An exploratory, randomized, double-blind, placebo-controlled, multicenter study to evaluate the efficacy, safety, tolerability and pharmacokinetics of orally administered GLPG2737 for 52 weeks, followed by an open-label extension period of 52 weeks in subjects with autosomal dominant polycystic kidney disease (ADPKD).

Autosomal dominant polycystic kidney disease (ADPKD) is the most common
hereditary kidney
disease with an estimated prevalence of 1-5 in 10.000 individuals.
Its course is characterized by the development and inexorable expansion of
multiple cysts
scattered throughout the kidney parenchyma. Progressive loss of kidney function
takes place over
many decades and frequently leads to end-stage kidney disease during or after
the sixth decade of
life.
ADPKD is caused by loss-of-function mutation in the PKD1 or PKD2 genes that
encode
polycystin-1 (PC-1) and polycystin-2 (PC-2), respectively. In 75% of cases of
ADPKD, the
mutations occur in PKD1, 15% present mutations in PKD2, and the other 10% are
undetermined.
PC-1 is an important regulator of several signaling pathways, and PC-2 is a
non-selective calcium
channel. Mutations in PC-1 and PC-2 appear to disrupt intracellular calcium
regulation, leading
to reduced intracellular Ca2+ levels. It is believed that reduced intracellular
Ca2+ levels contribute
to the increased cyclic adenosine monophosphate (cAMP) levels observed in ADPKD
human
kidney epithelial cells. Increased levels of cAMP contribute to the progression
of
cystogenesis, by stimulating epithelial cell proliferation as well as by
stimulating fluid secretion.
cAMP-dependent anion secretion to the cyst lumen has been reported to be
mediated by the
luminal cystic fibrosis transmembrane conductance regulator (CFTR).

The mechanism underlying this regulation has not been totally elucidated,
although the CFTR
chloride channel has been shown to contribute to disease progression by driving
fluid secretion to
the cyst lumen, promoting cyst growth. Cyst and kidney growth is hypothesized
to cause loss of
functioning renal mass, and eventually leads to end-stage kidney disease.
GLPG2737 is a CFTR inhibitor. In vitro, CFTR inhibitors have been shown to
reduce cyst
growth in mouse and human cells of renal tubular origin. In vivo, CFTR
inhibitors have been shown to reduce cyst growth in models of
ADPKD, in conditional PKD1 knock-out (KO) mouse. In patients with both ADPKD
and cystic fibrosis (CF) with a deletion of
phenylalanine in position 508 of the CFTR (F508del-CFTR; lacking functional
CFTR), renal
function declines at a slower rate than that in family members who have ADPKD
alone.

Therefore it is expected that administration of the CFTR inhibitor GLPG2737 to
patients with
ADPKD will lead to a reduction in cyst growth, slowing down kidney volume
growth, and
reducing the rate of decline of renal function and delay progression to
end-stage kidney disease.

Main objective
- To characterize the effect of GLPG2737 on growth in total kidney
volume (TKV) compared to placebo.
- To evaluate the safety and tolerability of oral doses of GLPG2737
compared to placebo.

Secondary objectives:
- To characterize the effect of GLPG2737 on renal function (estimated glomerular
filtration rate; eGFR) compared to placebo.
- To characterize the pharmacokinetics (PK) of oral doses of GLPG2737
and its major metabolite G1125498 (M4) using population PK analyses.

An exploratory, randomized, double-blind, placebo-controlled, multicenter study
to evaluate the efficacy, safety, tolerability and pharmacokinetics of orally
administered GLPG2737 for 52 weeks, followed by an open-label extension period
of 52 weeks, in subjects with autosomal dominant polycystic kidney disease

Patients should visit the clinics and be willing to receive their study drug
comparator an/or placebo according to the dosing scheme. Furthermore their data
of Medical history and demographic data will be collected They must undergo
physicial and vital signs examinations. ECG and MRI tests will be done. made.
Blood and urine will be collected and a patient diary needs to be kept.

The study drug may reduce cyst growth, slowing down kidney volume growth, and
reducing the rate of decline of renal function, but this is not certain. The
disease may return or worsen at any time during this study.
In previous studies, GLPG2737 was well tolerated by healthy adults who took
single doses in the range of 25 mg to 600 mg, and daily doses for 14 days in
the range of 25 mg to 250 mg. The most common adverse effects in previous
studies were:
Dry mouth, throat, or skin
Inflammation of nose/throat
Acne
Sore throat
Tiredness
Headache


Participation in the study also means:
- additional time;
- additional or longer hospital visits;
- additional tests;
- instructions the patient need to follow.