Alimentary Pharmacology and Therapeutics

Randomised clinical trial: effects of monotherapy with

ADX10059, a mGluR5 inhibitor, on symptoms and reflux
events in patients with gastro-oesophageal reflux disease
F. Zerbib*, S. Bruley des Varannes , S. Romanà, R. Tutuian§, J.-P. Galmiche , F. Mionà, J. Tack–, P. Malfertheiner** &
C. Keywood

*Gastroenterology Department, CHU SUMMARY

Bordeaux, Saint André Hospital, and
Université Victor Segalen Bordeaux 2,
Bordeaux, France.
Centre d’Investigation Clinique (CIC-
INSERM 04), Institut des Maladies de
l’Appareil Digestif, Centre Hospitalier
Universitaire de Nantes, Nantes,
France.
à
Digestive Diseases Department,
Hospices Civils de Lyon, Hospital E.
Herriot, and Université Lyon 1, Lyon,
France.
§
Division of Gastroenterology, Univer-
sity Clinic for Visceral Surgery and
Medicine, Bern University Hospital,
Inselspital, Bern, Switzerland.
–
Division of Gastroenterology, Univer-
sity Hospital Leuven, Leuven, Belgium.
**Department of Gastroenterology,
Hepatology and Infectious Diseases,
University of Magdeburg, Magdeburg,
Germany.
Addex Pharma SA, Geneva, Switzer-
land.
Correspondence to:
Dr C. Keywood, Addex Pharma SA,
12 Chemin des Aulx, 1228 Plan-
les-Ouates, Geneva, Switzerland.
E-mail: charlotte.keywood@
addexpharma.com
Publication data
Submitted 24 December 2010
First decision 12 January 2011
Resubmitted 17 January 2011
Accepted 19 January 2011
EV Pub Online 14 February 2011
Background
ADX10059, a metabotropic glutamate receptor 5 (mGluR5) negative allosteric
modulator, has been shown to reduce gastro-oesophageal reflux events and
oesophageal acid exposure in patients with gastro-oesophageal reflux disease
(GERD) and healthy subjects.
Aim
To evaluate the effects of ADX10059 monotherapy for 2 weeks on symptom con-
trol in patients with GERD.
Methods
This was a double-blind, placebo-controlled, multi-centre trial in GERD patients
who were responders to proton pump inhibitors (PPIs). Following PPIs with-
drawal, a 2-week baseline washout period was followed by 2-week treatment with
either ADX10059 120 mg or placebo b.d. The primary clinical efficacy endpoint
was the number of GERD symptom-free days in treatment week 2 compared
with the last 7 days of baseline. The effect on reflux events using 24-h imped-
ance–pH monitoring was also determined in a subset of 24 patients.
Results
The full analysis set comprised 103 patients ADX10059 (N = 50), Placebo (N = 53).
In treatment week 2, ADX10059 significantly increased GERD symptom-free days
(P = 0.045) and heartburn-free days (P = 0.037), reduced antacid use (P = 0.017),
improved total symptom score (P = 0.048) including subscale heartburn ⁄ regurgita-
tion (P = 0.007) and sleep disturbance because of GERD (P = 0.022). ADX10059
significantly reduced total (P = 0.034) and acidic reflux events (P = 0.003).
ADX10059 was well tolerated. Most common adverse events for ADX10059 were
mild to moderate dizziness 16% and vertigo 12% (placebo 4% and 2%).
Conclusions
Inhibition of mGluR5 with ADX10059 monotherapy reduces reflux events and
improves symptoms in GERD patients. This mechanism has promise for the
management of GERD (ClinicalTrials.gov, number NCT00820079).

