Safety and Tolerability of an Antibody Against Yellow Fever Virus (TY014) in Humans
Condition: Treatment of Acute Yellow Fever Virus Infection
MeSH terms: Yellow Fever; Fever
Study type: Interventional
Phase: Phase 1

Summary: 
      Yellow Fever is an acute viral hemorrhagic disease caused by the Yellow Fever Virus (YFV), a
      re-emerging arbovirus transmitted by the same mosquito vector (Aedes aegypti) that transmits
      Dengue virus (DENV) and Zika virus (ZIKV). YFV is endemic in tropical and subtropical areas
      of South America and Africa, causing an estimated 200,000 infections and 30,000 deaths
      annually. It has now become a growing public health problem, rapidly spreading throughout the
      two (2) continents in a cyclical pattern. With climate change, global travel and
      urbanisation, which increase the chance for mosquito-borne diseases to spread rapidly, the
      risk of YFV establishing its foothold in the Asia-Pacific region with periodic epidemic
      bursts remains a real public health concern.

      Although there is currently a safe and effective vaccine available on the market, global
      shortages of supplies have severely hampered any efforts in the prevention and control of YFV
      outbreaks. To date, no YFV therapy (biologic or small molecule) has advanced to clinical
      trials. TY014 will be the first therapeutic in the world, specifically targeting YFV, to
      enter clinical trials. It is anticipated that a monoclonal antibody therapeutic could be
      administered to infected cases to reduce disease severity within the patient and their
      contacts.

      This is a Phase 1, first-in-human TY014, YFV monoclonal antibody (mAb), study to be conducted
      in two (2) arms:

        -  Safety Arm (1A): Healthy adult volunteers

        -  Efficacy Arm (1B): Healthy adult volunteers challenged with YF-17D Vaccine Strain 24
           hours prior to TY014 dosing

      TY014 will be administered once through single IV infusion over 30 minutes. Total duration of
      study participation is estimated at approximately 114 days from the date of screening.

      The main objectives of this study are to: (a) evaluate the safety of TY014 in healthy adult
      volunteers, and (b) evaluate the safety of TY014 in YF-17D Vaccine Strain-challenged healthy
      adult volunteers. Percentage aviremia of YF-17D Vaccine Strain-challenged subjects within 48
      hours after IV infusion of TY014 will also be assessed.
    

Detailed description: 
      Safety Arm (1A):

      Safety Arm is a phase 1A First-in-Human, Time Lagged, Single Ascending Dose Study of TY014 in
      Healthy Adult Volunteers.

      Safety, tolerability and PK of TY014 will be assessed. The dose escalation will include 27
      healthy volunteers in five (5) dose cohorts:

        -  0.5 mg/kg, N = 2 TY014 + 5 Placebos

        -  2 mg/kg, N = 5 TY014

        -  5 mg/kg, N = 5 TY014

        -  10 mg/kg, N = 5 TY014

        -  20 mg/kg, N = 5 TY014 Subjects will be required to be inpatient at the trial site for
           approximately 72 hours.

      Dose escalations will be guided by a safety review of clinical signs, adverse events (AEs),
      and laboratory tests (excluding lipase) of the prior group (up to 48 hours post-dose for
      cohort 1, and up to Day 7 post-dose for cohorts 2 - 5).

      A minimum of 20-hour interval from the first TY014 treatment subject dosing must take place
      before the second TY014 treatment subject can be dosed within each cohort. No such time
      interval will be required for dosing of subsequent TY014 treatment subjects (third subject
      onwards) within the same cohort, as well as Placebo dosing in dose cohort 1 (i.e. all five
      placebos can be dosed at the same time).

      After 72 hours, subjects will be discharged from trial site and to return for scheduled
      follow-up visits.

      Subjects will be followed for up to approximately Day 84 for PK sampling, with serum samples
      taken at specified times.

      Dose escalations for the Safety (1A) Arm will be guided by a safety review of clinical signs,
      adverse events (AEs), and laboratory tests (excluding lipase) of the prior dose cohort (up to
      Day 7).

