Evaluate Efficacy, Safety and Tolerability, PK and PD of Emapalumab in Children and Adults With MAS in Still's or SLE

The purpose of this study is to assess the safety, tolerability and efficacy of emapalumab in children and adults with macrophage activation syndrome (sHLH/MAS) in Still's disease (including systemic juvenile idiopathic arthritis and adult onset Still's disease) or with sHLH/MAS in systemic lupus erythematous, resenting an inadequate response to high dose glucocorticoid treatment.

Study NI-0501-14 is a two-cohort trial that enrolls subjects who are diagnosed with sHLH/MAS (MAS being a form of secondary HLH) and who are presenting an inadequate response to high doses of GCs. These subjects will be enrolled in 2 cohorts as per their background disease. The cohorts are defined as follows:

* Cohort 1: MAS in the context of sJIA and AOSD.
* Cohort 2: MAS in the context of pediatric and adult SLE.

The study has the objectives to investigate the efficacy, safety and tolerability, for 8 weeks, and PK and PD, QoL and immunogenicity in these 2 cohorts for up to 1 year after last dose of of emapalumab.

Macrophage Activation Syndrome (MAS) Secondary Hemophagocytic Lymphohistiocytosis (sHLH) systemic Juvenile Idiopathic Arthritis (sJIA) Adult-onset Still's Disease (AOSD) Systemic Lupus Erythematosus (SLE)

Eligibility Criteria:
Inclusion criteria Run-in phase in all cohorts

1. Informed consent provided by the subject or by the subject s' legally authorized representative(s) with the assent of subjects who are legally capable of providing it, as required by local law.
2. Male and female subjects aged between 6 months and 80 years of age at the time of diagnosis of MAS.
3. MAS defined as per the criteria defined below for each cohort and requiring treatment with GCs.

Interventional phase in all cohorts

1. Informed consent provided by the subject or by the subject's legally authorized representative(s) with the assent of subjects who are legally capable of providing it, as as required by local law.
2. Male and female subjects aged between 6 months and 80 years of age at the time of diagnosis of active MAS.
3. Subjects who have shown an inadequate response to high dose intravenous (i.v.) GCs administered for at least 3 days according to local standard clinical practice, including but not limited to pulses of 30 mg/kg PDN on 3 consecutive days. High i.v. GCs dose is recommended not to be lower than 2 mg/kg/ day PDN equivalent (or at least 60 mg/day in pediatric subjects of 30 kg or more, and at least 1g/day in adult MAS subjects). In case of rapid worsening of the subject's condition and/or laboratory parameters, as per Investigator judgment, inclusion may occur within less than 3 days from starting high dose GCs.
4. Diagnosis of active MAS confirmed by the treating rheumatologist, having ascertained the followings:

   a. Febrile subjects presenting with ferritin \> 684 ng/mL. b. and any 2 of: i. Platelet count ≤ 181 x109/L ii. AST-level \> 48 U/L iii. Triglycerides \> 156 mg/dL iv. Fibrinogen level ≤ 360 mg/dL
5. Female subjects of child-bearing potential willing to use highly effective methods of contraception from study drug initiation to 6 months after the last dose of study drug.

   Specific inclusion criteria to Cohort 1 and Cohort 2
6. Cohort 1:

   1. Confirmed sJIA diagnosis. For subjects presenting with MAS in the context of the onset of sJIA, high presumption of sJIA will suffice for eligibility.
   2. Confirmed diagnosis of AOSD as per Yamaguchi criteria.
7. Cohort 2:

   1. Confirmed diagnosis of SLE as per SLICC'12 criteria.

Exclusion criteria

1. Primary HLH documented by either the presence of a known causative genetic mutation or abnormal perforin expression and CD107a degranulation assay as described with primary hemophagocytic lymphohistiocytosis or by the presence of family history.
2. Confirmed malignancy. Note: subjects with a suspected malignancy should have mononuclear cells typed by flow cytometry and/or tissue biopsy, as applicable, to rule out malignancy.
3. Treatment with canakinumab, JAK inhibitors, TNF inhibitors and tocilizumab at the time of emapalumab initiation.
4. Ongoing treatment with anakinra at a dose above 4 mg/kg at time of emapalumab initiation.
5. Subjects treated with etoposide for MAS in the last 1 month.
6. Clinically active mycobacteria (typical and atypical), Histoplasma Capsulatum, or Salmonella infections.
7. Evidence of leishmania infections.
8. Evidence of latent tuberculosis.
9. History of hypersensitivity or allergy to any component of the study drug.
10. Receipt of a Bacillus Calmette-Guerin (BCG) vaccine within 12 weeks prior to screening.
11. Receipt of a live or attenuated live (other than BCG) vaccine within 4 weeks prior to screening.
12. Pregnancy or lactating female subjects.