Aliment Pharmacol Ther 2011; 33: 911–921

ª 2011 Blackwell Publishing Ltd 911

doi:10.1111/j.1365-2036.2011.04596.x

F. Zerbib et al.
INTRODUCTION
Gastro-oesophageal reflux disease (GERD) is a common
disorder caused by the reflux of gastric contents into the
oesophagus. According to a recent global definition,
GERD can cause oesophageal and extra-oesophageal syn-
dromes, which can be associated or not in the same indi-
vidual.1 The diagnosis of GERD relies on typical
symptoms such as heartburn and regurgitation as well as
the presence oesophageal mucosal breaks at endoscopy.
GERD management is primarily based on lifestyle modi-
fications and acid suppressive therapies, especially the
proton pump inhibitors (PPIs) which are effective
achieving both mucosal healing and symptom relief.2
However, a subgroup of GERD patients are refractory to
acid suppressive therapy and, although there is no widely
admitted definition of ‘refractoriness’ to PPIs, it is gener-
ally admitted that up to 40% of patients have inadequate
symptom relief after a 4-week course of a single dose of
PPI,2 especially when no oesophagitis is demonstrated at
endoscopy (the so-called ‘non-erosive reflux disease’).3
In unselected patients with persistent symptoms on
double-dose PPIs, combined ambulatory pH-impedance
studies have shown that 50–60% of them do not have
symptoms which are associated with GER, 10% have
symptoms associated with acid reflux and 30–40% have
symptoms associated with non-acid reflux.4, 5 These
results demonstrate that, in a substantial group of
patients with GERD, there is room for therapies that can
restore an efficient antireflux barrier.
Gastro-oesophageal reflux disease is primarily a motil-
ity disorder in which impaired lower oesophageal sphinc-
ter (LOS) function plays a crucial role. Most reflux
episodes result from transient LOS relaxations (TLOSRs)
rather than from low resting LOS pressure alone 6, 7 and
therefore, controlling the occurrence of TLOSRs appears
to be a relevant therapeutic objective in GERD. TLOSRs
occurrence involves a vago-vagal reflex triggered by gas-
tric distension, the excitatory signal being conveyed
through afferent vagal pathways to the dorsal motor
nucleus of the vagus where the origin of vagal efferents
is located.8
Studies in animal models of GER have identified
gamma-aminobutyric acid (GABA) type B (GABAB)
receptor agonists and metabotropic glutamate receptor 5
(mGluR5) antagonists as promising agents for the treat-
ment of reflux disease. Mechanistic studies and short-
term therapeutic trials in healthy subjects and in patients
with GERD have confirmed the efficacy of GABAB
receptor agonists, in reducing TLOSRs, reflux events and
reflux symptoms.9–15
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Metabotropic glutamate receptor 5 antagonists repre-
sent a novel, promising class of compounds for the treat-
ment of GERD. Endogenous glutamate mediates slow
pre- and postsynaptic neurotransmission within the cen-
tral nervous system (CNS).16 Moreover, transmission of
signals from vagal afferent terminals in the Nucleus
Tractus Solitarius is mainly glutamatergic and mGluR5
have been shown to modulate the mechanosensitivity of
gastro-oesophageal vagal afferents.17 Inhibition of
mGluR5 has been shown to reduce TLOSRs induced by
gastric distension in dogs 18 and ferrets 19 thus suggest-
ing that endogenous activation of mGluR5 is an impor-
tant component of the pathway(s) triggering or
regulating TLOSRs.
ADX10059 is a selective mGluR5 negative allosteric
modulator which was tested in clinical trials for the
treatment of GERD. An initial single-blind, placebo-con-
trolled, 2-day study was performed in 24 GERD patients
to evaluate the effect of orally administered ADX10059
on acid reflux and clinical symptoms of GERD.20 This
study showed that on a single day of dosing, ADX10059
(250 mg t.d.s.) significantly reduced oesophageal acid
exposure together with reflux-related symptoms. These
very promising results were hampered by sub-optimal
tolerability related to the compound’s CNS activity and
the rapid absorption of the oral formulation used in the
study. A subsequent modified-release formulation of
ADX10059, studied in healthy subjects, had improved
tolerability and further confirmed that negative modula-
tion of mGluR5, reduces gastro-oesophageal reflux events
21
at an effective dose that was lower than in the first
study. However, there are no data available on longer
term administration of ADX10059 in patients with path-
ological GER.
The aim of this study was to evaluate the effect of a
2-week treatment with ADX10059 monotherapy on
symptom control and reflux events, in patients with
GERD. Despite encouraging results, further development
of ADX10059 was halted after completion of this study,
because of safety issues observed in another longer term
trial in migraine.
MATERIALS AND METHODS
Study design and objectives
The study was a phase IIB, randomised, double-blind,
placebo-controlled parallel group, multi-centre study in
GERD patients who were not receiving concurrent acid
suppressant or antireflux therapy. The study was con-
ducted in an out-patient setting. The duration of the trial
Aliment Pharmacol Ther 2011; 33: 911–921
ª 2011 Blackwell Publishing Ltd

Randomised clinical trial: refl
was approximately 5 weeks with a 2-week PPI washout
period, followed by a 2-week treatment with study medi-
cation and a 1-week follow-up period.
The primary objective of the study was to evaluate the
effect of ADX10059 monotherapy on GERD symptoms.
Secondary objectives were to evaluate the effect of
ADX10059 on impedance–pH measured reflux events as
well as ADX10059 safety and tolerability in GERD
patients.
Conduct of the study
The study was conducted at 11 study sites in France,
Belgium, Germany and Austria. The study was per-
formed in accordance with the ethical principles stated
in the Declaration of Helsinki as revised by 52nd General
Assembly in Edinburgh, 2000. After Ethics Committee
approval, the study was conducted between December
2008 and October 2009 in accordance with Good
Clinical Practice (GCP).
Patients
The patients were male or female aged 19–70 years, with
a body mass index £32 kg ⁄ m2, who had provided written
informed consent. The patients had a history of typical
GERD which was well controlled on a standard dose of
PPI treatment, defined as <2 days of mild heartburn
and ⁄ or regurgitation per week while on treatment. Dur-
ing the last 7 days of the baseline PPI washout period,
patients were to have mild symptoms of heartburn
and ⁄ or regurgitation on ‡4 of 7 days or moderate ⁄ severe
Figure 1 | Flow diagram for the
study (FAS, full analysis set;
PP, per-protocol).
Aliment Pharmacol Ther 2011; 33: 911–921
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fluux inhibition with the mGluR5 NAM ADX10059
symptoms on ‡2 of 7 days. The main exclusions were
patients with exclusively atypical symptoms of GERD in
the absence of heartburn and ⁄ or regurgitation), a history
of moderate to severe erosive oesophagitis, a documented
history of hiatus hernia >3 cm. Patients with other sig-
nificant psychiatric or physical disease, including signifi-
cant abnormalities on screening blood tests and ECG,
which could interfere with the conduct of the study, and
pregnant or breast feeding women were also excluded.
Patients were provided with standard antacid rescue
medication throughout the study and were not permitted
to use any other antacid, acid suppressant or antireflux
medication during the 4 weeks from screening to the
end-of-treatment visit.
Procedures and data collection
Screening and randomisation. At screening (visit 1, day
)14  1 day) after giving informed consent, patients
underwent medical history, physical examination, vital
signs, ECG and laboratory safety testing as well as train-
ing on how to complete the eDiary. They then entered a
2-week PPI washout period, the last 7 days of which
acted as the baseline period for symptom evaluation. At
the end of the washout period patients returned to the
clinic.
At visit 2 (day )1), the eDiary and safety data were
reviewed and eligible patients were randomised to take
study medication twice daily for 15 days (Figure 1),
according to a computer-generated randomisation
schedule.
913

