A75-24 Targeting Tnf-α to Preserve Lung Function in Pulmonary Sarcoidosis: Results From a Phase 1b/2a Multiple-ascending-dose Trial of Xtmab-16

Introduction

Sarcoidosis is a chronic, systemic rare disease that can cause multi-organ dysfunction and diminished quality of life (Saketkoo et al, 2021). Its clinical course is widely variable, and no approved drugs have been developed specifically for sarcoidosis, representing an unmet need. Treatment goals are focused on suppressing inflammation-induced organ dysfunction while avoiding comorbidities and toxic side effects. However, these measures may be misleading as many patients continue to feel unwell despite objective improvement (Drent et al, 2021).

Rationale

Tumor necrosis factor-alpha (TNFα) is a key pro-inflammatory cytokine implicated in granuloma formation and disease persistence in sarcoidosis. XTMAB-16 is a monoclonal antibody targeting TNFα with a differentiated molecular profile. In preclinical translational work, XTMAB-16 significantly inhibited non-caseating granuloma formation, supporting mechanistic relevance in sarcoidosis (Offman et al, 2023). We report results from Part A of a Phase 1b/2 trial evaluating the safety, pharmacokinetics (PK), and preliminary efficacy of XTMAB-16 in patients with pulmonary sarcoidosis requiring systemic corticosteroids and second-line immunosuppressive therapy.

Methods

XTMAB-16-201 Part A was a randomized, double-blind, placebo-controlled, multi-ascending-dose trial (NCT05890729) of 39 adults with pulmonary sarcoidosis. Four XTMAB16 regimens (2 mg/kg or 4 mg/kg administered intravenously every 2 or 4 weeks) were evaluated using a 3:1 randomization (XTMAB-16:placebo) for 12 weeks, followed by optional enrollment into an open-label extension study (NCT06169397). The primary objectives were to assess safety and tolerability and dose determination. Additional assessments included PK, pharmacodynamics, immunogenicity, pulmonary function, imaging, QOL measures, biomarkers, and corticosteroid dose modifications to inform dose selection for Phase 2.

Results

XTMAB-16 was well tolerated across all dose regimens, with no dose-limiting toxicities, treatment-induced serious adverse events, or discontinuations due to adverse events. Mean forced vital capacity percent predicted remained stable or showed modest improvement in XTMAB-16-treated participants, whereas placebo participants experienced a decline at Week 12 (-5.3%).Participants receiving XTMAB-16 achieved greater corticosteroid reduction than placebo. The largest percent reduction from baseline occurred in the 4 mg/kg Q4W group (-85.0%), with all active treatment groups outperforming placebo. Although placebo participants reduced steroid dose (mean -4.45 mg), pulmonary function declined. Biomarker analyses demonstrated reductions in inflammatory biomarkers, including soluble TNFα in XTMAB-16-treated participants, consistent with on-target TNF blockade.

Conclusions

XTMAB-16 demonstrated a favorable safety and tolerability profile in patients with pulmonary sarcoidosis, without unexpected TNF-inhibitor class effects. Preliminary efficacy signals suggest that XTMAB-16 may facilitate corticosteroid reduction while preserving lung function and improving patient-reported outcomes, supporting continued clinical development of XTMAB-16.

This abstract is funded by: Industry