Gamifant (emapalumab-lzsg): The One and Only

Ashley Sabus, PharmD
PGY2 Pediatric Pharmacy Resident
Children’s Hospital Colorado
Aurora, CO

Background
Hemophagocytic lymphohistiocytosis (HLH) is a disease characterized by abnormal activation of the immune system and impaired cytotoxic function, resulting in hemophagocytosis, hypercytokinemia, and hyperinflammation. Cytokines released by activated macrophages, including interferon gamma (IFN gamma), interleukin (IL)-6, IL-10, and tumor necrosis factor (TNF) alpha, infiltrate body tissues, leading to progressive tissue damage and multi-organ failure.¹ HLH is classified as either primary HLH, which is a heterogeneous autosomal recessive disorder, or secondary HLH, caused by infection, rheumatic disease, or malignancy. Primary HLH occurs in 1:30,000–1:50,000 live births and commonly presents before the age of 1 year (70%–80% of cases).² Clinically, both primary and secondary HLH look very similar and may be equally severe. Symptoms manifest as prolonged fever, splenomegaly, cytopenia, hyperferritinemia, hypertriglyceridemia, and hypofibrinogenemia. Major complications include severe infection, hepatitis, multi-organ failure syndrome, and central nervous system disease.² If left untreated, HLH is fatal.¹

Developmental Process and Clinical Data
Preliminary data from animal models suggest that hyperactivity of CD8+ T cells and subsequent elevations in IFN gamma are responsible for the hypercytokinemia and activated lymphocytes that cause HLH complications.^3,4 Investigators discovered that mice with high circulating levels of IFN gamma had clinical and laboratory features similar to those of human HLH disease. When treated with anti–IFN gamma antibody, the abnormalities resolved, and life span was prolonged.⁴ The robust role of IFN gamma in the pathogenesis of HLH disease, as well as promising results from animal studies, provided a rationale for developing a targeted therapy to neutralize IFN gamma action while minimizing systemic adverse effects of treatment. In November 2018, the U.S. Food and Drug Administration (FDA) approved emapalumab-lzsg, a fully human immunoglobulin G1 (IgG1) anti–IFN gamma monoclonal antibody, for the treatment of pediatric and adult patients with primary HLH who have refractory, recurrent, or progressive disease or intolerance to conventional HLH therapy.⁵ Prior to the market introduction of emapalumab, no medications for this disease had been approved by the FDA. The standard of care for primary HLH is protocol HLH-94, an etoposide- and dexamethasone-based treatment regimen, followed by continuation therapy and eventually hematopoietic stem cell transplantation (HSCT).^2,6 A combination of corticosteroids and T cell–directed agents, such as cyclosporine, alemtuzumab, or antithymoglobulin, may also be incorporated into treatment regimens.⁷ Despite efforts to improve the HLH-94 protocol, overall probability of survival in patients with primary HLH remains low, with mortality rates approaching 40%–50%.^6,8,9 Further, myelosuppression and immunosuppression induced by T cell–directed therapies are major limitations to treatment.² Emapalumab is one of the first significant medical advancements for primary HLH induction therapy in more than 20 years.¹⁰

Emapalumab gained FDA approval following a pivotal phase 2/3 multicenter open-label single-arm clinical trial (NCT01818492) of 34 patients 18 years of age or younger (median age: 1 year; range 0.1–13 years). The patients had a diagnosis of primary HLH based on genetic confirmation, family history, or the presence of five or more of the eight HLH-2004 diagnostic criteria: fever; splenomegaly; cytopenias affecting 2 of 3 lineages in the peripheral blood; hypertriglyceridemia and/or hyperfibrinogenemia; hemophagocytosis in bone marrow, spleen, or lymph nodes with no evidence of malignancy; low or absent NK-cell activity; ferritin levels of 500 mcg/L or higher; and soluble CD25 levels of 2,400 U/mL or higher.^6,11 Twenty-seven of the included patients (79%) had previously failed conventional HLH therapy, while seven were treatment naïve. It is important to note that the FDA approved emapalumab solely for patients who had failed standard therapy. Emapalumab was administered intravenously twice weekly, or every 3 days, at a starting dose of 1 mg/kg. Subsequent doses were titrated to a maximum of 10 mg/kg on the basis of clinical and laboratory results. Of note, 44% of patients remained at a dose of 1 mg/kg. All patients received 5–10 mg/m²/day of dexamethasone concurrently. Treatment duration was 4–8 weeks but could be extended to allogeneic HSCT, if needed. The primary efficacy endpoint was overall response rate (ORR), defined as normalization or at least 50% improvement from baseline of fever, splenomegaly, cytopenias, hyperferritinemia, fibrinogen and/or D-Dimer levels, and central nervous system abnormalities, with no sustained worsening of soluble CD25 serum levels. At the end of treatment, ORR for the subset of patients failing conventional therapy was 63% (95% confidence interval [CI]: 42%–81%, p = .0134), which exceeded the investigators’ estimated null hypothesis of 40%. Median time to response was 8 days (95% CI: 7–14), and the majority of patients (70.4%) proceeded to HSCT. In an analysis of all treated patients (n = 34), ORR was 64.7% (95% CI: 46%–80%, p = .0031).