F. Zerbib et al.
Study drug dosing and follow-up periods. Patients took
study medication orally twice daily for 15 days, 30 min
before breakfast and 30 min before the evening meal.
The first dose was taken before breakfast on day 1 and
the last dose before the evening meal on day 15. Patients
noted the use of study medication in the eDiary.
Patients with impedance–pH recordings: the first dose
of study medication was taken on day 1 when the patient
attended the clinic for removal of the impedance–pH
catheter at the end of the pre-treatment mechanistic
monitoring period. The dose was administered after
removal of the catheter, and 30 min prior to a standar-
dised light breakfast. The morning dose on day 15 was
taken when the patient attended the clinic for visit 3 at
the start of the 24-h recordings, and 30 min prior to a
standardised light breakfast.
At the end of treatment visit 3 (day 16 + 2 days)
treatment and eDiary compliance were checked along
with safety and tolerability. Patients were allowed to
resume PPI or other acid suppressing medications if
desired. A final follow-up was made at visit 4 (day
22  2 days).
Efficacy measures
GERD clinical symptoms. Gastro-oesophageal reflux dis-
ease clinical symptoms (heartburn and regurgitation),
occurrence and severity, were collected by the patients
who completed an eDiary twice daily, prior to going to
bed at night and upon waking in the morning, from visit
1 until visit 3. The patient assessment of upper gastroin-
testinal symptom severity index (PAGI-SYM)22 was
recorded pre-treatment, at visits 2 and 3.
The primary endpoint was the number of GERD
symptom (heartburn and ⁄ or regurgitation)-free days in
week 2 of study medication.
The major clinical secondary variables were as follows:
The number of GERD symptom-free days in week 1 and
the overall treatment period; for week 1, week 2 and
overall, the number of heartburn-free days and regurgita-
tion-free days, the severity of heartburn and regurgita-
tion, the number of days with postprandial GERD
symptoms, the number of nights and proportion of
patients with no sleep disturbance and sleep disturbance
severity, the number of days with antacid rescue medica-
tion use and proportion of patients using antacid; also at
the end of treatment total PAGI-SYM score and the
subscales heartburn ⁄ regurgitation, fullness ⁄ early satiety,
nausea ⁄ vomiting, bloating, upper abdominal pain and
lower abdominal pain.
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24-h impedance–pH monitoring. At six centres, all the
patients included underwent 24-h oesophageal imped-
ance–pH monitoring. Recordings were performed on
pre-treatment day )1 to day 1 and on treatment day 15
to day 16 using a Sleuth Multi-channel Intraluminal
Impedance ambulatory system (Sandhill Scientific, Inc.,
Highland Ranch, CO, USA). The system includes a por-
table data logger with impedance–pH amplifiers and a
catheter containing one antimony pH electrode and eight
impedance electrodes. Analysis included identification
and characterisation of individual reflux events, and
measure of clearance times (bolus and pH clearance).
Mealtimes were excluded from the analysis. Reflux epi-
sodes were characterised by pH-metry as acid, weakly
acidic or weakly alkaline according to a consensus report
on detection and definitions of gastro-oesophageal reflux
23
(i) Acid reflux: reflux episodes with a pH <4 which
can either reduce the pH of the oesophagus to below 4
or occur when oesophageal pH is already below 4; (ii)
Weakly acidic reflux: reflux episodes during which nadir
pH is between 4 and 7; (iii) Weakly alkaline reflux:
reflux episodes during which nadir pH does not drop
below 7. The nocturnal period was defined as being
between 22:00 and 08:00 hours.
The primary mechanistic variables were impedance–
pH parameters, comprising the number of total reflux
episodes, the number of weakly acidic reflux episodes,
oesophageal acid exposure, oesophageal bolus exposure
and the number of reflux episodes extending 15-cm
proximal to the LOS. The secondary impedance–pH
variables were median reflux bolus clearance time (deter-
mined 5 cm above LOS) and acid clearance time
(defined for acid reflux events as the time during which
pH was below 4).
Safety and tolerability
Safety assessments were performed at Screening and visit
3 and comprised physical examination HR, BP, 12-lead
ECG, blood biochemistry, haematology, dipstick urinaly-
sis and urine pregnancy for women of child-bearing age.
Documentation of exposure to study medication was col-
lected at visit 3. Tolerability was assessed by routine
enquiry about adverse events (AEs) throughout the
study.
Statistics
Sample size calculation. Based on the literature review,
the anticipated mean number of symptom-free days on
placebo in week 2 was approximately 3. An increase of
Aliment Pharmacol Ther 2011; 33: 911–921
ª 2011 Blackwell Publishing Ltd
 13652036, 2011, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/j.1365-2036.2011.04596.x by Nat Prov Indonesia, Wiley Online Library on [14/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Randomised clinical trial: refl
fluux inhibition with the mGluR5 NAM ADX10059

