GLPG2737 in lumacaftor/ivacaftor-treated CF subjects homozygous for the F508del mutation: A randomized phase 2A trial (PELICAN).

BACKGROUND: Triple combinations of cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulators demonstrate enhanced clinical efficacy in CF patients with F508del mutation, compared with modest effects of dual combinations. GLPG2737 was developed as a novel corrector for triple combination therapy. METHODS: This multicenter, randomized, double-blind, placebo-controlled, phase 2a study evaluated GLPG2737 in F508del homozygous subjects who had been receiving lumacaftor 400mg/ivacaftor 250mg for ≥12weeks. The primary outcome was change from baseline in sweat chloride concentration. Other outcomes included assessment of pulmonary function, respiratory symptoms, safety, tolerability, and pharmacokinetics. RESULTS: Between November 2017 and April 2018, 22 subjects were enrolled and randomized to oral GLPG2737 (75mg; n=14) or placebo (n=8) capsules twice daily for 28days. A significant decrease from baseline in mean sweat chloride concentration occurred at day 28 for GLPG2737 versus placebo (least-squares-mean difference-19.6mmol/L [95% confidence interval (CI) -36.0, -3.2], p=.0210). The absolute improvement, as assessed by least-squares-mean difference in change from baseline, in forced expiratory volume in 1s (percent predicted) at day 28 for GLPG2737 versus placebo was 3.4% (95% CI -0.5, 7.3). Respiratory symptoms in both groups remained stable. Mild/moderate adverse events occurred in 10 (71.4%) and 8 (100%) subjects receiving GLPG2737 and placebo, respectively. Lower exposures of GLPG2737 (and active metabolite M4) were observed than would be expected if administered alone (as lumacaftor induces CYP3A4). Lumacaftor and ivacaftor exposures were as expected. CONCLUSIONS: GLPG2737 was well tolerated and yielded significant decreases in sweat chloride concentration versus placebo in subjects homozygous for F508del receiving lumacaftor/ivacaftor, demonstrating evidence of increased CFTR activity when added to a potentiator-corrector combination. FUNDING: Galapagos NV. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT03474042.

GLPG1837, a CFTR potentiator, in p.Gly551Asp (G551D)-CF patients: An open-label, single-arm, phase 2a study (SAPHIRA1).

BACKGROUND: Investigation of novel cystic fibrosis transmembrane conductance regulator (CFTR) potentiators, such as GLPG1837, for CF patients with gating mutations is challenging as trials require patients to withhold ivacaftor, the current standard of care. This study explored the feasibility of such a study and the impact of one-week ivacaftor withdrawal. METHODS: This open-label, single-arm study aimed to enrol 32 adults ≥18 years of age with CF and at least one p.Gly551Asp (G551D) mutation. Patients received three increasing GLPG1837 dosages twice-daily for two 7-day and one 14-day period following a one-week ivacaftor washout. The primary outcome was safety; secondary outcomes were changes in sweat chloride concentration, spirometry outcomes, and pharmacokinetics. RESULTS: Twenty-six patients enrolled; 24 completed the study. Adverse events were reported by 53.8-76.9% of patients (dosage-dependent), with respiratory adverse events most common. Mean sweat chloride concentrations decreased from 97.7 mmol/L (baseline) to 68.7 mmol/L (end of GLPG1837 treatment). In ivacaftor-pre-treated patients, mean sweat chloride concentrations rose from 42.5 mmol/L at screening to 98.5 mmol/L after ivacaftor washout. Levels were decreased following GLPG1837 treatment (to 68.8 mmol/L at treatment end). Percent predicted forced expiratory volume in 1 s declined from 73.3% at screening to 68.5% after ivacaftor washout but returned to screening level at treatment end (73.1%). CONCLUSIONS: Patient willingness to participate in the study suggests that the need for a short period of ivacaftor withdrawal may not be a barrier to development of novel potentiators, such as GLPG1837. A one-week ivacaftor washout was generally well tolerated, but resulted in a decline in lung function, which was reversed with GLPG1837 treatment to pre-washout levels. Combined with the concentration-dependent decrease in sweat chloride concentration, results show that GLPG1837 increases CFTR activity in G551D-CF patients. FUND: This work was supported by Galapagos NV. CLINICAL TRIAL REGISTRATION NUMBERS: NCT02707562; EudraCT 2015-003291-77.

CFTR activity is enhanced by the novel corrector GLPG2222, given with and without ivacaftor in two randomized trials.

