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

Summary

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.

Introduction

Autotaxin is the primary enzyme responsible for the production of lysophosphatidic acid (LPA),¹ which is essential for a diverse range of cellular processes. LPA and autotaxin have been implicated as key factors in several disorders and pathologies.¹ Increased autotaxin concentrations have been found in lung tissue in people with idiopathic pulmonary fibrosis (IPF), and increased concentrations of LPA have been found in bronchoalveolar lavage fluid (BALF) and exhaled breath condensate,2, 3 suggesting that the autotaxin-LPA pathway has a pathogenic role in this disorder. Autotaxin inhibition might be a novel therapeutic target in the treatment of IPF.

IPF is characterised by progressive accumulation of collagen scar tissue in the lungs that leads to irreversible loss of lung function⁴ and in most patients death due to respiratory failure.⁵ Prognosis is poor,5, 6 with 5 year survival of 20–30%.⁵ The cause of IPF remains poorly understood. Based on pivotal phase 3 trial results,7, 8, 9 the antifibrotic treatments pirfenidone and nintedanib received approval worldwide for the treatment of IPF. Both agents slow disease progression,10, 11 but neither stabilises or improves lung function, and both therapies have tolerability issues and substantial discontinuation rates.7, 8, 9, 12, 13, 14 As such, an unmet need exists for more effective and better tolerated novel therapies.

Research in context

Evidence before this study

We searched PubMed with the term “idiopathic pulmonary fibrosis” for articles that were published from Jan 1, 2000, to Jan 29, 2018, and contained the term in the title or abstract. Of the 5443 articles retrieved, 180 were clinical trials. After excluding those that listed nintedanib or pirfenidone in the title or abstract, 145 articles remained. Among these, multiple potential pharmacotherapies for idiopathic pulmonary fibrosis (IPF) were discussed, including interferon, immunoglobulin, N-acetylcysteine, recombinant human pentraxin-2, thrombomodulin, ciclosporin, antibodies against CD20 or tumour necrosis factor, octreotide, bosentan, colchicine, everolimus, imatinib, lecithinised superoxide dismutase, collagen, endothelin-A-receptor antagonists, polymyxin-B-immobilised fibre, warfarin, heparin, C-C motif chemokine-2 inhibitors, tyrosine-kinase inhibitors, and Feiwei granules. The breadth of targets under investigation for these drugs highlights the pressing need for novel therapies for the treatment of IPF and the interest in this field.

Added value of this study

We believe this study to be unique among IPF clinical trials because it reports phase 2 results, including innovative endpoints, for a treatment with a novel mechanism of action in IPF. This small proof-of-concept study was intended to bridge the gap between the early pharmacokinetic and pharmacodynamic findings for GLPG1690 (Galapagos, Mechelen, Belgium) and assess its characteristics in people with IPF before moving to larger trials.

Implications of all the available evidence

Our results and the previous preclinical and phase 1 data support the further development of GLPG1690 for the treatment of patients with IPF. Longer-term data will provide further insights into the potential of GLPG1690 to address the unmet need in the treatment of IPF, including therapies with improved tolerability that are able to halt disease progression.

GLPG1690 (Galapagos, Mechelen, Belgium) is a potent and selective inhibitor of autotaxin that in rats has been associated with reduced concentrations of LPA C18:2 species in plasma after oral administration.¹⁵ Compared with pirfenidone, GLPG1690 was significantly superior in reducing the Ashcroft fibrotic score at prophylactic¹⁵ and therapeutic¹⁶ doses in mice with bleomycin-induced pulmonary fibrosis. An additive inhibitory effect on profibrotic mediators was seen in ex-vivo assessment of fibroblasts isolated from IPF lung tissue after use of combined GLPG1690 and nintedanib.¹⁷ A phase 1 first-in-human study showed that GLPG1690 had good oral exposure and was generally well tolerated.¹⁸ Plasma concentrations of LPA C18:2 decreased with increasing concentrations of GLPG1690.¹⁸

The evidence implicating autotaxin and LPA in IPF and the efficacy and tolerability issues associated with current IPF treatments suggest that GLPG1690 could provide a novel treatment option for IPF. In this study we aimed to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of GLPG1690 in people with IPF. We additionally explored efficacy, biomarkers, functional respiratory imaging, and health-related quality of life.