Study to Investigate Safety, Efficacy of an Anti-IFNγ mAb in Children With Primary Haemophagocytic Lymphohistiocytosis

Study to Investigate Safety, Efficacy of an Anti-IFNγ mAb in Children With Primary Haemophagocytic Lymphohistiocytosis

A Phase 2/3 Open-label Single Arm Multicentre Study to Assess Safety Tolerability Pharmacokinetics and Efficacy of i.v. Administrations of NI-0501 an Anti-IFNγ mAb in Paediatric Patients With Primary Haemophagocytic Lymphohistiocytosis

The purpose of this study is to assess the safety, tolerability and efficacy of a new drug aimed at controlling disease activity in patients diagnosed with primary haemophagocytic lymphohistiocytosis. The new drug can be administered as the first-line therapy, to patients not previously treated with the current standard of care, or can be given to patients who have either failed or were unable to tolerate the current standard of care. Administration will be on top of a glucocorticosteroid, which is usually part of the current recommended treatment.

The purpose of this study is to assess the safety, tolerability and efficacy of a new drug aimed at controlling disease activity in patients diagnosed with primary haemophagocytic lymphohistiocytosis. The new drug can be administered as the first-line therapy, to patients not previously treated with the current standard of care, or can be given to patients who have either failed or were unable to tolerate the current standard of care. Administration will be on top of a glucocorticosteroid, which is usually part of the current recommended treatment. All participants in the NI-0501-04 study (NCT01818492) were invited to participate in the long-term follow-up study NI-0501-05 (NCT02069899). For the primary completion date, mentioned here, we refer to the NI-0501-04 study, even though in accordance with the NI-0501-04 study objectives, namely the assessment of long-term efficacy and safety endpoints, the study analyses also included data collected in the long-term follow-up study NI-0501-05. Hence these data are reported together. Study NI-0501-05 accepts patients from NI-0501-04 and NI-0501-06. Data collection for the patients from NI-0501-04 is completed. The primary efficacy and safety analyses are based on the regulatory cut-off date of 20 July 2017. Refer to the publication in N Engl J Med 2020 May 7; 382 (19):1811-1822. Follow-on analyses have been conducted on all patients enrolled in the study, i.e. including the patients enrolled after the cut-off date of 20 July 2017. The results reported here refer to the totality of the 45 patients enrolled.

Achievement of either Complete (CR) or Partial Response (PR), or HLH Improvement (HI) at End of Treatment of Study NI 0501-04 (EOT 04), based on pre-specified algorithm. CR: no fever, normal spleen size, no cytopenia (ANC ≥ 1.0x109/L and platelet count ≥ 100x109/L), no hyperferritinemia (serum ferritin <2000 μg), no coagulopathy (normal D-dimer and/or fibrinogen >150 mg/dL), no neurological and CSF abnormalities attributed to HLH, no sustained worsening of sCD25. PR: at least 3 HLH clinical and laboratory criteria (including CNS abnormalities) met the CR criteria, no progression of other aspects of HLH disease pathology. HI: improvement (>50% change from baseline) of at least 3 HLH clinical and laboratory criteria (including CNS involvement).

End of Treatment (3 days after the last infusion of emapalumab in study NI-0501-04, occurring between 4 and 8 weeks)

Achievement of either Complete (CR) or Partial Response (PR), or HLH Improvement (HI) at End of Treatment of Study NI 0501-04 (EOT 04), based on pre-specified algorithm. CR: no fever, normal spleen size, no cytopenia (ANC ≥ 1.0x109/L and platelet count ≥ 100x109/L), no hyperferritinemia (serum ferritin <2000 μg), no coagulopathy (normal D-dimer and/or fibrinogen >150 mg/dL), no neurological and CSF abnormalities attributed to HLH, no sustained worsening of sCD25. PR: at least 3 HLH clinical and laboratory criteria (including CNS abnormalities) met the CR criteria, no progression of other aspects of HLH disease pathology. HI: improvement (>50% change from baseline) of at least 3 HLH clinical and laboratory criteria (including CNS involvement).

End of Treatment (3 days after the last infusion of emapalumab in study NI-0501-04, occurring between 4 and 8 weeks)

Achievement of either Complete (CR) or Partial Response (PR), or HLH Improvement (HI) at End of Treatment of Study NI 0501-04 (EOT 04), based on pre-specified algorithm. CR: no fever, normal spleen size, no cytopenia (ANC ≥ 1.0x109/L and platelet count ≥ 100x109/L), no hyperferritinemia (serum ferritin <2000 μg), no coagulopathy (normal D-dimer and/or fibrinogen >150 mg/dL), no neurological and CSF abnormalities attributed to HLH, no sustained worsening of sCD25. PR: at least 3 HLH clinical and laboratory criteria (including CNS abnormalities) met the CR criteria, no progression of other aspects of HLH disease pathology. HI: improvement (>50% change from baseline) of at least 3 HLH clinical and laboratory criteria (including CNS involvement).

