Abstract: Background: Primary hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening, immune disorder characterized by a hyperinflammatory state in which patients typically develop fever, splenomegaly, cytopenias and coagulopathy. In patients with primary HLH, interferon gamma (IFNy) is considered to be the key player driving the hyperinflammatory state. The treatment goal of primary HLH is to stabilize the disease by controlling the associated hyperinflammation in order to bring patients to allogeneic hematopoietic stem cell transplantation (HSCT), the only potentially curative therapy. Current conventional therapy for HLH is based on the combined use of dexamethasone and etoposide, and, although effective in many patients, these drugs may promote the development of opportunistic infections and tissue toxicity, and are associated with high morbidity and mortality. Emapalumab is a fully human, anti-IFNy monoclonal antibody that neutralizes IFNy. It is 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. Herein, we report on the safety of emapalumab in primary HLH seen in the pivotal phase 2/3 study (Locatelli et al. NEJM 2020) and investigate the relationship of adverse events (AE) to dose and duration of treatment. Methods: Due to the rare and life-threatening nature of the disease, the efficacy and safety of emapalumab was assessed in an open-label pivotal study (NCT01818492) which included patients aged ≤18 years with a diagnosis of primary HLH and active disease (Locatelli et al NEJM 2020). The initial dose of emapalumab was 1 mg/kg given intravenously every 3 days. Subsequent doses could be increased to 3, 6 and 10 mg/kg if required, based on predefined laboratory and clinical response parameters. Treatment duration was 8 weeks, with possible shortening to a minimum of 4 weeks, or extension up to the time of HSCT if needed. Analysis was performed on 34 patients at a database cut-off date of July 2017 (Locatelli et al NEJM 2020). The relationship of AE to emapalumab treatment was reported by the study investigator. The impact of treatment duration on AE or infection occurrence was measured by the number of events with onset in a predefined time interval from emapalumab initiation. The impact of the dosing scheme on AE and infection occurrence was assessed by the number of AEs or infections in a predefined dose range. Results: Overall, 29% of patients had at least one AE deemed related to emapalumab use. Most (90%) of these events were infusion-related reactions, all of which were mild to moderate and resolved. No severe or serious hypersensitivity reactions were reported. Infections caused by pathogens potentially favored by IFNy neutralization occurred in 1 patient during emapalumab treatment (disseminated histoplasmosis) and resolved with appropriate treatment. There was no increase in AE frequency or the number of viral, bacterial, or fungal infections with increased dose or duration of emapalumab treatment. Conclusion: Neutralization of IFNy with emapalumab in this very fragile population of patients with active primary HLH was associated with a favorable and manageable safety profile across all doses and treatment durations assessed, allowing for flexible and tailored use based on patient clinical response. In addition, 102 patients have been treated in the US following FDA approval, and post-marketing surveillance has not revealed any additional safety concerns with the use of emapalumab in primary HLH (cutoff date 19 May 2020). Taken together, these safety results suggest that emapalumab may offer an additional advantage over conventional HLH therapies. Disclosures Locatelli: Jazz Pharmaceeutical: Speakers Bureau; Medac: Speakers Bureau; Miltenyi: Speakers Bureau; Bellicum Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Jordan:Sobi: Consultancy. Allen:Sobi: Other: Scientific Steering Committee, Data And Safety Monitoring. Rizzari:Sobi: Consultancy, Other: Advisory Board. Rao:Sobi: Consultancy, Other: Advisory Board. Sevilla:Novartis: Other: Advisory Board; Amgen: Other: Advisory Board; Rocket Pharma: Consultancy; Sobi: Other: Advisory Board. Henry:Sobi: Consultancy. De Benedetti:Pfizer: Research Funding; Novartis Pharma: Research Funding; Sanofi-Aventis: Research Funding; Sobi: Consultancy, Research Funding; Abbvie: Research Funding; F Hoffmann-La Roche AG: Research Funding. Grom:Novartis Pharma: Consultancy; Sobi: Consultancy; AB2Bio: Consultancy. de Min:Sobi: Consultancy.

