Our fibrosis programs
We are building a fibrosis portfolio with different modes of action, with an initial focus on IPF and aim to expand to other forms of organ and skin fibrosis. To this end, we are currently working on a number of drug candidates with distinct novel mechanisms of action, which are fully proprietary to us. In IPF, we believe that having multiple mechanisms of action within our own portfolio of candidates allows the exploration of combinations of therapies. We also recently expanded clinical research into SSc, and plan to explore additional fibrotic indications with our earlier stage compounds in 2019.
Moreover, we actively pursue business development opportunities in the space. In January 2019, we announced a global collaboration with Fibrocor, focused on a novel target for IPF and other fibrotic indications, followed by a collaboration with Evotec for an undisclosed target in fibrosis, announced in February.
The following is an overview of our IPF portfolio and expected clinical development in 2019:
IPF is a chronic, relentlessly progressive fibrotic disorder of the lungs that typically affects adults over the age of 40. According to GlobalData, IPF affects approximately 200,000 patients in the United States and Europe, and this population is expected to grow, in part thanks to improved diagnosis. Furthermore, prevalence is expected to increase with the aging population1https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3848422/. The clinical prognosis of patients with IPF is poor, as the median survival at diagnosis is two to four years. Currently, no medical therapies have been found to cure or stop the progression of IPF. The medical treatment strategy aims to slow disease progression and improve quality of life. Lung transplantation may be an option for appropriate patients with progressive disease and minimal comorbidities.
Regulatory agencies have approved Esbriet2Esbriet® (pirfenidone) is an approved drug for IPF, marketed by Roche/Genentech and Ofev3Ofev® (nintedanib) is an approved drug for IPF, marketed by Boehringer Ingelheim for the treatment of mild to moderate IPF. Both Esbriet and Ofev have been shown to slow the rate of functional decline in IPF and are gaining ground as the standard of care worldwide. Combined sales of both drugs reached $1.9 billion in 2017, with 74% of global revenues being in the United States. These regulatory approvals represent a major breakthrough for IPF patients; yet neither drug stops the decline in lung function, and the disease in most patients on these therapies continues to progress. Moreover, the adverse effects associated with these therapies are considerable (e.g., diarrhea, liver function test abnormalities with Ofev; nausea and rash with Esbriet). Therefore, there is still a large unmet medical need as IPF remains a major cause of morbidity and mortality. We estimate that the market of approved IPF drugs will grow to $5 billion by 2025.
Our IPF trials
Our most advanced IPF asset is our product candidate GLPG1690, a potent and selective inhibitor of ATX, which is fully proprietary to us. We identified ATX as a potential target for IPF, after finding the target using an inflammation assay in our target discovery platform. Pharmacology and translational studies published by other parties since then suggest that ATX may also play a role in metabolic disease, arthritic pain, oncology, and lung disease. Palmer et al published in Chest in 2018 on Bristol Meyers Squibb’s LPA1 inhibitor tested in Phase 2, showing activity in reducing loss of Forced Vital Capacity in mL (FVC) in IPF patients. LPA1 is downstream of ATX, supporting further evaluation of ATX inhibition. We evaluated GLPG1690 in a preclinical lung fibrosis model (bleomycin-treated mice) and observed effects on reducing the fibrotic score, numerically favoring GLPG1690 over Esbriet.
In August 2017, we announced positive topline results for our Phase 2a FLORA trial in IPF patients. This randomized, double-blind, placebo-controlled trial investigated a once-daily 600 mg oral dose of GLPG1690, administered for 12 weeks in 23 IPF patients, 17 of whom received GLPG1690 and six placebo. Primary objectives of the trial were to assess safety, tolerability, pharmacokinetics and pharmacodynamics of GLPG1690 in an IPF patient population. Secondary objectives included the evaluation of lung function, changes in disease biomarkers, functional respiratory imaging (FRI), and quality of life. The IPF diagnosis was confirmed by central reading.
Over the 12-week period, patients receiving GLPG1690 showed an FVC increase of 8 mL, while patients on placebo showed an FVC reduction of 87 mL (mean from baseline):
FVC: stabilization by ‘1690
In addition to the demonstrated absence of lung function decline over the 12 week period, sensitive FRI confirmed disease stabilization in the GLPG1690 arm, versus the expected disease progression in the placebo arm, reaching statistical significance on two specific parameters, despite the trial not being powered for significance:
FRI: airway volume & resistance
Significant difference between ‘1690 & placebo
Source: Mignot et al. ATS 2018
Patients on GLPG1690 treatment showed a clear reduction of serum LPA18:2, a biomarker for autotaxin inhibition, as expected based on the mechanism of action of GLPG1690. Thus, the level of target engagement observed in Phase 1 with healthy volunteers was confirmed in IPF patients in FLORA.
GLPG1690 was found to be generally well-tolerated in this Phase 2 trial. Rates of discontinuation due to adverse events, as well as serious adverse event rates, were similar between patients on GLPG1690 and placebo.