1.5 or 2 symptom-free days on ADX10059 compared

Table 1 | Patient demographics
with placebo was considered a clinically relevant differ-
ence. With a common standard deviation (s.d.) of 2.5, Placebo (N = 53) ADX10059 (N = 50)
80% power could be achieved at a 5% significance level Age (years)
with a two-sided test with 45 patients per group and a Mean (s.d.) 53.3 (12.5) 50.2 (13.5)
treatment difference of 1.5 days. If the treatment differ- Range 19–69 22–70
ence was 2 days, the power was 96%.
Age (years)
The safety population was used for the summary and
<50 20 (38%) 25 (50%)
analysis of all safety data and included all randomised
patients who received at least one dose of study medica- ‡50 33 (62%) 25 (50%)
tion. The full analysis set (FAS) was used to analyse all Ethnic origin
efficacy data and included all randomised patients who White 53 (100%) 48 (96%)
received at least one dose of study medication and had Afro Caribbean 0 1 (2%)
post-randomisation efficacy data. The per-protocol (PP) Other 0 1 (2%)
population was a subset of patients of the FAS who Gender
completed the study and were deemed to be protocol Male 27 (51%) 27 (54%)
compliant. Female 26 (49%) 23 (46%)
The primary efficacy variable was analysed using an 2
BMI (kg ⁄ m )
analysis of covariance (ANCOVA) model. Week 2 was
Mean (s.d.) 26.8 (3.1) 26.6 (3.9)
compared with baseline with treatment group included
as a factor and baseline values included in the model as Range 19–32 17–34
appropriate. Least square (LS) estimates of the GERD
symptom-free days at week 2 were reported together symptom-free days in week 2 of treatment (P = 0.045).
with their standard errors and 95% confidence intervals. The mean (S.E.) number of GERD symptom (heartburn
In addition, the estimated difference (with 95% confi- and ⁄ or regurgitation)-free days at baseline, week 1, week
dence interval) between the treatment groups was 2 and overall are shown in Figure 2. The mean number
reported together with the P-value for this difference. of GERD symptom-free days improved by approximately
Secondary efficacy variables which were numbers of days, 2 days, from 0.5 days at baseline to 2.5 days at week 2 in
numbers of reflux episodes and PAGI-SYM scores were the ADX10059 treatment group compared with an
analysed by ANCOVA in the same manner. improvement of approximately 1 day from 0.7 days as
Logistic regression was used to analyse data expressed baseline to 1.7 days at week 2 in the placebo treatment
as proportions. Odds ratios and associated 95% confi- group. The LS mean (95% CI) treatment difference for
dence intervals were presented for the treatment compar- ADX10059 vs. placebo at week 1 was 0.3 ()0.5, 1.0) days
ison of ADX10059 vs. placebo. (P = 0.475), week 2 0.9 (0.0, 1.8) days (P = 0.045) and
overall 0.6 days ()0.1, 1.3) (P = 0.077). The results for
RESULTS the PP population supported the analysis for the FAS,

Patient demographics
A total of 103 patients were randomised of whom 100
completed the study. The Safety population and the FAS
had 53 patients in the placebo group and 50 in the
ADX10059 group (Figure 1). The overall population
mean age was 51.8 years, mean BMI 26.7 kg ⁄ m2 and
52% of patients were male. The treatment groups were
matched for demographic characteristics and GERD his-
tory characteristics (Table 1).

Clinical efficacy Figure 2 | Mean (+S.E.) number of GERD symptom-

free days with ADX10059 and placebo. * P = 0.045
GERD symptom-free days. Compared with placebo,
(ANCOVA).
ADX10059 significantly increased the number of GERD

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ª 2011 Blackwell Publishing Ltd
 13652036, 2011, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/j.1365-2036.2011.04596.x by Nat Prov Indonesia, Wiley Online Library on [14/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
F. Zerbib et al.

with an almost identical treatment difference observed.
ADX10059 tended to increase the proportion of patients
who had a 50% reduction in days with GERD symptoms.
For week 2, 11 (21%) patients in the placebo treatment
group and 17 (34%) patients in the ADX10059 treatment
group had a 50% reduction in GERD symptom days
(P = 0.081).
Heartburn, regurgitation and GERD symptom severity. As
shown in Table 2, ADX10059 tended to have a greater
effect on heartburn than regurgitation, although the
medication did improve both symptoms. In week 2, the
number of heartburn-free days increased significantly fol-
lowing ADX10059 (P = 0.037) and heartburn severity
decreased (P = 0.054). There was no significant effect of
ADX10059 on either regurgitation-free days or severity
of regurgitation. Patients were significantly more likely to
be heartburn free (OR: 7.56; 95% CI: 1.6, 56.5;
P = 0.049) and regurgitation free (OR: 4.4; 95% CI: 1.6,
12.2; P = 0.005) in all of week 2 in the ADX10059
group.
Postprandial GERD. Days with GERD symptoms occur-
ring after any meal decreased significantly more follow-
ing ADX10059 treatment from mean 5.1 days at baseline
(5.0 placebo) to 2.8 days at week 2 (placebo 3.8,
P = 0.034). The major effect was on symptoms of heart-
burn with a treatment difference of )1.0 days
(P = 0.042) (Table 2).
Sleep disturbance due to GERD. ADX10059 treatment
significantly increased the proportion of patients with no
sleep disturbance due to GERD in all of week 2 (OR 4.6
(95% CI 1.8, 12.2); P = 0.002) and in the overall 2 weeks
(OR 4.0 (95% CI 1.4, 11.7) P = 0.011) (Figure 3). The
number of nights with no sleep disturbance was
increased in the ADX10059 group during week 2
(P = 0.053) and overall (P = 0.043). Severity of sleep dis-

Placebo ADX10059 Treatment difference (95% CI) P-value Table 2 | Efficacy of

Number of heartburn-free days
ADX10059 (N = 50) and pla-
cebo (N = 53) on gastro-
Baseline 1.3 (1.9) 1.0 (1.4) 1.0 (0.1, 1.9) 0.037 oesophageal reflux disease
Week 2 2.1 (2.3) 2.9 (2.6) (GERD) symptoms [mean
Number of regurgitation-free days (s.d.)]
Baseline 2.8 (2.4) 2.5 (2.4) 0.5 ()0.4, 1.5) 0.270
Week 2 3.9 (2.3) 4.3 (2.8)
Summation score of symptom severity for heartburn
Baseline 11.5 (5.0) 11.6 (4.4) )1.8 ()3.6, 0.0) 0.054
Week 2 7.9 (4.6) 6.1 (5.2)
Summation score of symptom severity for regurgitation
Baseline 8.0 (5.5) 8.6 (5.3) )1.5 ()3.4, 0.3) 0.104
Week 2 5.2 (4.8) 3.9 (5.1)
Number of days with postprandial GERD
Baseline 5.0 (2.2) 5.1 (1.9) )1.0 ()1.9, )0.1) 0.034
Week 2 3.8 (2.6) 2.8 (2.8)
Number of days with postprandial heartburn
Baseline 4.5 (2.5) 4.6 (2.1) )1.0 ()1.9, )0.0) 0.042
Week 2 3.5 (2.7) 2.5 (2.7)
Number of days with postprandial regurgitation
Baseline 3.1 (2.6) 3.2 (2.5) )0.6 ()1.3, 0.2) 0.153
Week 2 2.0 (2.1) 1.5 (2.3)
Number of days with rescue medication
Baseline 4.6 (2.3) 4.5 (2.4) )1.2 ()2.2, )0.2) 0.0165
Week 2 3.6 (2.8) 2.3 (2.5)