BACKGROUND: Several treatment approaches in cystic fibrosis (CF) aim to correct CF transmembrane conductance regulator (CFTR) function; the efficacy of each approach is dependent on the mutation(s) present. A need remains for more effective treatments to correct functional deficits caused by the F508del mutation. METHODS: Two placebo-controlled, phase 2a studies evaluated GLPG2222, given orally once daily for 29 days, in subjects homozygous for F508del (FLAMINGO) or heterozygous for F508del and a gating mutation, receiving ivacaftor (ALBATROSS). The primary objective of both studies was to assess safety and tolerability. Secondary objectives included assessment of pharmacokinetics, and of the effect of GLPG2222 on sweat chloride concentrations, pulmonary function and respiratory symptoms. RESULTS: Fifty-nine and 37 subjects were enrolled into FLAMINGO and ALBATROSS, respectively. Treatment-related treatment-emergent adverse events (TEAEs) were reported by 29.2% (14/48) of subjects in FLAMINGO and 40.0% (12/30) in ALBATROSS; most were mild to moderate in severity and comprised primarily respiratory, gastrointestinal, and infection events. There were no deaths or discontinuations due to TEAEs. Dose-dependent decreases in sweat chloride concentrations were seen in GLPG2222-treated subjects (maximum decrease in FLAMINGO: -17.6 mmol/L [GLPG2222 200 mg], p < 0.0001; ALBATROSS: -7.4 mmol/L [GLPG2222 300 mg], p < 0.05). No significant effects on pulmonary function or respiratory symptoms were reported. Plasma GLPG2222 concentrations in CF subjects were consistent with previous studies in healthy volunteers and CF subjects. CONCLUSIONS: GLPG2222 was well tolerated. Sweat chloride reductions support on-target enhancement of CFTR activity in subjects with F508del mutation(s). Significant improvements in clinical endpoints were not demonstrated. Observed safety results support further evaluation of GLPG2222, including in combination with other CFTR modulators. FUNDING: Galapagos NV. Clinical trial registration numbers FLAMINGO, NCT03119649; ALBATROSS, NCT03045523.

Safety, tolerability, pharmacokinetics, and pharmacodynamics of GLPG1690, a novel autotaxin inhibitor, to treat idiopathic pulmonary fibrosis (FLORA): a phase 2a randomised placebo-controlled trial.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) causes irreversible loss of lung function. People with IPF have increased concentrations of autotaxin in lung tissue and lysophosphatidic acid (LPA) in bronchoalveolar lavage fluid and exhaled condensate. GLPG1690 (Galapagos, Mechelen, Belgium) is a novel, potent, selective autotaxin inhibitor with good oral exposure. We explored the effects of GLPG1690 in patients with IPF. METHODS: This was a randomised, double-blind, placebo-controlled phase 2a study done in 17 centres in Italy, Ukraine and the UK. Eligible patients were aged 40 years or older, non-smokers, not taking pirfenidone or nintedanib, and had a centrally confirmed diagnosis of IPF. We used a computer-generated randomisation schedule to assign patients 1:3 to receive placebo or 600 mg oral GLPG1690 once daily for 12 weeks. The primary outcomes were safety (adverse events), tolerability, pharmacokinetics, and pharmacodynamics. Spirometry was assessed as a secondary outcome. This trial is registered with ClinicalTrials.gov, number NCT02738801. FINDINGS: Between March 24, 2016, and May 2, 2017, 72 patients were screened., of whom 49 were ineligible and 23 were enrolled in eight centres (six in Ukraine and two in the UK). Six patients were assigned to receive placebo and 17 to receive GLPG1690. 20 patients completed the study after one in each group discontinued because of adverse events and one in the GLPG1690 group withdrew consent. Four (67%) patients in the placebo group and 11 (65%) in the GLPG1690 group had treatment-emergent adverse events, most of which were mild to moderate. The most frequent events in the GLPG1690 group were infections and infestations (ten events) and respiratory, thoracic, and mediastinal disorders (eight events) with no apparent differences from the placebo group. Two (12%) patients in the GLPG1690 group had events that were judged to be related to treatment. Serious adverse events were seen in two patients in the placebo group (one had a urinary tract infection, acute kidney injury, and lower respiratory tract infection and the other had atrioventricular block, second degree) and one in the GLPG1690 group (cholangiocarcinoma that resulted in discontinuation of treatment). No patients died. The pharmacokinetic and pharmacodynamic profiles of GLPG1690 were similar to those previously shown in healthy controls. LPA C18:2 concentrations in plasma were consistently decreased. Mean change from baseline in forced vital capacity at week 12 was 25 mL (95% CI -75 to 124) for GLPG1690 and -70 mL (-208 to 68 mL) for placebo. INTERPRETATION: Our findings support further development of GLPG1690 as a novel treatment for IPF. FUNDING: Galapagos.

