Assessment of safety, tolerability, pharmacokinetics and pharmacodynamics of multiple oral doses of the combination of GLPG2451 and GLPG2222, with or without GLPG2737, in adult subjects with cystic fibrosis

There is a high unmet medical need for subjects with CF, including subjects
that are either homozygous or heterozygous for the F508del mutation (with a
potentiator non-responsive mutation on the second allele). For the
latter patient population, no CFTR modulator treatment options are
currently available. For F508del homozygous patients, Orkambi is
licensed to treat CF patients aged 12 years and above. In pivotal studies,
Orkambi treatment was associated with modest improvement in pulmonary function
and also led to a reduction in the number of exacerbations requiring hospital
admission or antibiotic therapy. In clinical study GLPG2737-CL-105, the use of
Orkambi is prohibited from 4 weeks prior to the first study drug administration
until 28 days after last study drug administration. It should be noted that the
decision to consider a CF patient homozygous for F508del for inclusion in this
study should be weighed by the investigator against the potential benefit from
treatment with Orkambi. This evaluation has to be done on a case by case basis.
Furthermore, the study permits the use of Orkambi after completion of 28 days
of follow-up. Beyond this follow-up period, all compounds will be essentially
eliminated with the exception of M31. Based upon in vitro results, the
likelihood of clinically meaningful interaction for M31 with Orkambi (or other
concomitant medications) is expected to be low and is therefore not expected to
have an impact on Orkambi*s PK and/or effectiveness.

Results from in vitro TransEpithelial Clamp Circuit (TECC) assays on primary
human bronchial epithelial (HBE) cells derived from patients with the above
described CFTR mutations indicate the potential for substantial functional
improvement of CFTR activity when three CFTR modulator compounds are combined
(see investigator's brochures [IB]).1,2,3
Consequently, it is expected that a triple combination therapy of a potentiator
and two complementary corrector molecules can bring clinically meaningful
benefit to patients with CF.

GLPG2451 is a CFTR potentiator, GLPG2222 is a CFTR corrector, and GLPG2737 is a
second CFTR corrector (with a different and complementary mechanism of action
to GLPG2222). It is to be noted that the pharmacological activity of these
three compounds on CFTR protein is complemented by the activity of two
major active metabolites; i.e., metabolite G1171564 (M31) of GLPG2451 and
metabolite G1125498 (M4) of GLPG2737 (see IBs for more details).1,2,3
The main objectives of this Phase Ib clinical study are safety, tolerability,
PK and pharmacodynamics (PD) of repeated doses of the combination of GLPG2451
(a CFTR potentiator) and GLPG2222 (a first CFTR corrector), before and after
the addition of GLPG2737 (a second CFTR corrector), in adult CF subjects.

PRIMARY OBJECTIVES

Parts 1 & 2
* To assess safety and tolerability of the combination of GLPG2451 and
GLPG2222, with and without GLPG2737 in adult subjects with CF
* To characterize the PK of GLPG2451 and GLPG2222, with and without GLPG2737 (&
active metabolites)


Part 2 only
* To assess changes in PD biomarkers of CFTR activity after
administration of the combination of GLPG2451 and GLPG2222 and GLPG2737,
administered to adult CF subjects

3.2. SECONDARY OBJECTIVE

Part 1 only
* To assess changes in PD biomarkers of CFTR activity after
administration of the combination of GLPG2451 and GLPG2222, with or without
GLPG2737, administered to adult CF subjects

This is a Phase Ib, multi-center, open-label, nonrandomized multiple cohorts
study to assess the safety, tolerability, PK and pharmacodynamics of multiple
doses of a combination treatment of GLPG2451 and GLPG2222, with or without
GLPG2737, in adult subjects with CF.
the study will consist of a screening period of maximum 4 weeks (starting when
the subject has signed the informed consent form [ICF]), a treatment period of
4 weeks, and a follow-up period of 24 weeks. Enrolled subjects will come to the
clinical study center at screening, on Days 1 (baseline), 2/3*, 7, 14, 15, 21,
and 28 and at the follow-up visits scheduled up to 24 weeks after last study
drug administration. There are additional time points for PK sampling (Day 5,
Day 18 and Day 29). If needed, a study nurse may collect these PK samples at
the subject*s home.
* An additional Day 3 visit is foreseen for Part 2 only as the loading doses
for Cohorts B and C are administered on 3 consecutive days.
Dual combination (GLPG2451 and GLPG2222) will be administered for 14 days,
followed by the triple combination (GLPG2451, GLPG2222 and GLPG2737) for 14
days, without washout in between the sequential treatment periods.