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ª 2011 Blackwell Publishing Ltd
 13652036, 2011, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/j.1365-2036.2011.04596.x by Nat Prov Indonesia, Wiley Online Library on [14/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Randomised clinical trial: refl
fluux inhibition with the mGluR5 NAM ADX10059

Table 3 | Treatment differences in PAGI-SYM scores

after 2 weeks of treatment with ADX10059 120 mg bd
(n = 50) and placebo (n = 53)
Treatment
difference (95% CI)
(ADX10059–placebo) P-value
Total score )0.29 ()0.57, )0.02) 0.037
Heartburn ⁄ )0.55 ()0.93, )0.16) 0.006
Figure 3 | Percentage of patients with no sleep distur- regurgitation score
bance related to GERD symptoms with ADX10059 and Fullness ⁄ )0.19 ()0.55, 0.16) 0.280
placebo. Values are predicted proportions (95% CI). early satiety score
* P = 0.002; ** P = 0.011 (logistic regression). Nausea ⁄ 0.01 ()0.24, 0.26) 0.919
vomiting score
Bloating score )0.31 ()0.80, 0.18) 0.206
turbance at week 2 was lower in the ADX10059 group
Upper abdominal )0.24 ()0.67, 0.19) 0.276
(P = 0.021).
pain score
Lower abdominal )0.44 ()0.74, )0.14) 0.005
Rescue medication. The number of days on which res- pain score
cue medication was used was significantly lower in the
ADX10059 treatment group in week 2 (P = 0.017) and
overall (P = 0.021) (Table 2). At baseline 93% and 88%
of patients took antacid rescue medication in the placebo
and ADX10059 treatment groups respectively. Compared
with the placebo group, rescue medication was used by
significantly fewer patients in the ADX10059 group in
week 1 (72% vs. 89%, P = 0.026) and week 2 (58 vs.
81%, P = 0.027) and in the overall 2-week period (78 vs.
93%, P = 0.042).

PAGI SYM and patient preference. Mean PAGI-SYM

scores at baseline were 2.0 for placebo and 2.1 for
ADX10059. This decreased to 1.7 for placebo and 1.3 for
ADX10059 at the end of treatment. The mean (s.d.)
change from baseline in PAGI-SYM total score was )0.2
(0.7) for patients in the placebo treatment group, com-
pared with )0.5 (0.8) for patients in the ADX10059
treatment group.
Results of ANCOVA for the total score and individual
subscales are shown in Table 3. ADX10059 significantly
reduced the total score, heartburn ⁄ regurgitation score
and lower abdominal pain score compared with placebo.
24-h impedance–pH studies
ADX10059 significantly reduced the total number of
reflux events in the 24 h (treatment difference ) 20.6
P = 0.034) (Figure 4) and the nocturnal periods (treat-
ment difference )6.3, P = 0.047 respectively). However,
the reduction in reflux events did not achieve statistical
significance in the diurnal period (treatment difference –
15.0, P = 0.105). ADX10059 also significantly reduced
Figure 4 | Number of gastro-oesophageal reflux epi-
sodes per 24 h detected with impedance–pH monitoring
at baseline and at the end of a 2-week treatment period
with ADX10059 (N = 10) and placebo (N = 14). There
was a significant reduction in total number of reflux
episodes (P = 0.034) (ANCOVA). Bars indicate means
(+S.E.).
the number of acid reflux events in the 24 h and diurnal
periods (P = 0.003 and 0.018 respectively). The reduction
in acid reflux events was not statistically significant in
the nocturnal period (P = 0.106). There was no signifi-
cant difference between ADX10059 and placebo regard-
ing the number of weakly acidic reflux events, number of
reflux event with proximal extent, oesophageal acid and
bolus exposures as well as for bolus and acid oesophageal
clearances (Table 4).

Aliment Pharmacol Ther 2011; 33: 911–921 917

ª 2011 Blackwell Publishing Ltd
 13652036, 2011, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/j.1365-2036.2011.04596.x by Nat Prov Indonesia, Wiley Online Library on [14/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
F. Zerbib et al.

Safety and tolerability DISCUSSION

No safety monitoring abnormalities (12-lead ECG,
bloods, HR and BP) were observed. No deaths or other
serious adverse events occurred during the study.
Adverse event incidence was higher after ADX10059
120 mg b.d., 62%, compared with placebo 28%: All AEs
were mild (66%) or moderate (34%). The most common
(>5%) AEs in the ADX10059 group were dizziness
(16%), vertigo (12%) upper abdominal pain (10%) and
sleep disorders (6%); the placebo incidence of these AEs
was 4%, 2%, 0% and 2% respectively. Nine (17%)
patients in the placebo group experienced AEs that were
considered by the investigator to be treatment related,
compared with 25 (50%) patients in the ADX10059
group. No patients taking placebo withdrew because of
AEs, whereas three (6%) taking ADX10059 had AEs
leading to withdrawal (difficulty sleeping, vertigo and
chest pain unrelated to study medication).
Previously, ADX10059 was shown to reduce 24-h
oesophageal acid exposure and clinical symptoms, on a
single day of dosing in GERD patients 20 as well as
showing evidence of reflux inhibition in healthy subjects,
following a challenge meal.21 This study adds to these
previous findings and shows that 2-week treatment with
ADX10059 (120 mg b.d.) as monotherapy has a clinically
meaningful effect on improving reflux symptoms and
decreasing the number of GER episodes in GERD
patients. These results confirm the potential for thera-
peutic application of mGluR5 inhibition, in the treatment
of GERD.
The population of GERD patients included in this
study had good symptom control on PPI and did not
require any other GERD treatment. As pH-monitoring
was not performed at screening to diagnose GERD, this
population of good PPI responders was specifically

