtau) from week 26 to 28 (AUCtau, W26–28), and maximum concentration (Cmax) over the dosing interval from week 26 to 28 (Cmax, W26–28). Secondary PK endpoints included: time to maximum concentration during the dosing interval from week 26 to 28; trough concentration (Ctrough) over the dosing interval from week 26 to 28; Ctrough after each switch at weeks 12, 16, and 20; ratio of Ctrough after the last administration of the study drug at week 26 versus week 12; Ctrough after the last administration of the study drug at week 26 in participants who were PASI75 responders; and percentage of anti-drug antibody (ADA)-negative participants at week 12.

2.4 Other Evaluations

Secondary objectives compared the immunogenicity, efficacy, and safety profiles of reference product with repeated switching of reference product and AVT02. Immunogenicity was evaluated using a one-assay approach to detect anti-AVT02 and anti-reference product (Humira) antibodies in one assay setup following current recommendations [16]. Serum samples for immunogenicity assessment were collected at weeks 1 (baseline), 12, 16, 20, 26, and 28 during the switching module and at weeks 42 and 52 during the optional extension phase. Efficacy endpoints were percentage improvement in PASI from week 1 to 28 and percentage improvement in PASI from week 12 to 28. During analysis, absolute improvement was also included as this was deemed a more clinically relevant endpoint. Change in DLQI was assessed from week 1 to 28 and week 12 to 28. The number and percentage of participants who achieved sPGA responses of clear (0) or almost clear (1) at weeks 12 and 28 were recorded. Only participants with PASI ≥ 50% were allowed to continue into the optional extension phase. Safety assessments included analysis of incidence, type, and severity of AEs (including adverse drug reactions), injection-site reactions (ISRs), ADAs, physical examination, and laboratory parameters (routine safety parameters, liver function parameters, serology screening test, QuantiFERON-TB Gold test). A complete physical examination consisted of general, head, eyes, ears, nose, throat, respiratory, gastrointestinal, extremity, musculoskeletal, cardiovascular, nervous system, lymph node, and dermatologic evaluations and height, weight, and any other physical conditions of note. A targeted physical examination consisted of vital signs and evaluations of skin and joints and cardiovascular, respiratory, neurologic, and any other systems associated with the participant’s complaints or AEs. Participants recorded any ISRs in the eDiary and on the paper ISR worksheet provided. Participants described the characteristics of the ISR (e.g., pain/tenderness, erythema/redness, induration/swelling, pruritus/itching, hematoma/ecchymosis/bruising) at the site of injection. Any findings were recorded on the ISR worksheet, and if the intensity grading was ≥ 1, were entered into the electronic case report form as an AE. AEs were reported from the lead-in period to the end of the optional extension phase of the study.

2.5 Statistical Analysis

The primary endpoints AUCtau, W26–28 and Cmax, W26–28 were analyzed using an analysis of covariance (ANCOVA) model, with the treatment group as a fixed effect and age and BMI at week 12 as the continuous covariates, to estimate the arithmetic least square (LS) means for each treatment group and the corresponding standard errors (SE). The analysis of the primary endpoints involved calculating the 90% confidence intervals (CIs) for the arithmetic means ratios, which were constructed using the Fieller’s theorem [17]. Arithmetic means were used in preference to geometric means due to the lack of normality for both AUCtau, W26–28 and Cmax, W26–28 on the natural log scale. Normality was satisfied, however, on the untransformed scale. A conclusion of equivalence was made on the basis of the 90% CIs being within the range 80–125% for the per protocol set for both AUCtau, W26–28 and Cmax, W26–28. Additionally, the arithmetic means ratios and associated 90% CIs are presented for the full analysis set (FAS), the per protocol set, and the subgroups defined according to the following: coronavirus disease 2019 (COVID-19) vaccination status, age, gender, BMI at week 12, ADA status, and neutralizing antibody (NAb) status.

In addition, descriptive statistics of AUCtau, W26–28 and Cmax, W26–28, percentage improvement in PASI, and change in DLQI and sPGA were further evaluated by treatment group for selected subgroups of the FAS. Descriptive statistics for Ctrough at weeks 12, 16, and 20 were provided by treatment group on the basis of observed data for the FAS. Moreover, the same model as for the primary analysis (ANCOVA) was provided for the evaluation of Ctrough after each switch on the basis of the observed data for the FAS.

Sample size was determined to ensure a sufficient number of participants were available for the primary endpoint analysis. Assuming that 71.5% of participants initially recruited would be PASI75 responders at week 12 [18] and assuming an 18% non-evaluable rate among the PASI75 responders (due to dropouts and those not providing data at week 26), 550 participants were planned to participate in the study at week 1 (baseline).

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