Study drugs will be taken on Days 1 to 28 in the morning, with a breakfast or
snack. During the follow-up period, subjects will come to the clinical study
center for PK sampling and safety assessments on pre-defined days presented in
the flow charts, up to 168 days post last dose.

The most common GLPG2451 side effects that were reported in previous clinical
research studies are headache, common cold, shoulder pain, lower back pain,
loose stools, decreased appetite, increased energy and sore throat. No serious
adverse events (SAEs) were reported.
GLPG2451 and its active metabolite G1171564 (a product that is formed during
the break-down of the study drug GLPG2451 in the body) have long half-lives,
meaning that after you have taken the last dose of study drug it may take
approximately 5 to 6 months for the break-down product to be removed from your
body.
GLPG 2451 has been studied in animals for up to 26 weeks. In these studies,
some of the animals had side effects on the testes (the male sex gland that
produces and stores sperm). It is not known whether humans will have the same
side effects that may affect your ability to father a child. However most men
with cystic fibrosis are unable to have biological children because they do not
have a vas deferens (a tube in a man*s body that carry sperm away from the
testes towards the penis). Furthermore, based upon the doses that will be
administered, we believe the risk for you to develop adverse effects on your
testes is very low.
Based on the results of 26-week rat studies and the long half-lives of GLPG2451
and its active metabolite G1171564, we believe there is a potential risk that
you could develop clouding of the lens of the eye that can cause images to
appear blurry (eye lens opacities) following participation in this study.
However, based upon the doses that will be administered, we believe the risk
for you to develop lens opacities is very low. Furthermore, no cases of lens
opacity have been observed in any of the human volunteers that have received
GLPG2451 in previous clinical research studies. Yet, if you would experience
any worsening of your vision, it is important to tell the study doctor,
regardless of whether or not you think it has to do with the study.
Furthermore, you will be reviewed by an ophthalmologist (eye doctor) at
screening to make sure that you had no pre-existing lens opacities before the
study started and this examination will be repeated at the end of the dosing
period and the end of the study.
Additional ophthalmological evaluations can be planned when deemed clinically
relevant by your study doctor.

GLPG2222 has been tested in a limited number of human volunteers and patients
with cystic fibrosis. Previous clinical studies with GLPG2222 showed that the
most common side effect was headache. Other side effects reported were abnormal
physical weakness or lack of energy, thirst, diarrhea, stomach pain or
discomfort, inflammation of the stomach and intestine, cough, becoming markedly
red in the face and often other areas of the skin, inflammation of the eyes and
pruritis.

The most common GLPG2737 adverse events/side effects that were reported in
previous clinical research studies in human volunteers are dry mouth or throat
or skin, common cold, acne, sore throat, tiredness, skin irritation at site of
ECG electrodes, cannula site reaction and headache. No serious adverse events
(SAEs) were reported in these phase I studies.
Some human volunteers had mild elevations of liver enzymes (substances in the
blood that measure how well your liver is functioning). These levels improved
after they stopped taking GLPG2737. Some human volunteers also had a mild
decrease in myeloperoxidase, a substance found in white blood cells (immune
cells). It is not clear what the significance of this finding is but
myeloperoxidase may play a role in fighting infections. However, this finding
was not associated with any evidence of increased infection among volunteers
during the study period.
GLPG2737 has been studied in animals. Some animals developed side effects on
the stomach which may lead to decrease in stomach acid production that in turn
may affect digestion. These findings were reversible 2- 4 weeks after stopping
GLPG2737. It is not known whether GLPG2737 will lead to a decrease in stomach
acid in humans.

Known side effects of the combination of GLPG2451 and GLPG2222:
The combination of GLPG2451 and GLPG2222 was considered to be well tolerated.
The most common side effects of the combination of GLPG2451 and GLPG2222 that
were reported in a previous clinical research study are headache, diarrhea and
sore throat. No serious adverse events (SAEs) were reported.

Known side effects of the combination of GLPG2451, GLPG2222 and GLPG2737:
The combination of GLPG2451, GLPG2222 and GLPG2737 has not been given to humans
before and therefore no information about adverse events in humans is known.

There is a high unmet medical need for subjects with CF, including subjects
that are either homozygous or heterozygous for the F508del mutation (with a
potentiator non-responsive mutation on the second allele). For the
latter patient population, no CFTR modulator treatment options are
currently available.

Results from in vitro TransEpithelial Clamp Circuit (TECC) assays on primary
human bronchial epithelial (HBE) cells derived from patients with the above
described CFTR mutations indicate the potential for substantial functional
improvement of CFTR activity when three CFTR modulator compounds are combined
(see investigator's brochures [IB]).1,2,3
Consequently, it is expected that a triple combination therapy of a potentiator
and two complementary corrector molecules can bring clinically meaningful
benefit to patients with CF.