JNK inhibitor slows lung function decline in idiopathic pulmonary fibrosis

Key takeaways:

• Two different doses of CC-90001 vs. placebo slowed decline of percentage of predicted FVC at week 24.
• Researchers reported that the treatment was “generally well tolerated” by patients.

Patients with idiopathic pulmonary fibrosis had less lung function decline with an oral c-Jun N-terminal kinase 1, or JNK, inhibitor vs. placebo, according to results published in American Journal of Respiratory and Critical Care Medicine.

“This was supported by improvements in circulating biomarkers of fibrosis and a reduction in respiratory [adverse events] in the CC-90001 arms,” Waldo L. L. D. Mattos, medical expert at Universidade Federal de Ciências da Saúde de Porto Alegre, and colleagues wrote. “These results provide experimental support for the potential for inhibition of the JNK pathway in the treatment of fibrosing parenchymal lung disease.”

In a phase 2, randomized, double-blind, placebo-controlled trial, Mattos and colleagues analyzed 112 patients (mean age, 70.2 years; 77.7% men; 96.4% white) with IPF to determine the impact of CC-90001 vs. placebo on percentage of predicted FVC (ppFVC) and patient safety after 24 weeks.

Included patients could be on background antifibrotics (n = 24).

Of the total cohort, 39 patients received a once daily 200 mg dose of CC-90001, 37 received a once daily 400 mg dose of CC-90001 and 36 received placebo.

Researchers had full treatment period data for 91 patients (200 mg CC-90001, n = 32; 400 mg CC-90001, n = 28; placebo, n = 31); the remaining patients discontinued treatment before week 24.

Patients in both CC-90001 groups frequently reported adverse events as the reason for discontinuing treatment (200 mg, n = 4; 400 mg, n = 5), whereas patients in the placebo group commonly reported consent withdrawal (n = 2).

Efficacy

Between baseline and week 24, the greatest least-squares mean change in ppFVC was observed in the placebo group (–3.1%). Researchers found smaller declines in the 200 mg CC-90001 group (–2.1%; difference vs. placebo, 1.1%) and the 400 mg CC-90001 group (–1%; difference vs. placebo, 2.2%) at week 24.

After dividing the study population based on use of background antifibrotics, the only time a difference in least-squares mean change from baseline in lung function occurred was among patients without background antifibrotics between the placebo and 400 mg group (3%).

When assessing disease progression, 6-minute walk test changes and quality of life changes at week 24, researchers noted that the CC-90001 groups did not differ numerically from the placebo group.

At both week 4 and week 24, patients receiving either dose of CC-90001 had lower PRO-C3 and PRO-C6 concentrations (biomarkers of collagen synthesis) compared with baseline, as well as lower TNC concentrations (biomarkers of extracellular matrix remodeling).

Safety

Treatment-emergent adverse events occurred in 76.9% of patients receiving 200 mg CC-90001, 91.9% of patients receiving 400 mg CC-90001 and 86.1% of patients receiving placebo.

The CC-90001 groups frequently reported nausea (200 mg, 25.6%; 400 mg, 32.4%) and diarrhea (200 mg, 25.6%; 400 mg, 18.9%), both of which did not occur as often in the placebo group (nausea, 11.1%; diarrhea, 8.3%).

Patients receiving CC-90001 also reported vomiting more often than patients receiving placebo (200 mg, 12.8%; 400 mg, 18.9% vs. placebo, 0%).

In the placebo group, cough was the most reported treatment-emergent adverse event (30.6%), and this outcome occurred less frequently in the CC-90001 groups (200 mg, 15.4%; 400 mg, 10.8%).

Fewer patients receiving placebo had serious treatment-emergent adverse events than patients receiving 200 mg or 400 mg CC-90001 (5.6% vs. 15.4% vs. 10.8%).

Only patients from the CC-90001 groups had a serious adverse event related to the study drug. One patient from the 400 mg group experienced pancreatitis, and one patient from the 200 mg group had drug-induced liver injury.

Researchers reported one death in the 400 mg CC-90001 group and two deaths in the placebo group, all unrelated to the study treatment.

“Although CC-90001 may reduce the decline in ppFVC that occurs over time as a result of IPF progression, a larger study that is sufficiently powered is needed in order to draw firm conclusions about the treatment effect of CC-90001,” Mattos and colleagues wrote.