What should be the approach for the ICH M11 Benefit/Risk Assessment in a Phase 1 clinical trial of CLXR-901 (humanized IgG1 monoclonal antibody) for treating plasmacytoid dendritic cell- and interferon-mediated autoimmune diseases?

ICH M11 Benefit/Risk Assessment for CLXR-901 Phase 1 Trial

Executive Summary

The benefit/risk assessment for this first-in-human trial of CLXR-901 should prioritize robust safety monitoring and risk mitigation strategies due to the potential for immune-related adverse events, while acknowledging the possible therapeutic benefit for patients with autoimmune diseases mediated by plasmacytoid dendritic cells and type I interferons.

Potential Benefits

Therapeutic Rationale

• CLXR-901 targets immunoglobulin-like transcript 7 (ILT7), a receptor exclusively expressed on plasmacytoid dendritic cells (pDCs)
• pDCs are specialized immune cells that produce large amounts of type I interferons (IFNs) 1
• Persistent activation of pDCs has been demonstrated in multiple autoimmune diseases 1, 2
• By selectively depleting pDCs, CLXR-901 may reduce pathological type I IFN production that drives autoimmune pathology

Potential Clinical Benefits

• Reduction in local type I IFN activity, which correlates with improvements in clinical disease activity in autoimmune conditions 1
• Targeting the pDC-IFN axis represents a novel therapeutic approach for autoimmune diseases where current treatments may be inadequate
• Similar approaches have shown that pDC depletion can reduce disease activity in patients with cutaneous lupus 1

Potential Risks

Immunological Risks

1. Immune-Related Adverse Events (irAEs)

   • As a monoclonal antibody targeting immune cells, CLXR-901 may cause immune-related adverse events similar to other immunotherapies 3
   • These could include dermatologic, gastrointestinal, hepatic, endocrine, and other organ system toxicities

2. Infection Risk

   • pDCs play a critical role in antiviral immunity through type I IFN production
   • Depletion of pDCs may potentially increase susceptibility to viral infections 4

3. Cytokine Release Syndrome

   • Antibody-dependent cellular cytotoxicity (ADCC) mechanism may trigger cytokine release
   • Grade ≥2 cytokine release syndrome is a potential risk factor in immunotherapy trials 5

Special Population Risks

1. Patients with Pre-existing Autoimmune Conditions

   • While the drug targets autoimmune pathology, patients with pre-existing autoimmune conditions may experience exacerbation of their disease 3
   • Approximately 27-42% of patients with pre-existing autoimmune conditions may experience flares when receiving immunomodulatory therapies 3

2. Patients with Chronic Infections

   • Patients with chronic viral infections (HBV, HCV, HIV) may have altered responses and potential risks 3

Risk Mitigation Strategies

Trial Design Elements

1. Dose Escalation and Cohort Expansion

   • Implement a conservative dose escalation scheme with adequate safety evaluation periods
   • Include sentinel dosing for initial cohorts
   • Establish clear dose-limiting toxicity criteria and stopping rules

2. Participant Selection

   • Exclude patients with:
     • Active or uncontrolled autoimmune diseases
     • Chronic viral infections unless adequately controlled
     • Baseline corticosteroid therapy (≥10 mg prednisone equivalent daily) 3
     • Abnormal baseline laboratory values (ALT >3x ULN, TBL >1.5x ULN) 3

3. Safety Monitoring

   • Implement comprehensive immunological monitoring
   • Establish baseline immunological parameters before treatment
   • Monitor for early signs of immune-related adverse events
   • Develop specific management algorithms for potential irAEs

Management of Potential Adverse Events

1. irAE Management

   • Develop specific protocols for management of immune-related toxicities
   • Grade 1-2 events: Consider temporary hold of treatment and monitoring
   • Grade 3-4 events: Permanent discontinuation and prompt immunosuppressive therapy (1-2 mg/kg/day prednisone or equivalent) 3

2. Infection Surveillance

   • Monitor for signs of new or reactivated infections
   • Consider prophylactic measures for patients requiring prolonged immunosuppression

Benefit/Risk Conclusion

The potential benefit of CLXR-901 in treating plasmacytoid dendritic cell- and interferon-mediated autoimmune diseases must be carefully weighed against the risks of immune-related adverse events and potential increased susceptibility to infections. Based on evidence from similar immunotherapeutic approaches 1, CLXR-901 has the potential to significantly reduce disease activity in targeted autoimmune conditions by depleting pDCs and reducing pathological type I IFN production.

Given that this is a first-in-human study in healthy participants, the primary focus must be on safety and tolerability. The proposed risk mitigation strategies, including careful participant selection, conservative dose escalation, and robust safety monitoring, should adequately address the identified risks while allowing assessment of the pharmacokinetic and pharmacodynamic properties of CLXR-901.

The benefit/risk assessment supports proceeding with the proposed Phase 1 trial with the implementation of the outlined risk mitigation strategies.