      Similar safety review (up to Day 7) will also be completed for the equivalent dose in Safety
      Arm (1A) prior to the commencement of the Efficacy Arm (1B) for each specified dose.

      Efficacy Arm (1B):

      Efficacy Arm is a phase 1B Sequential Time Lagged, Parallel-Group, Randomised,
      Placebo-Controlled, Double-Blind, Single Ascending Dose Study of TY014 in YF-17D Vaccine
      Strain-Challenged Healthy Adult Volunteers.

      Safety, tolerability and time to achieve aviremia through negative YFV isolation from blood
      in YF-17D Vaccine Strain-challenged healthy adult volunteers when given an IV infusion of
      TY014 will be assessed.

      Eligible subjects will be randomised into TY014 or Placebo Group in each cohort.

      The dose escalation will include up to 40 healthy volunteers in up to four (4) dose cohorts:

        -  2 mg/kg, N = 5 TY014 + 5 Placebos

        -  5 mg/kg, N = 5 TY014 + 5 Placebos

        -  10 mg/kg, N = 5 TY014 + 5 Placebos

        -  20 mg/kg, N = 5 TY014 + 5 Placebos Efficacy Arm (1B) will be based on an adaptive trial
           design, with ten (10) YF-17D vaccinated subjects from each dose cohort being randomised
           1:1 into either TY014 or Placebo group, five (5) subjects in each group. After TY014 or
           placebo administration, safety and efficacy of TY014 in YF-17D Vaccine Strain-Challenged
           subjects will be assessed.

           i) If current dose of TY014 shows safety but not efficacy*, Efficacy Arm (1B) will
           escalate to the next dose cohort.

      ii) If current dose of TY014 is safe and efficacious*, efficacious dose of TY014 is
      established and the Efficacy Arm (1B) of the trial is completed.

      *Efficacy of TY014 is defined as aviremia by virus isolation being observed in 100% of
      vaccinated subjects within 48 hours post-dosing.

      Subjects will be required to be inpatient at the trial site for approximately 96 hours.

      Subjects will be vaccinated with the YF-17D Vaccine on Day -1. On Day 0, 24 hours after
      vaccination, subjects will then be administered TY014 or Placebo.

      A minimum of 20-hour interval from the first two (2) subjects dosing (1 treatment and 1
      placebo concurrently) must take place before the third subject can be dosed within each
      cohort. No such time interval will be required for dosing of subsequent subjects (fourth
      subject onwards) within the same cohort.

      After 96 hours, subjects will be discharged from trial site and are to return for scheduled
      follow-up visits.

      PD and PK measurements will be conducted at various time points throughout the study.
      Subjects will be followed for up to approximately Day 84 post-dose. Samples for PD (serum and
      urine) and PK (serum) assessments will be taken at specified time points.

      Dose escalations for the Efficacy (1B) Arm will be guided by a safety review of clinical
      signs, adverse events (AEs), laboratory tests (excluding lipase) and presence of viremia (via
      virus isolation) of the prior dose cohort (up to Day 14). Escalation to the next dose cohort
      (e.g. from dose cohort 1 (2 mg/kg) to dose cohort 2 (5 mg/kg), from dose cohort 2 (5 mg/kg)
      to dose cohort 3 (10 mg/kg) and from dose cohort 3 (10 mg/kg) to dose cohort 4 (20 mg/kg))
      will only be conducted if from prior dose cohort (e.g. dose cohort 1 (2 mg/kg), dose cohort 2
      (5 mg/kg) and dose cohort 3 (10 mg/kg) respectively):

        1. safety (up to Day 14 post-dose) has been established through a safety review, and

        2. presence of viremia (up to 48 hours post-dose) via virus isolation in any of the
           TY014-treated subjects.
    

Intervention name(s): TY014; 0.9% Saline
Intervention type(s): Biological; Other
Intervention description(s): TY014 Injection, (100 mg/5 mL/Vial), Yellow Fever Virus (YFV) Monoclonal Antibody (mAb); Placebo
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment