Ziritaxestat fails to improve lung function in patients with idiopathic pulmonary fibrosis

Key takeaways:

• Patients with idiopathic pulmonary fibrosis taking ziritaxestat vs. placebo saw no improvement in lung function or clinical outcomes.
• Increased mortality rates were found among patients receiving ziritaxestat.

WASHINGTON — In patients with idiopathic pulmonary fibrosis, yearly lung function decline rates did not improve with two different dosages of ziritaxestat, according to an American Thoracic Society International Conference presentation.

“Unfortunately, ziritaxestat did not improve clinical outcomes compared with placebo in patients with IPF receiving standard of care,” Toby M. Maher, MD, PhD, professor of clinical medicine at Keck School of Medicine of USC, said during the presentation. “I would, however, argue that this was an important study. It is the first phase 3 study in the advent of effective antifibrotic drugs, and even though we haven’t got a new drug to report for IPF patients, we have learned a lot about delivering phase 3 trials going forward.”

In two randomized, multicenter phase 3 trials (ISABELA 1 and ISABELA 2), Maher and colleagues analyzed 1,306 patients with IPF taking pirfenidone (Esbriet, Genentech), nintedanib (Ofev, Boehringer Ingelheim) or neither for at least 2 months to measure the annual rate of FVC decline when they received ziritaxestat, an autotaxin inhibitor, vs. placebo.

Notably, the independent data and safety monitoring committee ordered early termination of both trials on the account of poor outcomes with ziritaxestat, according to the study.

The ISABELA 1 trial was made up of 525 patients (mean age, 70 years; 82.4% men), whereas ISABELA 2 consisted of more patients (n = 781; mean age, 69.8; 81.2% men).

Within the first trial, 174 patients were treated with 600 mg of ziritaxestat, 175 were treated with a 200 mg dose and 174 were treated with placebo. In the second trial, 259 patients took the 600 mg dose, 260 took the 200 mg dose and 258 took the placebo.

Since both trials demonstrated negative results, Maher highlighted data pooled from both trials when discussing outcomes during the presentation.

Lung function decline

Compared with patients receiving placebo, patients receiving 200 mg of ziritaxestat had higher least-squares mean annual FVC decline (–165.7 mL; 95% CI, –194.9 to –136.4 mL vs. –173.7 mL; 95% CI, –202.7 to –144.7 mL). On the other hand, patients receiving 600 mg of ziritaxestat had lower least-squares mean annual FVC declines compared with placebo patients (–156.5 mL; 95% CI, –186.2 to –126.7 mL vs. –165.7 mL; 95% CI, –194.9 to –136.4 mL); however, researchers reported that the treatment did not improve this outcome.

Researchers also evaluated yearly lung function decline across the treatment groups based on the patient’s background therapy or lack of one. During his presentation, Maher said that among patients receiving placebo, those on pirfenidone had a least-squares mean annual FVC loss of 189 mL (95% CI, –231.6 to –146.3 mL), those on nintedanib had a loss of 163.1 mL (95% CI, –205.7 to –120.5 mL) and those on neither therapy had a loss of 149.1 mL (95% CI, –199.5 to –98.6 mL).

“I think one of the interesting parts of this study is that the patients we are seeing recruited into trials now that we have antifibrotic therapies available have changed compared to those that were recruited in 2014 before we had any approved treatments,” Maher said during the presentation.

Secondary outcomes

In addition to lung function decline, researchers analyzed differences between treatment groups in terms of disease progression, time to first respiratory-related hospitalization and St. George’s Respiratory Questionnaire scores.

When assessing disease progression and changes in St. George’s Respiratory Questionnaire scores, researchers said that each treatment group demonstrated comparable results with one another at week 52. Compared with patients receiving placebo, more patients receiving either dose of ziritaxestat were hospitalized for a respiratory-related issue.

Additionally, increased mortality rates were found among patients receiving the drug. Compared with placebo patients, more all-cause mortality was observed in patients receiving 600 mg of ziritaxestat (ISABELA 1, 6.3% vs. 8%; ISABELA 2, 4.7% vs. 9.3%), as well as in patients receiving the 200 mg dose in the ISABELA 2 trial (4.7% vs. 8.5%).

Across all treatment groups, the percentage of patients who experienced treatment-emergent adverse events, as well as severe events, was similar, Maher said.

Maher added that gastrointestinal disorders were found to occur most frequently in patients who received ziritaxestat (ISABELA 2: 600 mg, 81.1% of patients; 200 mg, 85.8% of patients), especially those who were also on nintedanib.

“It’s worth noting that ziritaxestat has a drug-drug interaction with nintedanib, and it actually increases plasma exposure to the nintedanib,” Maher said during the presentation. “So, when you look at the breakdown of adverse events, the majority of nausea and diarrhea occurred in patients on nintedanib, presumably because we were increasing plasma exposure to a drug that has a known dose relationship with diarrhea.”

“We’re still digging into the data and doing more work with the blood samples and the biomarkers to try and understand what it was that led to failure in this study,” Maher concluded.

Reflecting on negative results, future trials

When commenting on why JAMA published this study with negative results, George T. O'Connor, MD, chair of the session, said those in the pulmonology field, specifically those treating patients with IPF, knew about the trial and were anticipating the findings.

“At JAMA, our role is to be neither happy nor unhappy with the results of the trial but to identify important studies that are well done and present the scientific evidence,” O’Connor said. “This trial was clearly negative in multiple endpoints, with even a possibility of an adverse effect. Our content reviewers indicated to us that the field had been awaiting the results of this trial, so it appears to be an important trial though negative, and really done quite rigorously, a very impressive ran multicenter, randomized clinical trial to run in parallel.”

On the topic of the negative results of this study and barriers involved in future trials investigating IPF treatments, O’Connor discussed an accompanying editorial by Anna J. Podolanczuk, MD, MS, assistant professor of medicine at Weill Cornell Medicine, and colleagues.

“[The editorial] puts out some of the challenges which Dr. Maher has alluded to, for example, patients in a randomized clinical trial of IPF now will be treated with nintedanib, pirfenidone or perhaps neither because they didn’t want to take it or didn’t tolerate it,” O’Connor said. “Heterogeneity of response, therefore, needs to be considered in terms of these different subgroups. [Maher] already mentioned there’s an interaction with nintedanib and ziritaxestat. Future therapeutics could also have interactions with one or the other.”

References:

• Maher TM, et al. JAMA. 2023;doi:10.1001/jama.2023.5355.
• Podolanczuk AJ, et al. JAMA. 2023;doi:10.1001/jama.2022.23955.