End of Treatment (3 days after the last infusion of emapalumab in study NI-0501-04, occurring between 4 and 8 weeks)

Overall Response Rate (ORR) at End of Treatment in Study NI-0501-04 (EOT 04) Follow-on Analysis Set: All Treated

Achievement of either Complete (CR) or Partial Response (PR), or HLH Improvement (HI) at End of Treatment of Study NI 0501-04 (EOT 04), based on pre-specified algorithm. CR: no fever, normal spleen size, no cytopenia (ANC ≥ 1.0x109/L and platelet count ≥ 100x109/L), no hyperferritinemia (serum ferritin <2000 μg), no coagulopathy (normal D-dimer and/or fibrinogen >150 mg/dL), no neurological and CSF abnormalities attributed to HLH, no sustained worsening of sCD25. PR: at least 3 HLH clinical and laboratory criteria (including CNS abnormalities) met the CR criteria, no progression of other aspects of HLH disease pathology. HI: improvement (>50% change from baseline) of at least 3 HLH clinical and laboratory criteria (including CNS involvement).

End of Treatment (3 days after the last infusion of emapalumab in study NI-0501-04, occurring between 4 and 8 weeks)

Time from the date of the first dose of emapalumab to first achievement of response (at least HLH improvement)

Assessed up to End of Treatment (3 days after the last infusion of emapalumab in study NI-0501-04, occurring between 4 and 8 weeks)

Assessed up to End of Treatment (3 days after the last infusion of emapalumab in study NI-0501-04, occurring between 4 and 8 weeks)

Number of patients able to reduce glucocorticoids by 50% or more and between ≥30%-<50%, of baseline dose at EOT 04.

End of Treatment (3 days after the last infusion of emapalumab in study NI-0501-04, occurring between 4 and 8 weeks.

Percent of treatment time in response from the first achievement of an Overall Response until HSCT conditioning, or End of Treatment 04/05 (if the patient did not have HSCT performed) Where applicable, data were collected in both NI-0501-04 and long-term follow-up study NI-0501-05.

up to start of HSCT conditioning, whenever HSCT conditioning is scheduled (at least 4 weeks after treatment start), or End of Treatment 04/05 (if the patient did not have HSCT performed)

Time from the date of first dose to the date of death, expressed in Kaplan-Meier survival probability estimates. Patients who receive HSCT will be censored at that date; patients who did not receive HSCT will be censored at last date of contact. Where applicable, data were collected in both NI-0501-04 and long-term follow-up study NI-0501-05.

Assessed up to HSCT, whenever HSCT occurred (up to approximately 6 months after treatment initiation)

Time from the date of first dose to the date of death, expressed in Kaplan-Meier survival probability estimates. Patients without an event will be censored at last assessment date in either the NI-0501-04 or NI-0501-05 study. Patients who do not proceed to HSCT will be excluded from this analysis.

Assessed up to Last Observation (up to 1 year after transplant, or up to approximately 18 months after treatment initiation)

Inclusion Criteria: Gender: male and female Age: up to and including 18 years at diagnosis of Haemophagocytic Lymphohistiocytosis Primary HLH patients Patient (if ≥ 18 years old), or patient's legal representative(s) must have signed informed consent Exclusion Criteria: Diagnosis of secondary Haemophagocytic Lymphohistiocytosis consequent to a proven rheumatic or neoplastic disease. Body weight < 3 kg. Patients treated with biologics within a specific timeframe Active Mycobacteria, Histoplasma Capsulatum, Shigella, Salmonella, Campylobacter and Leishmania infections. Presence of malignancy. Concomitant disease or malformation severely affecting the cardiovascular, pulmonary, liver or renal function

Alfred I. duPont Hospital for Children - Nemours Center for Cancer and Blood Disorders - Division of Pediatric Hematology Oncology

Locatelli F, Jordan MB, Allen C, Cesaro S, Rizzari C, Rao A, Degar B, Garrington TP, Sevilla J, Putti MC, Fagioli F, Ahlmann M, Dapena Diaz JL, Henry M, De Benedetti F, Grom A, Lapeyre G, Jacqmin P, Ballabio M, de Min C. Emapalumab in Children with Primary Hemophagocytic Lymphohistiocytosis. N Engl J Med. 2020 May 7;382(19):1811-1822. doi: 10.1056/NEJMoa1911326.