An Investigation of the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of GSK2245035 in Healthy Volunteers and Allergic Rhinitics.
Condition: Rhinitis, Allergic, Seasonal
MeSH terms: Rhinitis; Rhinitis, Allergic; Rhinitis, Allergic, Seasonal
Study type: Interventional
Phase: Phase 1

Summary: 
      GSK2245035 is a highly selective Toll-like Receptor 7(TLR7) agonist capable of preferentially
      inducing the production of interferon alpha (IFNα) versus tumor necrosis factor alpha (TNFα).
      The aim of this FTIH study is to collect tolerability, pharmacokinetic (PK) and
      pharmacodynamic (PD) information to enable the identification of appropriate safe doses of
      intranasal (i.n) GSK2245035, associated with up-regulation of TLR7-mediated genes in the
      nasal milieu, for use in subsequent clinical drug development studies. There will be two
      parts to the study: Healthy Volunteers will be dosed in escalating single doses in Part 1,
      followed by Allergic Rhinitis (AR) subjects dosed similarly in Part 2.
    

Detailed description: 
      This is a First Time in Human (FTIH) study to investigate the safety, tolerability,
      pharmacokinetics (PK) and pharmacodynamics (PD) of single, escalating doses of intranasal
      (i.n.) GSK2245035 in healthy male volunteers (HVT) and male subjects with allergic rhinitis
      (AR). The safety and tolerability of single i.n. GSK2245035 dosing will be assessed and
      established in HVT before the initiation of evaluation in AR.

      GSK2245035 is a highly selective Toll-like Receptor 7 (TLR7) agonist capable of
      preferentially inducing the production of IFNα rather than TNFα. Activation of TLR7 is known
      to result in upregulation of co-stimulatory signals on antigen-presenting cells and in
      generation of pro-inflammatory mediators that can shift bystander immune responses towards a
      Helper T-cell Type 1/ Regulatory T cell (Th1/Treg) phenotype and therefore reduce the
      magnitude of Helper T-cell Type 2 (Th2) reactivity. In this context, it is proposed that i.n.
      GSK2245035 administration may alter the airways immune environment in a way that results in
      long-lasting control of AR symptoms and potentially disease remission through persistent
      modification of the underlying aberrant Th2 responsiveness to aeroallergens.

      The aim of this study is to collect tolerability, PK and PD information to enable the
      identification of appropriate safe doses of i.n. GSK2245035, associated with up-regulation of
      TLR7-mediated genes in the nasal milieu, for use in subsequent clinical drug development
      studies. The study will be divided in to two parts. Part 1, involving only healthy
      volunteers, will consist of 8 cohorts receiving doses from 2 nanograms (2 ng) to 4000ng or a
      placebo dose. Administration within each cohort will be staggered so that two subjects (one
      receiving drug and one placebo) will be dosed and monitored for 24 hours before any
      subsequent doses.

      Screening for part 2 of the study will begin once data from cohort 4 in part 1 has been found
      to be satisfactory. Part 2 will involve subjects with Allergic Rhinitis and be divided into
      three cohorts receiving doses between 20ng and 4000ng or a placebo dose.
    

Intervention name(s): 2 ng GSK2445053; 20ng GSK2445053; 100ng GSK2445053; 200ng GSK2445053; 400ng GSK2445053; 1000ng GSK2445053; 2000ng GSK2445053; 4000ng GSK2445053; Placebo
Intervention type(s): Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug
Intervention description(s): 2ng GSK2445053 administered intranasally; 20ng GSK2445053 administered intranasally; 100ng GSK2445053 administered intranasally; 200ng GSK2445053 administered intranasally; 400ng GSK2445053 administered intranasally; 1000ng GSK2445053 administered intranasally; 2000ng GSK2445053 administered intranasally; 4000ng GSK2445053 administered intranasally; Placebo administered intranasally
Allocation: Randomized
Intervention model: Single Group Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Allergic Rhinitis; Healthy Volunteers; Single Dose Escalation; TLR7 agonist; First Time in Human Study