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LBA-6 Safety and Efficacy of Emapalumab in Pediatric Patients with Primary Hemophagocytic Lymphohistiocytosis

Program: Special-Interest Sessions
Session: ASH-FDA Joint Symposium on New Drug Approvals in Non-Malignant Hematology
Hematology Disease Topics & Pathways:
Biological, Diseases, antibodies, Therapies, Pediatric, immunodeficiency, Immune Disorders, Study Population, Clinically relevant
Monday, December 3, 2018, 4:30 PM-6:00 PM
Hall AB (San Diego Convention Center)

Franco Locatelli1, Michael B. Jordan, MD2, Carl E. Allen, MD, PhD3, Simone Cesaro, MD4*, Carmelo Rizzari, MD5*, Anupama Rao, MD6*, Barbara Degar, MD7*, Timothy Garrington8*, Julian Sevilla, MD, PhD9*, Maria Caterina Putti, MD10*, Franca Fagioli, MD11*, Martina Ahlmann, MD12*, Jose-Luis Dapena, MD13*, Alexei A. Grom, MD14*, Fabrizio De Benedetti, MD15*, Walter Giovanni Ferlin, PhD16*, Maria Ballabio, MD16* and Cristina De Min, MD16*

1Department of Onco-hematology, Bambino Gesù Children’s Hospital IRCCS, Rome, Italy
2Division of Immunobiology, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
3Department of Pediatrics, Texas Children's Cancer Center, Texas Children's Hospital, Houston, TX
4Department of Pediatric Onco-hematology, University Hospital Verona, Verona, Italy
5Department of Pediatrics, San Gerardo Hospital, University of Milano-Bicocca, Monza, Italy
6Department of Haematology, Great Ormond Street Hospital, London, United Kingdom
7Division of Pediatric Hematology/Oncology, Dana-Farber Cancer Institute, Boston, MA
8Center for Cancer and Blood Disorders, Children's Hospital Colorado, Aurora, CO
9Department of Pediatric Onco-hematology, University Children Hospital Niño Jesús, Madrid, Spain
10Division of Pediatric Hematology and Oncology, Department of Pediatrics, University of Padova, Padova, Italy
11Division of Pediatric Onco-hematology, Regina Margherita-S. Anna Hospital, Turin, Italy
12Department of Pediatric Hematology and Oncology, University Children's Hospital Muenster, Muenster, Germany
13Department of Pediatric Hematology and Oncology, University Hospital Vall d’Hebron, Barcelona, Spain
14Division of Rheumatology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
15Division of Rheumatology, Bambino Gesù Children's Hospital IRCCS, Rome, Italy
16Novimmune SA, Geneva, Switzerland

Introduction: Primary hemophagocytic lymphohistiocytosis (pHLH) is a rare, genetic life-threatening syndrome characterized by hyper-inflammation that is mainly driven by high production of interferon (IFN)-𝛾, leading to the development of fever, splenomegaly, cytopenias and coagulopathy. There are currently no approved treatments for HLH, and recent attempts to improve the dexamethasone/etoposide-based regimen (HLH-94) did not show a significant improvement in overall probability of survival. Emapalumab (NI-0501) is a fully human, anti-IFN-𝛾 monoclonal antibody that binds to and neutralizes IFN-𝛾 and is in development for treatment of HLH.

Methods: This open-label pivotal study (NCT01818492) includes patients ≤18 years with a diagnosis of pHLH based on genetic confirmation, family history, or the presence of ≥5 of the 8 HLH-2004 diagnostic criteria. Patients were either treatment-naïve or had failed previous conventional HLH therapy prior to study entry. The emapalumab initial dose was 1 mg/kg given intravenously every 3-4 days. Subsequent doses could be increased up to 10 mg/kg based on the evolution of clinical and laboratory response parameters. Emapalumab was administered concomitantly with 5 to10 mg/m2/day of dexamethasone which could be tapered during the study. Treatment duration was 8 weeks (with possible shortening to a minimum of 4 weeks). Treatment could be extended up to allogeneic hematopoietic stem cell transplantation (HSCT) whenever needed. The primary efficacy endpoint of the study was overall response at end of treatment assessed by pre-defined objective parameters. Overall Response Rate (ORR) was assessed as normalization or at least 50% improvement from baseline of fever, splenomegaly, cytopenias, hyperferritinemia, fibrogen and/or D-Dimer levels, central nervous system (CNS) abnormalities, with no sustained worsening of sCD25 serum levels. The primary analysis used an exact binomial test to evaluate the null hypothesis that ORR be at most 40% at a one-sided 0.025 significance level. Data presented are from 34 patients of whom 27 entered the study after failing conventional HLH therapy. Following completion of the main study patients entered into an extension phase (NCT02069899). The data cut-off applied is July 20 2017.

Results: Patient characteristics are summarized in Table 1. Disease presentation at study entry was consistent with the broad spectrum of pHLH abnormalities, both in terms of HLH-2004 diagnostic criteria and other known HLH features; over 30% of patients had signs and/or symptoms of CNS disease. Efficacy results are summarized in Table 2. ORR was significantly higher than the pre-specified null hypothesis of 40%; thus the primary endpoint was met. The response rate based on investigator’s clinical judgement was 70.6% and 70.4% in the two groups. Emapalumab infusions were in general well tolerated, with mild to moderate infusion-related reactions reported in 27% of patients. The observed safety events pre-HSCT conditioning mostly included HLH manifestations, infections or toxicities due to other administered drugs. Infections caused by pathogens potentially favored by IFN-𝛾 neutralization occurred in 1 patient during emapalumab treatment (Disseminated histoplasmosis), and resolved with appropriate treatment. No off-target effects were observed.

Conclusions: This is the first prospective HLH study that reports response rates based on pre-defined objective criteria. Our results indicate that emapalumab should be considered as a new therapeutic option in pHLH thanks to its targeted mode of action. Treatment with emapalumab was able to control HLH activity with a favorable safety and tolerability profile in a very fragile population. The majority of patients proceeded to HSCT with favorable outcome.

Disclosures: Jordan: Novimmune: Consultancy, Membership on an entity's Board of Directors or advisory committees. Allen: Novimmune: Membership on an entity's Board of Directors or advisory committees. Sevilla: Novimmune: Other: currently participating in and have participated in Novimmune-sponsored clinical trials within the past two years ; Rocket Pharmaceuticals Inc: Honoraria, Patents & Royalties. Grom: NovImmune: Consultancy, Membership on an entity's Board of Directors or advisory committees; AB2Bio: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. De Benedetti: Pfizer: Research Funding; Novimmune: Research Funding; Abbvie: Research Funding; Eli-Lylli: Consultancy; UCB: Consultancy; Sanofi: Consultancy, Research Funding; Roche: Consultancy, Research Funding; SOBI: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Ferlin: Novimmune: Employment, Equity Ownership, Patents & Royalties. Ballabio: Novimmune: Employment, Equity Ownership. De Min: Novimmune: Employment, Equity Ownership.