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.

Inclusion criteria

• Male/female/diverse adults who are 18-65 years old at time of enrollment
• Subject is able and willing to give informed consent
• Signed informed consent prior to initiation of any trial related measure
• Diagnosis of PAIS as defined by WHO for PCS, wi th other infectious triggers
• Diagnosis of ME/CFS according to CCC criteria with PEM > 14 hours = PAIS/CFS
• Detection of autoantibodies (elevated ß2R adrenergic AAB) prior to immunoadsorption or prior to inclusion to PIONEER
• Pre-treatment with immunoadsorption in the immunoadsorption studies at least 6 months before study inclusion
• Documented clinical response to immunoadsorption (minimum increase in SF-36 PF of 10 points at week 8) followed by consecutive worsening of symptoms (minimum decrease in SF-36 PF of 10 points for at least 3 months)
• Evidence of activated pro inflammatory immune cell status
• Bell score at screening visit: 30-60
• Normal thyroid function or sufficiently medicated dysfunction
• For women of childbearing potential (WOCBP):

• Confirmed post-menopausal state, defined as amenorrhea for at least 12 months, or
• If being of childbearing potential: Negative highly sensitive urine or serum pregnancy test before randomization, and practicing a highly effective birth control method (failure rate of less than 1%)

Exclusion criteria

• Contraindication against IMP or AMP
• Hypersensitivity to the active substance or any of the other ingredients
• Vaccination less or up to 4 weeks before first visit
• Immunomodulative therapy < 3 month before screening visit
• Concomitant and previous use of IMP
• Known SARS-CoV-2 or other infection related organ damage/comorbidity
• Pre-infection history of chronic fatigue syndrome or other fatigue syndromes that are due to associated diseases (e.g., cancer, autoimmune diseases [patients with a preexcisting Hashimoto thyroiditis and/or fibromyalgia without fatigue syndromes can be included])
• Serious infections, including active or latent and chronic infections such as tuberculosis, HIV, Lues, hepatitis B and C
• Immune- and immunoglobulin-deficiency or severely immunocompromised condition
• Any other severe or unstable medical conditions (immune, cardiovascular, respiratory, endocrine, gastrointestinal, hematological, neurological, psychiatric, systemic) or any other condition deemed by the Investigator to pose unacceptable risk, interfere with IP evaluation, or confound study results.
• At screening : aspartate transaminase (AST) > 2.5 × upper limit of normal (ULN), alanine transaminase (ALT) > 2.5 × ULN, total bilirubin > 1.5 × ULN (unless due to Gilbert's syndrome), platelet count < 75,000/µL, hemoglobin < 8 g/dL, eGFR<30 mL/min/1.73 m², total immunoglobulin < 900 mg/dL, absolute neutrophil count < 1200 cells/µL, CD4 T lymphocyte count < 300 cells/µL
• Concomitant diseases or health constellations causing general physical weakness or fatigue, like: i) renal insufficiency with eGR< 15 or diyalsis, ii) impaired liver function with elevated liver enzymes a) Aspartate aminotransferase (AST) and b) Alanin-Aminotransferase (ALT), both >35 U/l for women or > 50 U/l for men, iii) anemia with low hemoglobin-concentrations <13,0 g/dL for males and <12,0 g/dL for females, and iv) adipositas grades II or higher (BMI: ≥ 35 kg/m 2) at screening
• Subject is pregnant or breastfeeding
• Subject is institutionalized by order of court or public authority
• Subject who might be dependent on the sponsor, the investigator, or the trial site
• Participation in another clinical trial with a medical device or an investigational medicinal product within 3 Months or 5 half-lives (whichever is longer) before screening visit