Placebo ADX10059 Treatment difference Table 4 | Efficacy of

(N = 14) (N = 10) (95% CI) P-value ADX10059 and placebo on
Total reflux events (n) gastro-oesophageal reflux

Baseline 77.0 (34.0) 64.9 (31.9) )20.6 ()39.5, )1.7) 0.034

End of treatment 78.4 (42.1) 47.9 (18.6)
Acid reflux events (n)
Baseline 55.7 (30.3) 52.1 (27.0) )19.7 ()32.0, )7.4) 0.003
End of treatment 59.7 (34.1) 37.0 (15.6)
Weakly acidic reflux events (n)
Baseline 20.2 (16.46) 12.6 (7.41) )3.75 ()12.83, 5.33) 0.400
End of treatment 18.4 (15.16) 10.7 (5.40)
24 h oesophageal acid exposure (%)
Baseline 6.7 (6.3) 5.9 (4.6) )0.95 ()3.24, 1.35) 0.401
End of treatment 5.5 (4.9) 4.2 (1.9)
24 h oesophageal bolus exposure (%)
Baseline 2.2 (1.5) 2.2 (1.5) )0.55 ()1.39, 0.28) 0.184
End of treatment 1.7 (0.8) 2.2 (1.7)
Reflux with proximal extent (n)
Baseline 7.8 (5.8) 4.0 (4.0) 0.41 ()4.3, 5.12) 0.859
End of treatment 7.3 (8.3) 4.3 (3.7)
Oesophageal acid clearance (s)
Baseline 116.6 (81.4) 125.5 (125.0) 13.9 ()28.3, 56.1) 0.500
End of treatment 92.0 (52.1) 107.0 (45.3)
Oesophageal bolus clearance (s)
Baseline 24.2 (12.7) 31.0 (23.3) 5.86 ()1.7, 13.5) 0.124
End of treatment 22.3 (7.9) 29.8 (11.3)
Results of 24-h oesophageal impedance–pH monitoring. [mean (s.d.)].

918 Aliment Pharmacol Ther 2011; 33: 911–921

ª 2011 Blackwell Publishing Ltd

Randomised clinical trial: refl
selected to ensure a high probability of the patients’ symp-
toms being a result of reflux. Compared with placebo,
ADX10059 consistently improved GERD symptoms as
demonstrated by the significant increase in GERD symp-
tom-free days, and a significant decrease in postprandial
GERD symptoms, sleep disturbance due to GERD, use of
rescue medication and improvement in the PAGI-SYM
scores. We observed a significant improvement in fre-
quency and severity of heartburn, although the improve-
ment in regurgitation was less marked and did not
achieve statistical significance. One interpretation of this
finding could be that when PPIs are withheld from
patients who normally have good symptom control, they
are more likely to complain about heartburn as a predom-
inant symptom, rather than regurgitation.
In the subgroup of patients who underwent imped-
ance–pH monitoring, ADX10059 decreased reflux events
by about 25% in the 24 h monitoring period including a
30% reduction in acid reflux events. These results proba-
bly account for the clinical efficacy of ADX10059,
although the number of patients who had impedance–
pH monitoring was too small to make a correlation
between clinical improvement and the reduction in the
number of reflux events. As mGluR5 have been shown
to modulate nociception in animal models,24 an effect on
oesophageal acid perception could also account for part
of the clinical improvement, but we did not perform any
specific analysis of symptom association that could sup-
port this hypothesis. There was no significant improve-
ment in other reflux parameters during the 24-h
recordings, including oesophageal acid exposure. This is
different to our previous 4-h stationary study in healthy
subjects, 21 but the values of 24-h oesophageal acid expo-
sure in this study were quite low, reflecting the mild
underlying reflux disease in the study patients, who were
only included if they had a history of non-erosive reflux
disease or mild oesophagitis (Los Angeles grade A). As
the patients had their PPIs withdrawn in the baseline
washout period, they did not have acid suppression.
Therefore, as expected, the majority of reflux events
observed were acidic and ADX10059 demonstrated a sig-
nificant effect on reducing acidic reflux episodes. As the
minority of reflux events were weakly acidic, although a
small numerical reduction was seen following
ADX10059, the number was not sufficiently high to
demonstrate a significant treatment difference. If the
monitoring had been performed in patients on PPIs, a
significant reduction in weakly acidic reflux events would
have been expected, because these are the predominant
type in patients taking acid suppressant therapy.
Aliment Pharmacol Ther 2011; 33: 911–921
ª 2011 Blackwell Publishing Ltd
13652036, 2011, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/j.1365-2036.2011.04596.x by Nat Prov Indonesia, Wiley Online Library on [14/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
fluux inhibition with the mGluR5 NAM ADX10059
Tolerability of new antireflux compounds is a crucial
issue as GERD is a chronic disease and long-term ther-
apy is needed in a majority of patients. Considering
that mGluR5 are involved in numerous CNS-mediated
pathways,16, 17 and that mGluR5 inhibitors may act on
reflux, at least in part, through a central effect, it could
be anticipated that effective mGluR5 inhibition might
be associated with CNS side effects. In this study, the
clinical effect was achieved with acceptable tolerability.
The majority of side effects were mild, transient and
their occurrence diminished with repeated use of the
compound. Only three patients (6%) discontinued
ADX10059 due to side effects. These results confirm
that the tolerability of mGluR5 inhibition is suitable for
use in GERD patients. However, despite good clinical
efficacy, tolerability and safety in this 2-week study,
longer term administration of ADX10059 in a study of
migraine patients, resulted in an unacceptably high inci-
dence of hepatic transaminase abnormalities and the
further development of this compound has been halted.
This effect on the liver has subsequently been shown to
be related to specifically to the metabolism of
ADX10059 and not to the mGluR5 inhibiting mecha-
nism of action (Addex data on file). Hence, the prob-
lem observed with ADX10059, should not hinder the
further development of other mGluR5 inhibitors in this
indication.
Symptomatic relief in patients with refractory GERD
remains an important unmet medical need when con-
sidering the high prevalence of GERD in Western
countries and the significant proportion (up to 40%) of
patients with persistent symptoms despite PPI therapy.3
Targeting the underlying pathophysiological cause of
GERD with reflux inhibitors is a logical treatment strat-
egy for this condition. GABAB agonists and mGluR5
inhibitors have shown promising results in early studies,
but more studies are warranted to establish the efficacy
of these compounds in large groups of patients. The
purpose of this study was to understand whether the
antireflux properties of the mGluR5 NAM could have
an impact on GERD symptoms. The reduction in clini-
cal symptoms observed in the absence of PPI therapy
can be considered to result from the inhibition of reflux
events by ADX10059. The precise role of reflux inhibi-
tors in the management of GERD, i.e. whether as add-
on therapy to PPIs 25 or monotherapy in selected
patient types, remains to be determined. However, dem-
onstrating that reflux inhibition with mGluR5 NAM
has a meaningful effect on GERD symptoms is an
important first step.
919
 13652036, 2011, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/j.1365-2036.2011.04596.x by Nat Prov Indonesia, Wiley Online Library on [14/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
F. Zerbib et al.

