Last updated May 26, 2022, by Marta Figueiredo, PhD
 Fact-checked by Joana Carvalho, PhD
What is ziritaxestat for PF?
Ziritaxestat (GLPG1690) is an orally available small molecule that was being investigated as a potential treatment for idiopathic pulmonary fibrosis (IPF).
Its development was discontinued in 2021, however, after an analysis found that the therapy’s potential benefits did not offset its possible risks.
Galapagos, which had discovered ziritaxestat, also at that time stopped the therapy’s development for all indications, including as a potential treatment for scleroderma, an autoimmune disease characterized by inflammation and scarring, or fibrosis.
These decisions were based on the recommendation of an Independent Data Monitoring Committee, which concluded that ziritaxestat’s benefit-risk profile no longer supported the therapy’s advancement. The committee had reviewed data from two Phase 3 trials for IPF.
Galapagos had in-licensed ex-European rights to ziritaxestat to Gilead Sciences in 2019 as part of a 10-year collaboration between the two companies. Under that agreement, Gilead was sharing Phase 3 trial costs and had been granted access to Galapagos’ therapeutic platform.
How does ziritaxestat work?
Ziritaxestat worked by suppressing the activity of autotaxin, an enzyme involved in the production of lysophosphatidic acid (LPA), a fatty signaling molecule with pro-fibrotic effects. Notably, the levels of both autotaxin and LPA are elevated in the lungs of people with IPF, and are associated with fibrotic conditions.
By blocking autotaxin, the therapy was expected to reduce LPA levels and its pro-fibrotic signals, ultimately halting or slowing tissue fibrosis.
Ziritaxestat in clinical trials
After showing promise in animal models of IPF, ziritaxestat was initially evaluated in a first-in-human Phase 1 trial (NCT02179502) involving 40 healthy men. The participants, recruited at a single center in Belgium, received either single or multiple ascending oral doses of the therapy, or a placebo.
Results showed that both the therapy’s single and multiple doses were generally safe and well-tolerated, had a favorable pharmacological profile, and resulted in a dose-dependent drop in LPA levels — providing proof-of-concept of its mechanisms of action.
FLORA Trial
The Phase 2a FLORA trial (NCT02738801) was conducted across study sites in Italy, Ukraine, and the U.K. Ziritaxestat, in a 600 mg dose, was tested against a placebo in 23 adults with IPF. The participants were not on Ofev (nintedanib) or Esbriet (pirfenidone) — two approved oral treatments for IPF.
The study’s results showed that three months of treatment with ziritaxestat were generally safe and well-tolerated, and effectively prevented lung function decline, as assessed with forced vital capacity (FVC). Of note, FVC is a lung function parameter that measures the maximum amount of air a person can forcibly exhale after a deep breath.
Specifically, mean FVC values were increased in ziritaxestat-treated patients, but reduced in those given a placebo.
ISABELA program
Based on the promising Phase 2a findings, Galapagos launched the global ISABELA program. It comprised two identical Phase 3 trials: ISABELA 1 (NCT03711162) and ISABELA 2 (NCT03733444). Together, they enrolled about 1,300 IPF patients, ages 40 and older, who were diagnosed within five years prior to enrollment.
Patients were randomly assigned to receive an oral tablet of either one of two doses of ziritaxestat (200 or 600 mg) or a placebo, once a day for one year.
Those on a stable dose of Ofev or Esbriet for at least two months before screening were allowed to continue treatment. This way, the trials could determine the therapy’s potential over a placebo not only when given alone, but also in combination with standard IPF treatment.
The main goal was to assess changes in lung function decline, as assessed with FVC, while key secondary goals included evaluating changes in disease progression, time to first respiratory-related hospitalizations, and quality of life.
In February 2021, Galapagos and Gilead decided to suspend the ISABELA program based on recommendations from the trials’ independent data monitoring committee. After reviewing data from both studies, the committee concluded that ziritaxestat’s potential benefits did not outweigh its possible risks. Subsequently, the committee recommended that both studies should stop.
Common side effects of ziritaxestat
According to clinical trial data, the most common side effects of ziritaxestat in IPF patients included lower respiratory tract infections, common cold, cough, and gastrointestinal problems. Notably, these side effects were reported at similar or inferior rates relative to those in patients on a placebo.
Pulmonary Fibrosis News is strictly a news and information website about the disease. It does not provide medical advice, diagnosis, or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.
