The high levels of IFNγ and of IFNγ-induced chemokines and their correlation with the severity of laboratory abnormalities of MAS suggest a pivotal role of IFNγ in MAS.

Toll-like receptor-4 (TLR4) pathways are major contributors to pathological inflammatory responses induced by tissue damage. NI-0101 is the first monoclonal antibody (mAb) blocking TLR4 signaling. This activity is independent of the ligand type and concentration, therefore, potentially blocking any TLR4 ligands. A phase I single ascending dose study was conducted in 73 healthy volunteers to evaluate NI-0101 tolerability, preliminary safety, pharmacokinetics (PKs), and pharmacodynamics (PDs), in absence and in presence of a systemic challenge with lipopolysaccharide (LPS), a TLR4 ligand. NI-0101 was well tolerated without safety concern. The PK profile was characterized by a half-life of ∼10 days at high concentrations and by a rapid elimination at low concentrations due to expected target-mediated drug disposition. NI-0101 prevented cytokine release following ex vivo and in vivo LPS administration and prevented the C-reactive protein (CRP) increase and the occurrence of flu-like symptoms expected following the in vivo administration of LPS.

ObjectivesAnti-citrullinated protein antibodies (ACPAs) form immune complexes with citrullinated proteins binding toll-like receptor (TLR) 4, which has been proposed as a mediator of rheumatoid arthritis (RA). NI-0101 is a first-in-class humanised monoclonal antibody blocking TLR4, as confirmed by inhibition of in vivo lipopolysaccharide-induced cytokine release in healthy volunteers. This study was design to confirm preclinical investigations supporting a biomarker-driven approach for treatment of patients with RA who present positive for these immune complexes.MethodsPlacebo-controlled, double-blind, randomised (2:1) trial of the tolerability and efficacy of NI-0101 (5 mg/kg, every 2 weeks for 12 weeks) versus placebo in ACPA-positive RA patients with inadequate response to methotrexate. Efficacy measures included Disease Activity Score (28-joint count) with C reactive protein (DAS28-CRP), European League Against Rheumatism (EULAR) good and moderate responses, and American College of Rheumatology (ACR) 20, ACR50 and ACR70 responses. Subgroup analyses defined on biomarkers were conducted. Pharmacokinetics, pharmacodynamics and safety were reported.Results90 patients were randomised (NI-0101 (61) and placebo (29)); 86 completed the study. No significant between-group difference was observed for any of the efficacy endpoints. Subgroup analyses using baseline parameters as covariants did not reveal any population responding to NI-0101. Treatment-emergent adverse events occurred in 51.7% of patients who received placebo versus 52.5% for NI-0101.ConclusionsWe demonstrate for the first time that in RA, a human immune-mediated inflammatory disease, blocking the TLR4 pathway alone does not improve disease parameters. Successful targeting of innate immune pathways in RA may require broader and/or earlier inhibitory approaches.

BackgroundMAS is a severe complication of rheumatic diseases, most frequently sJIA, caused by excessive activation and expansion of T cells and macrophages. It is characterized by fever, hepatosplenomegaly, liver dysfunction, cytopenias, coagulation abnormalities and hyperferritinemia, possibly progressing to multiple organ failure and death. MAS is categorized as a secondary form of HLH. A vast body of evidence points to uncontrolled overproduction of IFNγ as a major driver of hyperinflammation and hypercytokinemia in MAS and HLH. Emapalumab has been shown to effectively control disease activity in patients with primary HLH.ObjectivesTo assess the pharmacokinetics (PK), efficacy and safety of intravenous (IV) emapalumab in patients with MAS and confirm the proposed dose regimen.MethodsThis is a pilot open-label single arm international study (NCT03311854). Patients had to have MAS (defined according to the 2016 ACR/EULAR classification criteria), on a background of confirmed, or high presumption of, sJIA, and inadequate response to high-dose IV glucocorticoids. Emapalumab initial dose was 6 mg/kg and treatment was continued at 3 mg/kg, twice weekly for a total of 4 weeks or less upon achievement of complete response. Serum concentrations of emapalumab, IFNγ-induced chemokine CXCL9 and sIL2R were measured. Safety assessments included adverse events (AEs) and laboratory abnormalities. Efficacy was defined as complete response by week 8, i.e. absence of MAS clinical signs plus white blood cell and platelet counts above lower limit of normal, LDH, AST/ALT<1.5 x upper limit of normal, fibrinogen >100 mg/dL, and ferritin decreased by ≥80% or to <2000 ng/mL, whichever was lower. Twin protocols are in place to recruit 5 patients each in Europe and North America (trial not started yet). We report data on the 6 patients recruited in the European protocol.ResultsSix patients (5 females, median age 11 years, range: 2-25 years) received emapalumab according to the prescribed dose regimen. Treatment duration ranged from 3 (2 patients) to 4 weeks. Prior to emapalumab, all patients failed methylprednisolone pulses, in 2 patients plus cyclosporine A (CsA) and in 2 patients plus CsA and anakinra. The achieved emapalumab concentrations led to rapid neutralization of IFNγ as indicated by CXCL9 levels and subsequent deactivation of T cells as indicated by sIL2R levels. In all patients, complete response was achieved by week 8, in 4 patients by end of treatment (Table). Systemic glucorticoids were weaned in all patients. Emapalumab infusions were well tolerated and none of the patients discontinued emapalumab. A CMV reactivation was reported by investigator as a serious event possibly related to emapalumab, but resolved completely with treatment.ConclusionEmapalumab administration with the tested dosing regimen led to rapid neutralization of IFNγ as shown by normalization of CXCL9, associated with evidence of decreased T cell activation. In all patients, emapalumab treatment was effective in controlling MAS with a favourable safety pr...

