1. Poster available online at: www.glpg.com
Pharmacokinetics and safety of a novel CFTR corrector molecule GLPG2222 in Subjects with Cystic Fibrosis (CF): results from a phase Ib study C. Gesson1, K. De Boeck2, F. Vermeulen2, K. Conrath3, H de Kock3, D.E. Geller4, D. Kanters3, O. Van de Steen3 1 Galapagos SASU, 102 Avenue Gaston Roussel, Romainville, France 2 Pediatric Pulmonology, Department of Pediatrics, University of Leuven, Leuven, Belgium 3 Galapagos NV, Generaal de Wittelaan L11 A3, 2800 Mechelen, Belgium 4 AbbVie Inc., North Chicago, IL., USA
ECFS 2017
Poster #58
Introduction
GLPG2222 (GLPG2222/ABBV-2222) is a novel cystic fibrosis transmembrane conductance regulator (CFTR) corrector in clinical development for the treatment of cystic fibrosis (CF). In cellular assays, GLPG2222 was shown to be a potent corrector (Singh et al., NACFC 2016), partially restoring F508del CFTR cell surface expression when using a CFBe41o- cell line harbouring HRP-tagged F508del CFTR. In primary bronchial epithelial cells derived from patients homozygous for F508del, the combination of GLPG2222 and a CFTR potentiator restores the function of F508del CFTR and exhibits potent activity with an EC50<10nM. GLPG2222 represents one component of a future potentiator/corrector(s) combination regimen targeting a broad CF patient population. We present results from this first clinical study conducted in patients with CF.
Pharmacokinetic Results
Table 1: Pharmacokinetic Results in adult subjects with CF
PK Parameter
GLPG2222, 150 mg
N=6
GLPG2222, 300 mg
Cmax (µg/mL)
1.59 (54.8)
4.54 (23.7)
Tmax (h)
1.5 ( )
1.0 ( )
AUC0-24h (µg.h/mL)
10.7 (31.0)
28.5 (46.2)
C24h (µg/mL)
(49.7)
0.258 (71.5)
Objectives
Figure 2: Mean GLPG2222 plasma levels in adult Subjects with CF
To evaluate the pharmacokinetic (PK) profile, safety and tolerability of single oral doses of GLPG2222 in adult subjects with CF
Methods
Figure 1: Study Design
Single Dose
GLPG mg
Single Dose
GLPG mg
Single Arm, Open-Label
2-Treatment Period
Washout Period ≥ 7 days
Mean (±SE) GLPG2222 plasma levels after single oral dose as oral nanosuspension in fed state; linear (left) and semi-logarithmic (right) plots
Day 1
Day 2
Day 1
Day 2
Key Eligibility Criteria
Table 2: Comparison PK Results Subjects with CF vs healthy Subjects*
Male subject ≥ 18 years of age with confirmed clinical diagnosis of CF and FEV1≥40% of predicted normal
F508del mutation on one allele; class I or class II or class III mutation on the 2nd allele in the CFTR gene
Exocrine Pancreatic insufficiency
PK Parameter
GLPG2222, 150 mg
N=6 CF
Healthy Subjects
Cmax (µg/mL)
1.59 (54.8)
1.36 (19.6)
Tmax (h)
1.5 ( )
2.0 ( )
AUC0-24h (µg.h/mL)
10.7 (31.0)
9.92 (23.5)
C24h (µg/mL)
(49.7)
0.120 (37.6)
Baseline Characteristics
Safety results
Overall, single doses of GLPG2222 were generally well tolerated when administered to adult patients with CF
Three transient adverse events were reported, two were mild (cough and productive cough) and one was moderate (headache)
No clinically significant changes in safety laboratory parameters, ECGs, physical examinations, vital signs and spirometry outcomes were reported
Characteristic
All Subjects
N=6
Age (years)
28.5 (23-31)
Height (cm)
176.5 ( )
Weight (kg)
69.5 (60-84)
BMI (kg/m²)
22.9 ( )
Male Gender, n (%)
6 (100%)
* Cross-study comparison: First-In-Human study GLPG2222 in Healthy Subjects
Conclusions
GLPG2222 given as an oral suspension was rapidly absorbed in CF patients (tmax 1.0 to 1.5 h). Overall, no marked deviation in dose-proportionality is observed on the PK of GLPG2222 in CF patients (2.7 to 2.9-fold increase in exposure (Cmax, AUC0-24h and C24h) for a 2-fold increase in dose).
Overall, PK of GLPG2222 is similar between healthy subjects and subjects with CF after single oral administration of 150 and 300 mg.
Ongoing Clinical Studies with GLPG2222
ALBATROSS: randomized, double-blind, placebo-controlled, parallel group study to evaluate 2 doses of GLPG2222 in adult subjects with CF harbouring a gating (class III) mutation and on stable treatment with ivacaftor (NCT )
FLAMINGO: randomized, double-blind, placebo-controlled, parallel group study to evaluate 4 doses of GLPG2222 in adult subjects with CF homozygous for the F508del CFTR mutation (NCT )
References
Van de Steen O, et al NACFC 2016
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