Effect of GSK962040 on Oesophageal Function
Condition: Gastrointestinal Motility
Study type: Interventional
Phase: Phase 1

Summary: 
      GSK962040 is a selective non-peptide motilin receptor agonist which is in development for the
      treatment of conditions associated with slow rates of gastric emptying. Single ascending
      doses (1 to 150 mg), and 14-days repeated doses (10 to 125 mg daily) have been investigated
      in two randomized, placebo-controlled trials. Results show that these doses were well
      tolerated with few mild to moderate adverse events (AE), and no clinically significant
      abnormal vital sign measurements, ECG changes or abnormal clinical laboratory findings.
      GSK962040 exhibited predictable PK with and without food. The mean within subject time for
      half a [13C]-containing meal to empty from the stomach (GE t½) decreased by 22-43% from
      placebo with GSK962040 50-150 mg single doses, and shortening of gastric emptying was
      confirmed at doses of 50 mg and above in the repeat dose study.

      Several studies have shown that motilin agonists increase lower oesophageal sphincter (LOS)
      pressure and have various dose dependent effects on oesophageal peristaltic amplitudes and
      propulsive contractions in both healthy volunteers and patients with gastro-oesophageal
      reflux disease (GORD). The purpose of the present study is to examine the effect of GSK962040
      on oesophageal function, using techniques such as high resolution oesophageal manometry, and
      pH/gastric transit using a wireless motility capsule.
    

Detailed description: 
      Motilin is a peptide found in specific endocrine cells in the epithelia of the upper small
      intestine . It is released during fasting to act at its own receptor (motilin receptor,
      previously known as GPR38) resulting in the initiation of Phase III of the migrating motor
      complex (MMC). MMCs begin in the upper regions of the gut and are usually characterized by
      three distinct phases (I, a period of near-quiescence; II, short- or non-propulsive
      contractions at irregular frequency; III, a final burst of high amplitude propulsive
      contractions), terminating within the distal regions of the small intestine. Phase III
      activity may help clear the stomach and intestine from any undigested material, prevent
      bacterial overgrowth in the upper gut and perhaps help develop the sensation of hunger. The
      association of motilin release with Phase III of the MMC, together with an ability of motilin
      to mimic the strong propulsive contractions which comprise Phase III, has argued for an
      involvement of motilin in the regulation of certain functions of the gut during fasting.

      Motilin receptor agonists can increase gastric emptying after ingestion of a meal; this
      action is mediated via the cholinergic system of the stomach. Erythromycin and motilides
      (non-peptide derivatives of macrolide antibiotics but devoid of antibiotic activity) are
      motilin receptor agonists and effective gastroprokinetic agents in patients. Erythromycin has
      been shown to stimulate gastric emptying in patients with diabetic, idiopathic and
      post-vagotomy gastroparesis, and in critically-ill patients receiving enteral nutrition,
      EM574 and KC 11458, and the peptide motilin receptor agonist atilmotin, also increase gastric
      emptying in humans.

      In addition to effects on gastric emptying, motilin also appears to produce an effect on the
      oesophageal musculature. In particular, several studies have shown that single doses of
      motilin agonists (erythromycin in healthy volunteers and in patients with gastro-oesophageal
      reflux disease (GORD), atilmotin, a peptide motilin agonist, in healthy volunteers) ,
      increase lower oesophageal sphincter (LOS) pressure and have various dose dependent effects
      on oesophageal peristaltic amplitudes and propulsive contractions in both healthy volunteers
      and patients with GORD. In addition, there is evidence that reduction of GORD in patients by
      using a motilin agonist may be useful clinically. For example, in a recent study in patients
      following lung transplantation, it was demonstrated that azithromycin, a motilin agonist
      macrolide antibiotic, reduced the number of reflux events and total oesophageal acid exposure
      as well as reduce the proximal extent to which reflux was regurgitated.

