A randomized, double-blind, placebo-controlled first time into human study to
investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of intranasal dosing with GSK2245035, a TLR7 agonist, in healthy volunteers and allergic rhinitics

The drug to be given, GSK2245035, is a new, investigational compound that may
eventually be used for the treatment of allergic rhinitis (for example with hay
fever) and potentially other allergic disorders, such as asthma. Of GSK2245035
is expected that, when administered in the nose, it alters the immune
environment of the airways in a way that results in long-lasting control of
allergic rhinitis symptoms. The study medication will be administered as a
nasal spray and will cause a local inflammatory reaction in the nose. This new
compound is not registered as a drug. This is the first time that this compound
is being given to humans.

Part 1
Primary:
- to evaluate the safety and nasal tolerability of single escalating i.n.
GSK2245035 doses in HV
Secondary:
- to evaluate the systemic PK of single i.n. GSK2245035 administration in HV
- to evaluate the induction of TLR7-associated PD blood biomarkers following
single i.n. GSK2245035 administration in HV
- to evaluate the induction of TLR7-associated PD biomarkers in nasal lavage
- to evaluate the correlation between i.n. GSK2245035 dose - systemic PK - PD
blood biomarkers * PD nasal biomarkers in HV

Part 2
Primary:
- to evaluate the safety and nasal tolerability of single escalating i.n.
GSK2245035 doses in individuals with AR
- to evaluate the induction of TLR7-associated PD biomarkers i) in nasal
lavage, and ii) in nasal tissues following single i.n. GSK2245035
administration versus placebo in individuals with AR

Secondary:
- to evaluate the systemic PK of single i.n. GSK2245035 administration in
individuals with AR
- to evaluate the induction of TLR7-associated blood PD biomarkers following
single i.n. GSK2245035 administration in individuals with AR
- to evaluate the correlation between i.n. GSK2245035 dose - systemic PK - PD
blood biomarkers - PD nasal biomarkers in individuals with AR

Part 1:
a randomized, double-blind, placebo-controlled, parallel group,
single-ascending dose study in one cohort of five healthy male subjects and
seven cohorts of seven healthy male subjects each receiving a single intranasal
dose of GSK2245035 or placebo (three active and two placebo on Cohort 1 and
five active and two placebo in Cohorts 2-8); each cohort will be staggered over
three days; two subjects (one active and one placebo) will be dosed and
monitored for 24 h on day 1, two subjects (active or placebo) will be dosed and
monitored for 24 h on day 2 and the remaining subjects will be dosed on day 3
(active or placebo)

Part 2:
a randomized, double-blind, parallel group study with three cohorts of seven
allergic rhinitis (AR) patients each receiving a single intranasal dose of
GSK2245035 or placebo (five active and two placebo)

Study Medication
Active substance: GSK2245035
Activity: TLR7 agonist
Indication: allergic rhinitis
Strength: 0.01, 0.1, 1, 10 and 100 *g/mL
Dosage form: nasal spray solution

Treatments
Part 1
Cohort 1: a single intranasal dose of 2 ng GSK2245035 or placebo on Day 1
(split into the two nostrils)
Cohort 2: a single intranasal dose of 20 ng GSK2245035 or placebo on Day 1
(split into the two nostrils)
Cohort 3: a single intranasal dose of 100 ng GSK2245035 or placebo on Day 1
(split into the two nostrils)
Cohort 4: a single intranasal dose of 200 ng GSK2245035 or placebo on Day 1
(split into the two nostrils)
Cohort 5: a single intranasal dose of 400 ng GSK2245035 or placebo on Day 1
(split into the two nostrils)
Cohort 6: a single intranasal dose of 1000 ng GSK2245035 or placebo on Day 1
(split into the two nostrils)
Cohort 7: a single intranasal dose of 2000 ng GSK2245035 or placebo on Day 1
(split into the two nostrils)
Cohort 8: a single intranasal dose of 4000 ng GSK2245035 or placebo on Day 1
(split into the two nostrils)

Part 2
Cohort 9: a single intranasal dose of 20 ng GSK2245035 or placebo on Day 1
(split into the two nostrils)
Cohort 10: a single intranasal dose of 200 ng GSK2245035 or placebo on Day 1
(split into the two nostrils)
Cohort 11: a single intranasal dose of 4000 ng GSK2245035 or placebo on Day 1
(split into the two nostrils)

Not applicable