Insights from the Phase 2 SPRING Trial: Nebokitug for Primary Sclerosing Cholangitis

The Phase 2 SPRING trial finds Nebokitug produces dose-dependent biomarker improvements in primary sclerosing cholangitis (PSC), with the 20 mg/kg dose showing the clearest signal and an acceptable tolerability profile—supporting further clinical development.

SPRING was a double-blind, placebo-controlled Phase 2 study that randomized 76 patients to intravenous Nebokitug 10 mg/kg, 20 mg/kg, or placebo every three weeks for 15 weeks. The trial was powered for safety and tolerability as the primary endpoint, with prespecified mechanistic biomarker secondary endpoints including ELF score, PRO-C3, and liver stiffness measurement (LSM). About half the cohort met criteria for moderate/advanced fibrosis, and the protocol included planned subgroup analyses and an extension option for responders. The randomized, placebo-controlled design and the use of multiple validated biomarkers strengthen the interpretation of coherent biological signals.

Nebokitug produced numerical improvements across inflammation and fibrosis biomarkers, most markedly at 20 mg/kg. At week 15, approximately half of patients in the 20 mg/kg arm showed improvements in ELF score, PRO-C3, and LSM versus none in placebo; LSM reductions reached statistical significance in the moderate/advanced fibrosis subgroup. Reductions in ELF and PRO-C3 were sustained among patients who continued treatment into the extension, and LSM trends were consistent with a potential slowing of fibrotic progression. These biomarker changes suggest possible disease‑modifying activity, while recognizing that biomarker response is not the same as proven clinical benefit.

Safety was acceptable through the randomized phase and the extension, with no new safety signal identified and a high rate of continuation into the open-label extension out to 48 weeks. Adverse events were generally manageable and occurred at similar frequency to placebo during the double-blind period; the report did not identify treatment-limiting events that would preclude further study. Overall, the safety profile supports progression to later-phase testing.

Development implications are immediate: a confirmatory Phase 3 program should prioritize the 20 mg/kg dose, embed clinically meaningful primary endpoints (for example, clinical events or transplant‑free survival), and prespecify stratification by fibrosis stage to preserve the signal seen in the moderate/advanced subgroup. Biomarkers can be used for interim assessments and cohort enrichment to improve efficiency, but the pivotal program must be designed to test whether the observed biological effects translate into measurable clinical benefit for patients with PSC.