      The clinical trials of promotility agents in GORD have not, however, shown consistent
      benefit. This may be related to compound characteristics. The dynamics of the relationship
      between PK and the effect on oesophageal function may be a factor as the most consistent data
      supporting their role as prokinetics in GORD come from studies which administered the drug
      intravenously, a route of administration which would not be suitable for a broader GORD
      population. In addition, if high doses of macrolides are required to have an effect on GORD,
      there is a risk of overlapping with antibiotic therapeutic doses, which would limit the
      interest of such approach. Macrolides also induce side effects such as nausea and abdominal,
      which makes macrolides difficult to tolerate for many patients. Another factor to consider is
      that repeat administration of macrolides induces desensitization of the motilin receptor
      reducing their efficacy over time, a phenomenon called tachyphylaxis. A strategy to decrease
      the tachyphylaxis to stimulation of motilin receptors is to identify agents that do not
      possess a complex motilide structure like erythromycin. This was the approach taken by
      GlaxoSmithKline (GSK) by which they identified GSK962040, a small molecule motilin receptor
      agonist, which is not a motilide.

      GSK962040 was designed using the recombinant human motilin receptor to enhance the
      specificity for the receptor and potentially decrease the negative characteristics
      encountered with compounds with complex and non-specific motilide structures. A range of in
      vitro and in vivo studies have been conducted using GSK962040 to investigate its primary,
      secondary and safety pharmacology and toxicology. In addition, the pharmacokinetics (PK),
      absorption, distribution, metabolism and elimination of GSK962040 have been investigated in
      non-clinical species through a series of oral and intravenous studies.

      The First Time in Human (FTIH) study (MOT107043) of GSK962040 is completed. It was an
      ascending single dose, randomised, placebo-controlled trial, with doses in the range of 1-150
      mg to assess safety and tolerability, PK and pharmacodynamic effects on gastric emptying (GE)
      in healthy male and female volunteers. Dosing with GSK962040 was well tolerated. The results
      demonstrated that GSK962040 has an approximate dose proportional PK profile. Single doses of
      GSK962040 in the range of 1 to 150 mg resulted in mean exposures less than 23 μg.h/mL (AUC).
      At single doses of 50 mg to 150 mg, the rate of GE measured by the 13C-octanoic acid breath
      test was significantly increased in healthy volunteers when compared with placebo. Increasing
      the dose above 50 mg did not result in a greater effect on GE. The mean within subject time
      for half a [13C]-containing meal to empty from the stomach (GE t½) decreased by 22-43% from
      placebo with GSK962040 50, 75, 125 and 150 mg single doses (p ≤ 0.02). Increases in the rate
      of gastric emptying occurred in 85% to 100% of those healthy subjects receiving the 50 to 150
      mg doses. The 14-day repeat dose study in healthy volunteers (MOT109681) was an ascending
      dose, randomised, placebo-controlled trial over the range of 10 mg to 125 mg daily. GSK962040
      was well tolerated over the 14- day administration period for the doses tested and exhibited
      predictable PK, with and without food. The results indicated that GE was enhanced at doses of
      50 mg and above, throughout the 14-day dosing. GSK962040 is currently in Phase II clinical
      development, being investigated in intensive care patients who receive enteral feeding, and
      in patients with diabetic gastroparesis. The present study will investigate effect of
      GSK962040 on oesophageal function because a combination of enhanced GE, barrier function
      (i.e. increase in LOS pressure) and oesophageal clearance would be potentially beneficial in
      patients with GORD or regurgitation.

      Non clinical and clinical data indicate that a motilin agonist such as GSK962040 may also
      influence oesophageal function as well as GE. The purpose of the present study is primarily
      to evaluate the physiological effect of clinical doses of GSK962040 on oesophageal function
      in healthy volunteers, using established methods (oesophageal manometry, ambulatory
      pH/Impedance monitoring). GE will also be measured, using wireless motility capsule (WMC)
      monitoring. Given this is a physiological assessment, the use of healthy volunteers is
      considered appropriate; in addition, the study population will comprise male volunteers only
      in order to reduce variability in the measurements and therefore sample size, as GE varies
      with gender. The information from this study will inform decision making as to whether
      GSK962040 could have utility in conditions in which lower oesophageal function is deranged
      such as GORD.
    

Intervention name(s): Active; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): GSK962040 125mg; Matching Placebo
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment