Pharmacokinetics, Safety and Tolerability Study of AVT04 to EU Approved and US Licensed Stelara (Ustekinumab)
Condition: Psoriasis
MeSH terms: Psoriasis
Study type: Interventional
Phase: Phase 1

Summary: 
      Protocol Title:

      A Phase 1, first-in-human, randomized, double-blind, single-dose, parallel-group, 3-arm study
      comparing the pharmacokinetic, safety, tolerability, and immunogenicity profiles of AVT04, EU
      approved Stelara®, and US-licensed Stelara® in healthy adult subjects

      Short Title:

      A first-in-human randomized, double-blind study to compare AVT04 with EU-approved Stelara and
      US-licensed Stelara as a single-dose subcutaneous injection in healthy adult subjects

      Rationale:

      Alvotech (hereafter, the Sponsor) is developing AVT04 globally as a proposed biosimilar to
      the reference product Stelara (ustekinumab) for subcutaneous (SC) use. This is a
      first-in-human (FIH) clinical study with AVT04. The study aims to demonstrate pharmacokinetic
      (PK) similarity of the proposed biosimilar test product AVT04 and the reference products EU
      approved Stelara and US-licensed Stelara, in addition to evaluating the safety and
      tolerability of AVT04, when administered as a single 45 mg/0.5 mL SC dose.
    

Detailed description: 
      Overall Design:

      This study is designed as a FIH, multicenter, randomized, double-blind, 3-arm, parallel-group
      study of AVT04 compared with EU-approved and US-licensed Stelara when administered as a
      single 45 mg/0.5 mL SC injection in healthy adult subjects.

      Subjects will undertake a Screening visit between Day -28 and Day -1 to determine their
      eligibility in the study. Subjects who meet the eligibility criteria will be admitted to the
      study site on the day prior to dosing (Day -1), during which their continued eligibility will
      be assessed up to Day 1 prior to dosing. On Day 1, eligible subjects will be randomized and
      will receive a single dose of one of the following: AVT04, US licensed Stelara, or EU
      approved Stelara.

      A staggered sentinel dosing strategy will be implemented as a safety measure, with equal
      numbers of subjects randomized to each treatment: Sentinel Group 1 (n = 3 subjects [1 per
      group]), Sentinel Group 2 (n = 6 subjects [2 per group]), and Sentinel Group 3 (n = 9
      subjects [3 per group]). Following investigational product (IP) administration, there will be
      at least 72 hours of close observation and safety monitoring by the Principal Investigator
      (PI) for each subject and between sentinel groups (ie, 72 hours should have elapsed following
      IP administration for the last subject in each sentinel group). Provided there are no
      significant safety or tolerability concerns (or events that meet the study stopping criteria)
      in the previous sentinel group following a safety review and discussion between the PI,
      Medical Monitor, and Sponsor, the next sentinel group of subjects will be randomized and
      dosed. Once the IP dose is deemed to be safe and well tolerated in all 3 sentinel groups, the
      remaining subjects (n = 276 subjects [92 subjects per group]) will be randomized and dosed.

      Sentinel subjects will remain confined to the study site from Day -1 to Day 4 (72 hours
      postdose); all remaining subjects will be confined to the study site from Day -1 up to Day 2
      (24 hours postdose). Following dosing, PK, safety, tolerability, and other assessments will
      be performed according to the Schedule of Assessments. Subjects will return to the study site
      on an outpatient basis daily up to Day 12, then once a week from Day 15 to Day 64, followed
      by once every 2 weeks up to Day 78, and finally on Day 92 for the End-of-Study (EOS) visit.

      Number of Subjects:

      Approximately 294 healthy subjects (98 per group) are planned to be enrolled at multiple
      study sites in New Zealand and Australia. Efforts will be made to include at least 10% of
      subjects (30 subjects, approximately 10 per group) who are of Japanese origin or ethnicity
      (defined as a second-generation Japanese person living abroad or born in Japan; and both
      parents and grandparents are of Japanese origin).

      A total of 45 subjects (15 per group) are planned to be included in the exploratory ex-vivo
      biomarker sub study.

      Treatment Groups and Duration:

      Eligible subjects will be randomly assigned in a 1:1:1 ratio to receive a single 45 mg/0.5 mL
      SC dose of ustekinumab as AVT04 (test product) or US licensed Stelara or EU approved Stelara
      (reference products) on Day 1. Randomization will be stratified by ethnicity and body weight
      at Day -1 as follows: Japanese, non Japanese ≤80 kg, and non-Japanese >80 kg.

      The study duration per subject will be approximately 17 weeks. The study will consist of a 4
      week Screening period, a 13-week treatment period and assessment period, and an EOS visit on
      Day 92.

      Study Stopping Criteria:

      If either of the following scenarios occur, study enrollment and dosing will be halted:

        -  If >2 subjects experience a suspected unexpected serious adverse reaction (defined as an
           adverse event [AE] that is serious, unexpected, and considered related to the IP).

        -  If the Sponsor or Investigator considers there to be an unfavorable benefit-risk ratio
           based on emerging safety data.

      If following consultation between the PI, Medical Monitor, and Sponsor, it is considered
      appropriate to restart study drug administration in the remaining subjects, justification
      will be submitted to the Health and Disability Ethics Committee/Human Research Ethics
      Committee for restarting the study.
    

Intervention name(s): Stelara PFS
Intervention type(s): Drug
Intervention description(s): Pre filled syringes filled with AVT04 and Stelara
Other intervention name(s): Ustekinumab
Intervention MeSH terms: Ustekinumab
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: A Phase 1, first-in-human, randomized, double-blind, single-dose, parallel-group, 3-arm study comparing the pharmacokinetic, safety, tolerability, and immunogenicity profiles of AVT04, EU approved Stelara®, and US licensed Stelara® in healthy adult subjects
Masking: Single (Investigator)
Primary purpose: Treatment