Will Chemomab start a Phase 3 trial of nebokitug (CM‑101) in patients with primary sclerosing cholangitis, and are there any other disease‑modifying therapies under development for primary sclerosing cholangitis?

Nebokitug Phase 3 Status and Disease-Modifying PSC Therapies

Nebokitug (CM-101) has completed Phase 2 trials showing tolerability and promising biomarker improvements in PSC patients with moderate/advanced fibrosis, but there is no publicly available evidence in the provided literature confirming initiation of Phase 3 trials. 1

Current Status of Nebokitug

The SPRING Phase 2 study enrolled 76 PSC patients who received nebokitug (an anti-CCL24 monoclonal antibody) at 10 mg/kg or 20 mg/kg IV every 3 weeks for 15 weeks, followed by an open-label extension up to 48 weeks 1. Key findings include:

• Safety profile: Well tolerated with no new safety signals through 48 weeks of treatment
• Efficacy signals: In the prespecified subgroup with moderate/advanced fibrosis (n=35), patients showed significant reduction in liver stiffness measurements (LSM)
• Overall population: No significant changes in liver tests, enhanced liver fibrosis (ELF) scores, or LSM in the total treatment population at week 15

The drug demonstrated biological activity specifically in patients with more advanced disease, suggesting a potential targeted population for future trials 1. However, the provided evidence does not confirm whether Chemomab has announced or initiated Phase 3 trials.

Disease-Modifying Therapies Currently in Development

The landscape for PSC treatment remains challenging, as current guidelines explicitly state that no drug treatments alter the outcome of classic PSC 2. However, multiple disease-modifying agents are under investigation:

Agents in Active Clinical Development:

1. Vancomycin (oral)

• Only agent demonstrating promising therapeutic effects in Phase 3 trials 3
• Targets gut microbiome alterations implicated in PSC pathogenesis
• Most advanced in the pipeline with consistent positive signals

2. Nor-ursodeoxycholic acid (norUDCA)

• Targets bile acid signaling pathways
• Currently in clinical trials 2, 4
• Different mechanism than standard UDCA (which is not recommended for PSC treatment) 2

3. Farnesoid X receptor (FXR) agonists

• Including obeticholic acid
• Target bile acid regulation 2, 4
• Multiple agents in this class under investigation

4. Bile salt transporter protein inhibitors

• Novel mechanism targeting bile acid absorption 2

5. Monoclonal antibody therapies (beyond nebokitug)

• Various targets related to inflammatory and fibrotic pathways 2, 4

Critical Context from Guidelines:

The 2022 EASL guidelines emphasize that drug development pipelines are significantly hampered by the shortage of consensus endpoints with proven relevance to risk of liver transplantation and death 5. This creates a major barrier to pharmaceutical industry interest and trial design.

Five priority research areas identified 5:

1. Early PSC diagnosis tools (minimal fibrosis detection)
2. Early cholangiocarcinoma detection in PSC
3. Endpoint clarification for Phase II/III trials
4. Pathophysiology and causal factors
5. Proof-of-concept clinical trials with patient-reported outcomes

Important Caveats:

• Most Phase 3 trials for PSC have been disappointing except vancomycin 3
• No established medications exist with efficacy and safety confirmed by Phase IV trials 3
• Current treatment remains symptomatic only: managing pruritus with cholestyramine, treating complications like dominant strictures endoscopically, and ultimately liver transplantation for end-stage disease 2
• Patients meeting inclusion criteria should be offered referral to centers participating in clinical trials 2

The search for disease-modifying PSC treatments continues actively, with multiple mechanisms under investigation targeting bile acid pathways, immune dysregulation, gut-liver axis, and fibrosis 3, 4, 6. However, the field awaits validation of surrogate endpoints that reliably predict transplant-free survival before breakthrough therapies can be definitively established.