At the end of the trial, patients had the option to enroll in an open-label extension study (NCT0269899) in which outcomes were evaluated for 1 year post HSCT or after the last dose of emapalumab. Twenty-two patients were included in this analysis.¹ In addition to clinical efficacy and safety outcomes, the study evaluated immunogenicity and pharmacodynamics. One patient (3%) developed treatment-emergent antitherapeutic antibodies (ATA) within the first 9 weeks of emapalumab exposure. Fortunately, the ATAs did not appear to alter the medication’s safety or efficacy profile. In regard to pharmacodynamics, emapalumab caused reductions in both serum IFN gamma and serum levels of an IFN gamma–induced chemokine, CXCL9.^2,11

Safety
Safety data from the pivotal phase 2/3 trial (NCT01818492) suggest that emapalumab is generally well tolerated, with the most common adverse effects being infection (56%), hypertension (41%), mild to moderate infusion-related reactions (27%), and pyrexia (24%).¹¹ One-third of the infusion-related reactions occurred during the first dose. Despite general tolerability, two patients experienced fatal adverse reactions resulting from septic shock and gastrointestinal hemorrhage. One patient withdrew from the trial because of disseminated histoplasmosis, which resolved with treatment. Suppression of IFN gamma increases risk for serious or fatal infections in patients receiving emapalumab. The most concerning pathogens are primarily intracellular and include mycobacteria, herpes zoster virus, and histoplasma capsulatum. All patients treated with emapalumab should receive prophylaxis for herpes zoster, Pneumocystis jirovecii, and fungal infections. Live vaccines and live attenuated vaccines should be avoided.¹¹

Future Directions
Despite promising efficacy and safety data supporting the use of emapalumab for primary HLH, many questions regarding long-term outcomes remain unanswered. An ongoing international multicenter extension of the pivotal phase 2/3 clinical trial (NCT02069899) aims to provide additional information regarding the long-term efficacy, safety, tolerability, and pharmacokinetic profile of emapalumab.^1,12 The study’s estimated completion date is September 2020. It is also unclear whether continuous blockade of IFN gamma will be required for sustained response, given that cytokine production occurs downstream from T cells.²

The role of emapalumab in secondary HLH is still unknown. Ongoing clinical trials in this population are limited to a phase 2 open-label single-arm multicenter study in Italy including pediatric patients (younger than 18 years old) with systemic juvenile idiopathic arthritis who developed macrophage activation syndrome or secondary HLH.¹³

Conclusions
Emapalumab, a fully human IgG1 anti–IFN gamma monoclonal antibody, meets an unmet medical need for pediatric and adult patients with primary HLH who have refractory, recurrent, or progressive disease or intolerance to conventional HLH therapy. Although emapalumab is generally well tolerated, patients should be carefully monitored for serious infections and infusion-related reactions. Ongoing clinical trials aim to provide more information regarding long-term outcomes and emapalumab’s role in the treatment of secondary HLH. Emapalumab is one of the most significant improvements in the treatment of primary HLH in more than 20 years and provides an opportunity to improve outcomes for patients with this devastating disease.

References

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10. Sobi. “FDA approves Gamifant® (emapalumab-lzsg), the first and only treatment indicated for primary hemophagocytic lymphohistiocytosis (HLH) [media release]. 2018. Available at https://www.businesswire.com/news/home/20181120005454/en/. Accessed February 10, 2019.
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