CONCLUSIONS Novartis, Nycomed, Ocera, Rose Pharma, SK Life Sci-

This study demonstrates for the first time that a 2-week
course with mGluR5 NAM, ADX10059, improves reflux
symptoms and decreases the number of GER episodes in
GERD patients. Both the clinical efficacy and the tolera-
bility profile of mGluR5 inhibition appears to be suitable
for long-term use and support the concept it represents
a clinically relevant target for the treatment of GERD.
ACKNOWLEDGEMENTS
Declaration of personal interests: We would like to thank
all the investigators and also Sue McKendrick from Quan-
ticate who devised and performed the statistical analysis.
Frank Zerbib has served as a speaker, a consultant and an
advisory board member for Addex Pharma SA, Xenoport,
Movetis, Norgine, Sanofi Aventis, AstraZeneca, Janssen
Cilag, Renckitt Benckiser, Abbott, Pfizer, Given Imaging
and has received research funding from Nycomed. Radu
Tutuian has served as a consultant for Addex Pharma,
AstraZeneca, Movetis, Nestle, Novartis, Sandhill Scientific
and MMS. Jan Tack has provided scientific advice to
Addex Pharma, Almirall, Aryx, Astellas, AstraZeneca,
Chugai, Danone, Ipsen, Menarini, Movetis, Norgine,
ences, Smartpill, Sucampo, Theravance, Tranzyme, Xeno-
port and Zeria. Jan Tack has served on the speaker
bureau of Abbott, AstraZeneca, Ipsen, Menarini, Movetis,
Novartis and Nycomed. François Mion has served as a
consultant to Addex Pharma. Sabine Roman has served as
a consultant to Addex Pharma. Stanislas Bruley des
Varannes has served as a speaker, a consultant and ⁄ or an
advisory board member for AstraZeneca, Janssen Cilag,
Takeda, Danone research, Cephalon, Iprad, Given Imag-
ing, Novartis, Ipsen Beaufour and Nycomed. Jean Paul
Galmiche has served as a speaker, a consultant and an
advisory board member for Addex Pharma SA, Xenoport,
Movetis, Norgine, AstraZeneca, Janssen Cilag, Renckitt
Benckiser, Given Imaging, Mauna Kea Technologies and
has received research funding from AstraZeneca, Mauna
Kea Technologies, Given Imaging and Janssen-Cilag.
Peter Malfertheiner has served as a speaker, a consultant
and ⁄ or advisory board member for AstraZeneca, Axcan,
Xenoport, Danone, Novartis, Nycomed, Bayer and
Norgine. Charlotte Keywood is an employee of Addex
Pharma SA. Declaration of funding interests: This study
was funded by Addex Pharma SA.

