A Phase IIa, randomized, double-blind, placebo-controlled study to evaluate multiple doses of GLPG2222 in subjects with Cystic Fibrosis who are homozygous for the F508del mutation

Cystic fibrosis (CF) is an autosomal recessive genetic disease caused by
mutations in the gene encoding for the cystic fibrosis transmembrane
conductance regulator (CFTR) protein, a cAMP-regulated anion channel expressed
primarily at the apical plasma membrane of
secretory epithelia. Over 2,000 mutations in the CFTR gene (CFTR) have been
identified, which are grouped into 6 classes (class I-VI). The F508del mutation
is by far the most common CFTR mutation globally, especially in the Caucasian
population. Approximately 80 to 90% of CF patients in the United States and
Europe have at least one copy of this mutation on one allele, with almost half
of them being F508del homozygous (i.e. the mutation is present on both
alleles). The F508del mutation impairs CFTR folding, stability at the
endoplasmic reticulum and plasma membrane, and chloride gating. Thus, the
F508del mutation results in very little to no CFTR protein in the apical
membrane. CFTR dysfunction
results in viscid secretions that are difficult to clear, affecting most
exocrine glands, notably the pancreas, intestine, liver, and bile duct.
However, most morbidity and mortality results from dehydration of the airway
surface liquid and impaired airway mucociliary clearance, which leads to cycles
of bacterial infection, chronic inflammation, bronchiectasis and progressive
decline in pulmonary function. There is a high medical need for efficacious
therapeutic approaches to treat CF subjects with the F508del mutation.

CFTR modulators are compounds designed to repair the consequences of CFTR
mutations on protein expression and/or function. Overall, 2 types of
small-molecule CFTR modulators are being developed: corrector molecules that
are designed to restore proper protein folding and
allowing for increased surface expression, and potentiator molecules targeted
at improving chloride-channel gating function. In order to bring optimal
clinical benefit to the F508del CF population, a combination of a potentiator
and corrector(s) is needed. GLPG2222 is a CFTR
corrector in development for the oral treatment of CF and represents the second
component of a future potentiator/corrector(s) combination therapy targeting
the F508del CF population.

To evaluate the safety and tolerability of 4 different doses of GLPG2222
administered orally and q.d. for 29 days in adult subjects with CF who
are homozygous for the F508del CFTR mutation.

Secondary objectives:
To assess changes in biomarkers of CFTR activity.
To assess changes in respiratory symptoms.
To assess the pharmacokinetics (PK) of GLPG2222.

This is a Phase IIa, multi-center, randomized, double-blind,
placebo-controlled, parallel-groupstudy to evaluate 4 different doses of
GLPG2222 administered orally and q.d. for 29 days to adult male and female
subjects with a confirmed diagnosis of CF and homozygous for the
F508del CFTR mutation. Eligible subjects must be on a stable concomitant
medication regimen for at least 4 weeks prior to the first study drug
administration and agree to continue the same regimen for the duration of the
study.

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 2 weeks. Enrolled subjects will come to the
clinical study center at screening, on Day 1 (baseline), Day 15, Day 29, and at
the follow-up visit (2 weeks after the last study drug administration).
Approximately 50 evaluable subjects are planned to be included sequentially in
the study: the first 25 subjects will be assigned to Cohort A (i.e. subjects 1
to 25) and the next 25 subjects will be assigned to Cohort B (i.e. subjects 26
to 50). Subjects participating in Cohort A are not allowed to participate in
Cohort B. In each study cohort, subjects will be randomized in a 2:2:1 ratio to
receive:
* Cohort A: 50 mg GLPG2222, 100 mg GLPG2222 or placebo q.d. for 29 days.
* Cohort B: 200 mg GLPG2222, 400 mg GLPG2222 or placebo q.d. for 29 days.

Additionally, subjects can choose to
participate in the optional substudy, in which nasal brushings will be
collected.

Treatment with the study drug GLPG2222/placebo:
Cohort A: 50 mg GLPG2222, 100 mg GLPG2222 or placebo q.d. for 29 days.
Cohort B: 200 mg GLPG2222, 400 mg GLPG2222 or placebo q.d. for 29 days.

After single doses there were a total of eight TEAEs in the pooled placebo
group and a total of 13 TEAEs in the combined GLPG2222 groups. Headache was the
most common TEAE in both the pooled placebo group (5/8) and in the combined
GLPG2222 groups (5/13). In the pooled placebo group, there were two reports of
fatigue. All other TEAEs were reported only once in either treatment group,
respectively. After repeated dosing, there were a total of 10 TEAEs in the
pooled placebo group and 10 TEAEs in the combined GLPG2222 groups. Headache was
the most common TEAE in the placebo group (4/10), all other TEAEs were reported
only once in either treatment group, respectively. There was no evidence of a
dose-response relationship following single or repeated dosing.
No clinically significant findings in physical examination findings, vital
signs, clinical laboratory safety tests, FEV1, ECG morphology or ECG time
intervals were reported up to 600 mg dosing.

GLPG2222 does not meet the criteria for a compound with high potential for risk
of harm to subjects for the following reasons:
* The compound is a small molecule, not a biological.
* GLPG2222 shows a mean apparent half-life of 10 to 16h.
* The compound does not exhibit a highly species-specific action.
* GLPG2222 is not directed towards adaptive immune system targets, as confirmed
by the absence of relevant hematological changes and histopathological findings
in the immune organs, up to the NOAEL in the 4-week GLP toxicity studies.

There is a high medical need for efficacious therapeutic approaches to treat CF
subjects with the F508del mutation.