The novel autotaxin inhibitor ziritaxestat has failed to improve clinical outcomes in patients with idiopathic pulmonary fibrosis (IPF), marking a key setback in the quest to find new therapies to manage the condition.
The drug is a small-molecule, selective inhibitor of autotaxin, the enzyme responsible for the production of lysophosphatidic acid, the downstream signalling of which mediates responses to tissue injury and has been implicated in the pathogenesis of fi- brotic conditions such as idiopathic pulmonary fibrosis and systemic sclerosis.
Two Phase III randomised trials, ISABELA 1 and ISABELA 2 – in which 1,306 patients with mild to moderate IPF were randomised to receive either ziritaxestat 600 mg or 200 mg – were stopped early after safety concerns and evidence suggesting a lack of efficacy.
According to the data, ziritaxestat failed to reduce the 52-week rate of decline for forced vital capacity (FVC) compared to placebo at either dose, both in patients receiving standard treatment with pirfenidone or nintedanib and in those who weren’t.
Data from both trials also showed numerically higher all-cause mortality rates for ziritaxestat 600mg than placebo, according to JAMA-published paper led by consultant respiratory physician Professor Toby Maher, also British Lung Foundation Chair in Respiratory Research and NIHR Clinician Scientist.
Pooled data from both trials showed an all-cause mortality rate of 8.9% for ziritaxestat 600mg, 7.0% with ziritaxestat 200mg, and 5.5% with placebo, while there was a greater proportion of patient deaths in the highest treatment group in ISABELA 1 and both doses in ISABELA 2.
The autotaxin inhibitor also failed to show a significant benefit on the secondary outcome of disease progression and was linked to worse outcomes versus placebo on others, including time to first respiratory-related hospitalisation, time to respiratory-related mortality and first acute IPF exacerbation.
Potential limitations of the ISABELA trials were highlighted by the investigators, including the fact that they were terminated early, that ISABELA 1 had incomplete enrolment and missing data because of the COVID pandemic.
However, the authors said the negative findings were somewhat surprising given its success at reducing FVC decline in prior Phase 2a research.
“It is unknown why the positive results of the prior phase 2a study were not replicated in the ISBAELA trials, but the limitations associated with early phase trials such as small sample sizes, short duration, and limited use of standard of care therapies may be contributing factors,” they said.
In a linked editorial, a group of international pulmonary specialists said the failure of the drug in Phase III “provides important lessons for future clinical trials in IPF”, and underscores the need for late-phase clinical trials to be “based on robust and high-quality preclinical and clinical data”.
For one, the earlier Phase 2a trial “did not allow for use of background antifibrotic therapy even though ziritaxestat increases plasma levels of nintedanib,” while “the small sample size and short duration of the phase 2a trial were significant limitations”, they said.
“Future phase 2 trials must be sufficiently powered to assess safety and heterogeneity of treatment response in the setting of background antifibrotic therapy,” they stressed.
Going forward, they also suggested use of a short-term (3-month) change in FVC to improve the efficiency of IPF clinical trials, and stressed that consideration of racial, ethnic, geo-graphic, and sex differences in disease pathogenesis and response to therapy should be considered.
“It is our hope that innovative approaches to clinical trials will improve their efficiency and safety while accelerating the approval of effective therapies so that patients living with IPF may benefit,” the editorialists said.