The Burden of Severe Respiratory Syncytial Virus Disease Among Children Younger than 1 Year in Central and Eastern Europe.

INTRODUCTION: Globally, respiratory syncytial virus (RSV) is the most common cause of serious lower respiratory tract infections (LRTIs) in young children, and is a major cause of hospital admission in children <1 year of age. The study evaluated the severity of RSV-associated LRTI disease among premature (<36 weeks gestational age (GA)) and term children <1 year of age and assessed the influence of GA on outcomes of RSV LRTI hospitalization in Central and Eastern Europe (CEE). METHODS: Retrospective cohort survey of children <1 year of age hospitalized with an LRTI during the periods of October 2009 to April 2010 or October 2010 to April 2011 in 12 CEE countries. RESULTS: Across two RSV seasons, 3474 evaluable children were hospitalized because of LRTI; 757 (21.8%) were premature and 2679 (77.1%) were term. RSV tests were positive in 1423 (42.4%) cases, of which 266 (18.7%) were premature and 1034 (72.7%) were term children. Among the RSV-positive patients, premature children had a significantly longer hospital stay (17 vs 8 days; P < 0.001), were more frequently hospitalized in the intensive care unit (ICU) (41.4% vs 12.6%) and remained in the ICU significantly longer (13 vs 6 days; P < 0.001) compared with term children. Premature children had a 3.3-fold (95% CI, 2.66-4.09) increased risk for ICU hospitalization compared with term children (P < 0.001). ICU hospitalization, prolonged hospital stay, supplemental oxygen administration and death occurred significantly more frequently among children with lower vs higher GA. CONCLUSION: RSV infection is associated with substantial morbidity in CEE among premature and term children. The attributable morbidity, however, is significantly greater among premature children compared with term children, including longer hospital stays and more frequent and longer stays in the ICU. These findings are consistent with previously published data outside of CEE, demonstrating prematurity as a significant and independent predictor for severe RSV disease. FUNDING: AbbVie Inc.

Cost-minimization comparison of darunavir plus ritonavir and lopinavir/ritonavir in HIV-1 infected treatment-naïve women of childbearing age.

BACKGROUND: Guidelines from the Department of Health and Human Services in the US recommend ritonavir-boosted lopinavir (LPV/r) as a preferred protease inhibitor (PI) for HIV-positive antiretroviral-naїve pregnant women. These guidelines also cite ritonavir-boosted darunavir (DRV + RTV) as an alternative PI in this clinical scenario. The purpose of this analysis was to compare economic outcomes for regimens based on these two treatments. STUDY DESIGN: An existing discrete event simulation (DES) model was adapted to conduct a cost-minimization analysis comparing the two regimens in HIV-infected women of childbearing age (WOCBA), from the perspective of a healthcare payer in the US. METHODS: The DES model was used to represent disease states, health events, healthcare encounters, pregnancy, and treatment choices in HIV-infected WOCBA starting treatment with regimens based on either LPV/r or DRV + RTV. It also incorporated parameters for individual patient characteristics, and for antiretroviral (ARV) treatment effectiveness, treatment sequencing, clinical progression, and resource use. Potential events included scheduled physician visits; viral suppression; viral rebound; AIDS-related complications; CHD events; treatment discontinuation and switching; ARV treatment side-effects (SE); and death. The primary outcomes were discounted 5-year and 10-year healthcare costs. Alternative scenarios considered different rates of switching from DRV + RTV to LPV/r upon conception. RESULTS: Compared with DRV + RTV, LPV/r was associated with similar clinical outcomes while offering savings at the 5- and 10-year horizons (of $24,904 and $43,502 per patient, respectively), and in extensive sensitivity analyses. The main driver of the savings was the difference in cost between PIs. CONCLUSIONS: Starting HIV-infected ARV-treatment-naїve WOCBA on an LPV/r-based regimen is cost-saving and provides similar patient outcomes compared to a DRV + RTV-based regimen.