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Background: Secondary hemophagocytic lymphohistiocytosis (sHLH) is a rare, life-threatening syndrome which may develop on the background of several clinical conditions (e.g., autoimmune disease, infection or malignancy) and is characterized by uncontrolled hyperinflammation. Preclinical data have shown the central role of interferon-gamma (IFNγ) in the pathogenesis of this disease (Strippoli et al. 2012; Prencipe et al. 2018), and observational studies confirm the presence of an IFNγ signature in sHLH (data on file, Buatois et al. 2017, Bracaglia et al. 2017, Akashi et al. 1994, Henter et al. 1991; Ohga et al. 1993; Maruoka et al. 2014). Emapalumab is a monoclonal antibody neutralizing IFNγ, approved by the FDA for the treatment of adult and pediatric patients with primary HLH with refractory, recurrent or progressive disease or intolerance with conventional HLH therapy. Study design: This open-label, single arm, multicenter, phase 2/3 interventional study (NI-0501-10; NCT03985423) enrolls adult patients diagnosed with any non-primary HLH. The study includes an initial phase enrolling 10 patients, with subsequent broadened enrollment if no untoward significant safety signal attributable to emapalumab treatment (as judged by an independent Data Monitoring Committee) is identified. Emapalumab is administered intravenously at an initial dose of 6 mg/kg (on a background of glucocorticoids), and continued at a dose of 3 mg/kg every 3 days until Study Day 15, and twice-a-week afterwards. If the treating physician deems appropriate, the dose of emapalumab may be increased, guided by clinical and laboratory response. Treatment shall continue until a clinically satisfactory response is achieved. After treatment discontinuation (for any reason), patients will continue in the study for long-term follow-up until 1 year after the last emapalumab administration (or after hematopoietic stem cell transplantation, if performed). Eligible patients include male and female patients 18 years and older at the time of HLH diagnosis, with fulfilment of at least 5 of the 8 HLH-2004 clinical criteria. Patients diagnosed with malignancy-associated HLH (M-HLH) must be treatment-naïve; patients diagnosed with HLH driven by any other etiology or idiopathic HLH can be either treatment-naïve or treatment-experienced. Patients who have already received conventional therapy for HLH must have failed prior treatment as per the treating physician's judgement. Excluded are patients with primary HLH, as well as patients receiving or scheduled to receive therapies known to trigger cytokine release syndrome, patients with a life-expectancy associated with the underlying disease (triggering HLH) <3 months, patients with active mycobacteria, Histoplasma capsulatum or Leishmania infections or with evidence of latent tuberculosis, patients who received bacillus Calmette-Guérin (BCG) vaccine within 12 weeks prior to screening, or a live or attenuated live (other than BCG) vaccine within 6 weeks prior to screening. The primary outcome measure of the study is Overall Response at Week 4. Secondary efficacy measures include survival, best response on treatment, Overall Response at end of treatment, time to Complete or Partial Response, duration of response, HLH relapse; safety endpoints include incidence, severity, causality and outcomes of adverse events; other endpoints include serum concentrations of emapalumab and biomarkers (IFNγ, CXCL9, sCD25, IL-6), and incidence of anti-drug antibodies. The primary analysis will evaluate the Overall Response Rate at Week 4. In this adaptive design, the data are reviewed periodically in order to assess each of the 2 etiologies (i.e., M-HLH and any other sHLH) for futility and efficacy. The first analysis will occur after 10 patients with one etiology reached the primary endpoint time point. Descriptive statistics and graphical methods will be used for the evaluation of the secondary efficacy endpoints. Safety data will be listed and summarized using descriptive statistics. Study status: The study is expected to open enrollment in the US in Q3 2019. Study results will be presented after completion of the study. Disclosures Asnaghi: EmaCo SA: Employment. Ballabio:EmaCo SA: Consultancy. Jacqmin:EmaCo SA: Consultancy. de Graaf:EmaCo SA: Consultancy. De Min:EmaCo SA: Employment. OffLabel Disclosure: Emapalumab is FDA-approved for primary HLH. This study will investigate the use of emapalumab in secondary HLH.