Abstract: Background: Primary HLH is a rare, life-threatening immune disorder characterized by a hyperinflammatory state. In patients with primary HLH, interferon gamma (IFNy) is often markedly elevated and is considered one of the key cytokine driving the hyperinflammatory state. The treatment goal of primary HLH is to stabilize the disease by controlling the associated hyperinflammation to bring patients to allogeneic hematopoietic stem cell transplantation, the only curative therapy. Conventional HLH therapy comprises immunotherapies (namely, dexamethasone and etoposide), which, unfortunately, predispose patients to infections and toxicity. Emapalumab is a fully human, anti-IFNy monoclonal antibody that neutralizes IFNy. Currently, there is no regulatory precedent or validated response criteria for efficacy assessment to guide clinical trials in primary HLH. In the pivotal study of emapalumab in primary HLH, objective response criteria were used to define the primary endpoint of overall response (Locatelli et al NEJM 2020). These response criteria were defined based on the Histiocyte Society HLH diagnostic criteria (Henter et al Pediatr Blood Cancer 2007), clinical considerations from the study's Scientific Steering Committee, and available experience reported with conventional HLH treatments. We now report on findings of a sensitivity analysis of overall response rate (ORR) to emapalumab using various assessment criteria. Methods: The open-label pivotal study included patients aged ≤18 years with a diagnosis of primary HLH and active disease (NCT01818492; Locatelli et al NEJM 2020). The initial dose of emapalumab was 1 mg/kg given intravenously every 3 days. Subsequent doses could be increased to 10 mg/kg if required, based on predefined laboratory and clinical response parameters, for a treatment duration of 8 weeks. In addition to emapalumab, all patients received dexamethasone, and a protocol amendment allowed for concomitant use of other HLH treatments if deemed appropriate by the investigator. ORR at end of treatment was analyzed as per the protocol definition in the 27 patients previously treated with conventional therapies. In addition, several pre-specified and post hoc sensitivity analyses were performed to pressure test the data; including: (i) a pre-specified analysis using a more conservative approach where any patient who received concomitant HLH therapies during the study was imputed as non-responder; (ii) a pre-specified analysis with physician-reported response rates recorded by the study investigators, based on their clinical judgement and previous experience in treating patients with primary HLH; and (iii) a post hoc sensitivity analysis using a previously published definition of overall response (Henter et al Pediatr Blood Cancer 2007). Results: 63% (95% confidence interval [CI], 0.42, 0.81) of 27 treatment-experienced patients had a response according to the pivotal study protocol definition of ORR (Fig. 1). A pre-specified sensitivity analysis on the primary endpoint where any patient who received concomitant HLH therapy and imputed as non-responders showed a magnitude of response similar to that observed in the protocol-defined primary analysis (59.3%; 95% CI 0.39, 0.78; n=22). Use of the response criteria defined by Marsh et al (Pediatr Blood Cancer 2013) in a retrospective analysis of 27 patients with primary HLH also resulted in a similar ORR to the protocol-defined primary endpoint in treatment-experienced patients (70.4%; 95% CI 0.50, 0.86). When platelet count was added to this analysis, the percentage of responders to emapalumab increased to 74.1% (95% CI 0.54, 0.89). The pre-specified analysis of physician-reported response rates was also in line with the primary analysis, with 70.4% (95% CI 0.50, 0.86) of 27 treatment-experienced patients deemed to have a response to emapalumab. Conclusion: The current analyses using different definitions of treatment response support the primary analysis results by having a numerically comparable point estimate to the primary endpoint, therefore confirming the positive benefit of emapalumab in patient's refractory or intolerant to conventional HLH therapies. Taken together, these findings also suggest that the clinically objective ORR, utilized in the pivotal emapalumab trial, may be used as a primary endpoint in primary HLH. Disclosures Locatelli: Jazz Pharmaceeutical: Speakers Bureau; Medac: Speakers Bureau; Miltenyi: Speakers Bureau; Bellicum Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Jordan:Sobi: Consultancy. Allen:Sobi: Other: Scientific Steering Committee, Data And Safety Monitoring. Rizzari:Sobi: Consultancy, Other: Advisory Board. Rao:Sobi: Consultancy, Other: Advisory Board. Sevilla:Amgen: Other: Advisory Board; Rocket Pharma: Consultancy; Sobi: Other: Advisory Board; Novartis: Other: Advisory Board. Henry:Sobi: Consultancy. De Benedetti:Abbvie: Research Funding; F Hoffmann-La Roche AG: Research Funding; Novartis Pharma: Research Funding; Pfizer: Research Funding; Sanofi-Aventis: Research Funding; Sobi: Consultancy, Research Funding. Grom:Sobi: Consultancy; Novartis Pharma: Consultancy; AB2Bio: Consultancy. Stoltenberg:Sobi: Current Employment. Vågerö:Sobi: Consultancy. de Min:Sobi: Consultancy.

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