A Study to Assess the Relative Bioavailability of Different Formulations of GSK2018682, a Sphingosine-1-phosphate Receptor Subtype 1 Agonist, in Healthy Volunteers.
Condition: Multiple Sclerosis, Relapsing-Remitting
MeSH terms: Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Sclerosis
Study type: Interventional
Phase: Phase 1

Summary: 
      GSK2018682 is a potent and selective agonist for the sphingosine-1- phosphate receptor
      subtype 1 (S1P1) with the potential to be an effective treatment for multiple sclerosis (MS).
      The immunomodulatory properties of GSK2018682 are related to functional antagonism of S1P1 on
      lymphocytes, resulting in sequestration of lymphocytes within the lymphoid organs, rendering
      them incapable of migrating to sites of inflammation and leading to lymphopenia. Orally
      administered GSK2018682 is very effective in murine experimental autoimmune encephalomyelitis
      (EAE), an animal model of human MS. This study will assess the relative bioavailability of
      different oral formulations of GSK2018682 in healthy volunteers. A tablet formulation is
      desired for progression into future clinical safety and efficacy studies as the current
      capsule formulation is not suited to large scale manufacture. The information obtained in
      this study will help to establish the optimal dosing form for future studies, and also
      determine the effect of food on the pharmacokinetics of GSK2018682.
    

Detailed description: 
      BACKGROUND:

      Multiple sclerosis (MS) is a debilitating, progressive neurological disease characterized by
      inflammation of the central nervous system (CNS), resulting in demyelination and axonal
      damage (for review see [Compston, 2008]). The clinical course for ~85% of MS patients at
      diagnosis is a relapsing remitting (RRMS) form, characterized by recurrent episodes of
      neurological dysfunction (relapses) interspersed with longer periods of gradual improvement
      (remissions). Typical symptoms during RRMS include limb weakness, sensory disturbance and
      visual impairment. Over time, disability accumulates such that after 10 years approximately
      half of RRMS patients do not suffer further relapses but show gradual progression of
      disability, termed secondary progressive (SP) MS [Confavreuax, 2000]. Excess mortality due to
      MS and quality of life is improving through more rapid and accurate diagnosis combined with
      better complication management and administration of disease modifying therapies [Bronnum,
      2006]. However, more efficacious and better tolerated medicines are needed to relieve the
      considerable social and economic burden associated with MS.

      Sphingosine 1 phosphate (S1P) is an endogenous ligand to a conserved family of five G-protein
      coupled receptors(S1P receptor subtype 1 -5), with effective concentrations (EC50) ranging
      from submicromolar to nanomolar levels [Chun, 2002]. Validation for a therapeutic approach
      targeting S1P receptors in autoimmune disease has been provided by the clinical development
      of FTY720 in MS (fingolimod; Novartis). GSK2018682 is an agonist at recombinant human S1P1
      with some activity at S1P5 receptors but displays no agonist activity towards human S1P2,
      S1P3 or S1P4 up to a concentration of 10 µM. This selectivity is anticipated to minimise
      known cardiovascular effects mediated by S1P2/3 subtypes. Orally administered GSK2018682 is
      very effective in murine experimental autoimmune encephalomyelitis (EAE), an animal model of
      human MS. GSK2018682 has been reasonably tolerated following single oral doses of 0.6mg to
      24mg in an ongoing study (P1A114070) in healthy volunteers

      STUDY RATIONALE:

      Two Phase I studies (P1A114070 & P1A114347) have been conducted in healthy volunteers using
      GSK2018682 in capsule formulation. These capsules were produced from a single batch of
      compound (second drug substance campaign, termed CD2) with a particle size of 15 µm (D90). In
      order to support further clinical development of GSK2018682, a new batch (CD3) of compound
      has been synthesized that has a slightly larger particle size (29 µm, D90). In addition, it
      is intended that longer term studies (Proof of Concept and beyond) will be conducted with a
      tablet form of the drug. There is also a possibility that obtaining a smaller particle size
      through micronisation of the CD3 batch (to produce particles with diameters of approximately
      3.8 µm, D90) may improve bioavailability; so a tablet made from micronized CD3 GSK2018682 is
      also being developed. In order to ensure appropriate dose selection for future studies, there
      is a need to investigate the pharmacokinetic profiles of both new tablet forms of GSK2018682
      (manufactured from CD3 campaign) and compare these to the original (CD2) capsule formulation.
      Therefore, this study will evaluate the relative bioavailability of single doses of each of
      the 3 different formulations (CD2 capsule, CD3 tablet and CD3 micronized tablet) of
      GSK2018682 in a cross over, randomized, 4 period, open label design. The fourth treatment arm
      will be added to examine the effect of food on relative bioavailability of the CD3 tablet
      formulation. The study will also measure the effects of each dose form of GSK2018682 on total
      lymphocyte counts.

      DOSE RATIONALE:

      A 2 mg dose will be used in the study as:

        -  PK can be well quantified at this dose.

        -  Significant (in excess of 100%) changes in PK parameters will be detectable.

        -  PK will be below level of quantification by 7 days after dosing.

        -  S1P1-mediated PD effects on lymphocytes and heart rate have not been detected.

        -  There is at least a 2 fold cover to exposures that do have PD effects on lymphocytes and
           heart rate.

        -  It is very likely to be a dose used in a future Phase II study (given the predicted
           accumulation ratio and exposure at steady state).

      STUDY DESIGN:

      This study will investigate single doses of GSK2018682 in a cohort of 16 healthy male and
      female (of non-childbearing potential) subjects according to a randomized, open-label, 4 way
      crossover design. The effect of food on the pharmacokinetics of the CD3 tablet formulation
      will be explored as it is the most likely to be used in a future Phase II study.

      Treatment regimens will include:

        -  CD2 Capsule

        -  CD3 non-micronised Tablet

        -  CD3 micronised Tablet

        -  CD3 non-micronised Tablet under fed conditions
    

Intervention name(s): GSK2018682 CD2 Capsule; GSK2018682 CD3 non-micronised Tablet; GSK2018682 CD3 micronised Tablet; GSK2018682 CD3 non-micronised Tablet in fed state
Intervention type(s): Drug
Intervention description(s): Four single dosing sessions where each regimen A,B C or D will be administered orally in a randomised, cross-over manner. At each dosing session, pharmacokinetic sampling time-points will be the same.
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Healthy volunteers; GSK2018682; Pharmacokinetics; Relapsing Remitting Multiple Sclerosis; Pharmacodynamics