CD19-B Cell Depletion in PAIS-ME/CFS Patients

Post-acute infection syndromes (PAIS) comprise persistent health problems that develop following an acute infection. The term encompasses post-COVID-19 condition (PCS) as well as post-infectious syndromes associated with other infectious triggers. A subset of patients with PAIS fulfils the Canadian Consensus Criteria (CCC) for myalgic encephalomyelitis/ chronic fatigue syndrome (ME/CFS), a chronic and disabling condition characterized by impaired physical and cognitive function and a range of other symptoms. Post-exertional malaise (PEM), defined by worsening of symptoms following physical or cognitive exertion, is a central feature of ME/CFS. Despite the substantial clinical burden associated with PAIS and ME/CFS, their underlying pathophysiological mechanisms remain incompletely understood, and no established treatment targeting the underlying disease process is available. Increasing evidence supports the hypothesis that immune dysregulation contributes to disease mechanisms in at least a subset of affected patients. Proposed mechanisms include B-cell dysregulation, autoimmune responses, and the production of autoantibodies, including autoantibodies directed against G-protein-coupled receptors. Associations between such autoantibodies, symptom severity, autonomic dysfunction, disability, and alterations of the central nervous system have been reported. The scientific rationale for PIONEER is further supported by previous therapeutic studies targeting antibodies or B cells. Immunoadsorption, which reduces circulating immunoglobulins, has been associated with clinical improvement in subsets of patients with ME/CFS and elevated β2-adrenergic receptor autoantibodies. Previous studies of B-cell depletion with rituximab have produced mixed results: responses were observed in earlier studies, whereas efficacy was not confirmed in a subsequent multicenter trial. These findings, together with the heterogeneity of ME/CFS, provide a rationale for evaluating B-cell-targeted therapy in a more specifically characterized population selected for features consistent with autoantibody-associated or B-cell-mediated disease. PIONEER evaluates inebilizumab, a humanized monoclonal antibody directed against CD19. Binding of inebilizumab to CD19-positive B cells results in their depletion. In contrast to therapies directed against CD20, CD19 targeting affects a broader range of B-cell subsets, including early B cells and plasmablasts. Inebilizumab is approved for the treatment of aquaporin-4 immunoglobulin G antibody-positive neuromyelitis optica spectrum disorder (NMOSD). However, it has not previously been investigated as a treatment for PAIS-associated ME/CFS. PIONEER is a prospective, randomized, double-blind, placebo-controlled, parallel-group Phase 2b trial designed to assess the efficacy and safety of inebilizumab in a selected subgroup of adults with PAIS-associated ME/CFS. The trial plans to randomize 38 participants to treatment with either inebilizumab or saline placebo. Inebilizumab is administered intravenously at a dose of 300 mg on Day 1, Day 15, and Week 24. The dose and administration schedule are based on the established dosing regimen for NMOSD. The placebo-controlled and double-blind design is intended to allow an unbiased comparison of treatment effects and safety outcomes. The study population is selected to address the hypothesis that B-cell depletion may be beneficial in a subgroup of patients with evidence consistent with autoantibody-associated or B-cell-mediated disease. Participants must have PAIS and meet the CCC for ME/CFS, including PEM lasting more than 14 hours. They must have evidence of elevated β2-adrenergic receptor autoantibodies and a pro-inflammatory immune cell status. In addition, participants must previously have received immunoadsorption in an immunoadsorption study at least 6 months before inclusion in PIONEER and have shown a documented clinical response, defined as an increase of at least 10 points in SF-36-PF at Week 8, followed by subsequent worsening of at least 10 points persisting for at least 3 months. This selection approach is intended to investigate the effect of CD19-targeted B-cell depletion in a clinically and immunologically characterized population. The primary objective is to determine whether inebilizumab improves physical function compared with placebo. The primary endpoint is the intra-participant change in SF-36-PF score from baseline to Month 9 (Week 36), comparing the mean change between the inebilizumab and placebo groups. Secondary efficacy assessments evaluate both the magnitude and breadth of potential treatment effects. A responder analysis will compare the proportion of participants achieving an increase of at least 20 points in SF-36-PF from baseline to Week 36. Further assessments examine changes in other SF-36 domains and improvement in other patient reported outcome measures (Bell disability score, CCC symptom score, COMPASS-31, Fatigue severity scale, PEM etc.). Objective and activity-related assessments complement the patient-reported outcomes and include: i) repetitive hand-grip testing to evaluate changes in hand-grip force, fatigability, and recovery, ii) NASA 10-minute Lean Test to assess changes in blood pressure and heart rate regulation during passive standing, and iii) daily step count as a measure of activity in everyday life. Safety is evaluated through the occurrence of adverse events, serious adverse events, and suspected unexpected serious adverse reactions. A comprehensive biomarker program accompanies the clinical trial. The analyses focus on B cells, autoantibodies, and soluble markers and are intended to explore biological characteristics associated with response to anti-CD19 treatment. By combining a randomized, double-blind, placebo-controlled clinical evaluation with biomarker analyses, PIONEER is designed to examine both the clinical effects of CD19-targeted B-cell depletion and biological characteristics that may be associated with treatment response. The resulting clinical and biomarker data are intended to provide a basis for the design of subsequent confirmatory studies and for further evaluation of biomarkers that may help characterize treatment response in autoimmune-associated post-infectious ME/CFS.