A Study to Assess the Relative Bioavailability of Different Formulations of GSK2018682, a Sphingosine-1-phosphate Receptor Subtype 1 Agonist, in Healthy Volunteers. — P1A114919  

Multiple Sclerosis, Relapsing-Remitting Clinical Trial

Official title: An Open-label, Randomised, Crossover Study to Assess the Relative Bioavailability of Different 2mg Formulations of GSK2018682(S1P1 Agonist) in Healthy Volunteers

Status Completed

Clinical Trial 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.

Clinical Trial 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 ;

Related Conditions & MeSH terms

• Multiple Sclerosis
• Multiple Sclerosis, Relapsing-Remitting
• Sclerosis

• NCT number: NCT01466322
• Study type: Interventional
• Source: GlaxoSmithKline
• Status: Completed
• Phase: Phase 1
• Start date: December 22, 2010
• Completion date: February 15, 2011