REFERENCES
1. Vakil N, van Zanten SV, Kahrilas P,
Dent J, Jones R. The Montreal definition
and classification of gastroesophageal
reflux disease: a global evidence-based
consensus. Am J Gastroenterol 2006;
101: 1900–20.
2. Chiba N, De Gara CJ, Wilkinson JM,
Hunt RH. Speed of healing and symp-
tom relief in grade II to IV gastroesoph-
ageal reflux disease: a meta-analysis.
Gastroenterology 1997; 112: 1798–810.
3. Fass R, Sifrim D. Management of heart-
burn not responding to proton pump
inhibitors. Gut 2009; 58: 295–309.
4. Mainie I, Tutuian R, Shay S, et al. Acid
and non-acid reflux in patients with
persistent symptoms despite acid sup-
pressive therapy: a multicentre study
using combined ambulatory impedance-
pH monitoring. Gut 2006; 55:
1398–402.
5. Zerbib F, Roman S, Ropert A, et al.
Esophageal pH-impedance monitoring
and symptom analysis in GERD: a study
in patients off and on therapy. Am J
Gastroenterol 2006; 101: 1956–63.
6. Dent J, Holloway RH, Toouli J, Dodds
WJ. Mechanisms of lower oesophageal
sphincter incompetence in patients with
symptomatic gastrooesophageal reflux.
Gut 1988; 29: 1020–8.
7. Sifrim D, Holloway R, Silny J, Tack J,
Lerut A, Janssens J. Composition of the
postprandial refluxate in patients with
gastroesophageal reflux disease. Am J
Gastroenterol 2001; 96: 647–55.
8. Mittal RK, Holloway RH, Penagini R,
Blackshaw LA, Dent J. Transient lower
esophageal sphincter relaxation. Gastro-
enterology 1995; 109: 601–10.
9. Lidums I, Lehmann A, Checklin H, Dent
J, Holloway RH. Control of transient
lower esophageal sphincter relaxations
and reflux by the GABA(B) agonist ba-
clofen in normal subjects. Gastroenterol-
ogy 2000; 118: 7–13.
10. Ciccaglione AF, Marzio L. Effect of acute
and chronic administration of the GABA
B agonist baclofen on 24 hour pH metry
and symptoms in control subjects and in
patients with gastro-oesophageal reflux
disease. Gut 2003; 52: 464–70.
11. Koek GH, Sifrim D, Lerut T, Janssens J,
Tack J. Effect of the GABA(B) agonist
baclofen in patients with symptoms and
duodeno-gastro-oesophageal reflux
refractory to proton pump inhibitors.
Gut 2003; 52: 1397–402.
12. Zhang Q, Lehmann A, Rigda R, Dent J,
Holloway RH. Control of transient lower
oesophageal sphincter relaxations and
reflux by the GABA(B) agonist baclofen
in patients with gastro-oesophageal
reflux disease. Gut 2002; 50: 19–24.
13. Boeckxstaens GE, Beaumont H, Mertens
V, et al. Effect of lesogaberan on reflux
and lower esophageal sphincter function
in patients with gastroesophageal reflux
disease. Gastroenterology 2010; 139:
409–17.
14. Boeckxstaens GE, Rydholm H, Lei A,
Adler J, Ruth M. Effect of lesogaberan, a
novel GABA(B)-receptor agonist, on
transient lower oesophageal sphincter
relaxations in male subjects. Aliment
Pharmacol Ther 2010; 31: 1208–17.
15. Gerson LB, Huff FJ, Hila A, et al. Arba-
clofen placarbil decreases postprandial
reflux in patients with gastroesophageal
reflux disease. Am J Gastroenterol 2010;
105: 1266–75.
16. Hornby PJ. Receptors and transmission
in the brain-gut axis. II. Excitatory
amino acid receptors in the brain-gut
axis. Am J Physiol Gastrointest Liver
Physiol 2001; 280: G1055–60.

920 Aliment Pharmacol Ther 2011; 33: 911–921

ª 2011 Blackwell Publishing Ltd

Randomised clinical trial: refl
17. Page AJ, Young RL, Martin CM, et al.
Metabotropic glutamate receptors inhibit
mechanosensitivity in vagal sensory neu-
rons. Gastroenterology 2005; 128: 402–10.
18. Jensen J, Lehmann A, Uvebrant A, et al.
Transient lower esophageal sphincter
relaxations in dogs are inhibited by a
metabotropic glutamate receptor 5
antagonist. Eur J Pharmacol 2005;
519: 154–7.
19. Frisby CL, Mattsson JP, Jensen JM,
Lehmann A, Dent J, Blackshaw LA.
Inhibition of transient lower esophageal
sphincter relaxation and gastroesopha-
geal reflux by metabotropic glutamate
receptor ligands. Gastroenterology 2005;
129: 995–1004.
20. Keywood CGA, Wakefield M, Tack J. A
proof of concept study evaluating the
Aliment Pharmacol Ther 2011; 33: 911–921
ª 2011 Blackwell Publishing Ltd
fluux inhibition with the mGluR5 NAM ADX10059
effect of adx10059, a metabotropic gluta-
mate receptor-5 negative allosteric mod-
ulator, on acid exposure and symptoms
in gastro-esophageal reflux disease. Gut
2009; 58: 1192–9.
21. Zerbib F, Keywood C, Strabach G. Effi-
cacy, tolerability and pharmacokinetics
of a modified release formulation of
ADX10059, a negative allosteric modula-
tor of metabotropic glutamate receptor
5: an esophageal pH-impedance study in
healthy subjects. Neurogastroenterol
Motil 2010; 22: 859–65.
22. Revicki DA, Rentz AM, Tack J, et al.
Responsiveness and interpretation of a
symptom severity index specific to
upper gastrointestinal disorders. Clin
Gastroenterol Hepatol 2004; 2: 769–77.
13652036, 2011, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/j.1365-2036.2011.04596.x by Nat Prov Indonesia, Wiley Online Library on [14/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
23. Sifrim D, Castell D, Dent J, Kahrilas PJ.
Gastro-oesophageal reflux monitoring:
review and consensus report on detec-
tion and definitions of acid, non-acid,
and gas reflux. Gut 2004; 53: 1024–31.
24. Bhave G, Karim F, Carlton SM, Gereau
R. Peripheral group I metabotropic glu-
tamate receptors modulate nociception
in mice. Nat Neurosci 2001; 4: 417–23.
25. Boeckxstaens GE, Beaumont H, Hatle-
bakk J, Silberg DG, Adler J, Denison H.
Efficacy and tolerability of the novel
reflux inhibitor, AZD3355, as add-on
treatment in GERD patients with
symptoms despite proton pump inhibitor
therapy. Gastroenterology 2009; 136:
A-436.
921