Following these encouraging results, in 2018 we announced the design of our worldwide Phase 3 program, ISABELA, based on feedback from the FDA and EMA. The ISABELA Phase 3 program consists of two identically designed trials, ISABELA 1 & 2, and plan to enroll a total of 1,500 IPF patients combined. Recruitment will be worldwide, with a significant proportion of patients in the U.S. and Europe. The program is intended to support application for a broad label in IPF in both the NDA and Market Authorization Application (MAA) submissions in, respectively, the U.S. and EU. Patients will continue on their standard of care and will be randomized to one of two doses of GLPG1690 or placebo. The primary endpoint will be the rate of decline of FVC (in mL) until week 52. Secondary assessments will include respiratory-related hospitalizations, mortality, quality of life, safety and tolerability.
All patients will continue on their treatment until the last patient in their respective trial has completed 52 weeks of treatment. Therefore, some patients will remain in the study for substantially longer than 52 weeks. This approach will allow assessment of less frequent clinical events that are otherwise difficult to assess in conventional clinical studies of one-year duration.
The following is an overview of the ISABELA trial design:
Phase 3 program ISABELA 1&2
- 1500 IPF patients total in two identical Phase 3 studies
- Patients remain on standard of care throughout
- Global program with U.S. & EU component
- Primary endpoint: FVC at 52 weeks
- Secondary: hospitalizations, mortality, quality of life, safety/tolerability
First patient dosing in ISABELA was announced in December 2018, and new centers are currently being opened, as recruitment efforts will continue throughout 2019.
We have received orphan drug designation for GLPG1690 in IPF from the FDA as well as from the European Commission.
The second product candidate for IPF in our pipeline is GLPG1205, currently in a Phase 2 trial called PINTA.
GLPG1205 is a fully proprietary small molecule selectively inhibiting GPR84, a target discovered by us. GLPG1205 showed a reduction in signs and symptoms in IPF animal models and has shown favorable tolerability in healthy volunteers and UC patients in previous trials.
PINTA is a randomized, double-blind, placebo-controlled trial investigating a 100 mg once-daily oral dose of GLPG1205. The drug candidate or placebo will be administered for 26 weeks in up to 60 IPF patients. Patients may remain on their local standard of care as background therapy. The primary objective of the trial is to assess the change from baseline (FVC in mL over 26 weeks compared to placebo. Secondary measures include FRI, safety, tolerability, pharmacokinetics and pharmacodynamics, time to major events, changes in functional exercise capacity, and quality of life. IPF diagnosis will be confirmed by central reading. Recruitment for PINTA is planned in 10 countries in Europe, North Africa, and the Middle East. The first patient dosing was announced in October 2018, and we expect to complete recruitment of this trial in the course of 2019.
PINTA Phase 2 in IPF
- 60 IPF patients on local standard of care
- Primary endpoint: forced vital capacity (FVC) at 26 weeks
- Secondary: safety, tolerability, broad range of measurements, incl. FRI
- Recruitment in 10 countries in Europe, North Africa, & Middle East
Recruitment completion targeted Q4 ‘19
Note: FRI = Functional respiratory imaging
Our fibrosis trials
Systemic sclerosis (SSc)
SSc is a severe autoimmune disease. One of the most visible manifestations is hardening of the skin. SSc affects approximately 95,000-155,000 patients in the U.S. and Europe, with a predominance of female patients (over 75%). Broadly speaking, there are two types of SSc: limited cutaneous SSc, where the skin involvement is restricted, and diffuse cutaneous SSc. In diffuse cutaneous SSc, which represents about 35% of the SSc patient population, skin thickening affects several body areas, and patients have a higher risk of developing fibrosis of various internal organs, such as the lung.
Currently, there are no approved drugs for this disease, which has one of the highest mortality rates among rheumatic diseases. Hence, SSc represents a significant unmet medical need. Current treatment mainly consists of immunosuppressive drugs and other symptom-alleviating therapies such as methotrexate or cyclophosphamide. These aim to avoid cutaneous fibrosis, interstitial lung disease and renal crisis.
NOVESA is a double-blind, placebo-controlled Phase 2a trial evaluating the efficacy, safety and PK/PD of GLPG1690 in patients with SSc. NOVESA is planned to recruit 30 patients with diffuse cutaneous SSc.
NOVESA Phase 2 in SSc
- 30 patients with progressive diffuse (multi-organ) SSc
- Recruitment in U.S. & 5 EU countries
- Primary endpoint: modified Rodnan Skin Score at 24 weeks
- Secondary & exploratory endpoints: safety, tolerability, broad range of measures (FVC, QoL, CRISS)
The primary endpoint of NOVESA is the modified Rodnan skin score (mRSS) at 24 weeks. The mRRS measures the skin thickness as a surrogate measure of disease severity and mortality, with an increase in thickness associated with involvement of internal organs and increased mortality. Secondary objectives and exploratory endpoints include FVC, quality of life, and other scores.
Early in 2019 we recruited our first patient for NOVESA.
2 Esbriet® (pirfenidone) is an approved drug for IPF, marketed by Roche/Genentech
3 Ofev® (nintedanib) is an approved drug for IPF, marketed by Boehringer Ingelheim