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INDICATIONS

Gamifant (emapalumab-lzsg) is an interferon gamma (IFNγ)-neutralizing antibody indicated for the treatment of adult and pediatric (newborn and older) patients with:

  • Primary hemophagocytic lymphohistiocytosis (HLH) with refractory, recurrent, or progressive disease or intolerance with conventional HLH therapy.
  • HLH/macrophage activation syndrome (MAS) in known or suspected Still’s disease, including systemic Juvenile Idiopathic Arthritis (sJIA), with an inadequate response or intolerance to glucocorticoids, or with recurrent MAS.
IMPORTANT SAFETY INFORMATION
Infections

Gamifant may increase the risk of fatal and serious infections with pathogens including mycobacteria, herpes zoster virus... and histoplasma capsulatum. Do not administer Gamifant in patients with these infections until appropriate treatment has been initiated.

INDICATIONS

Gamifant (emapalumab-lzsg) is an interferon gamma (IFNγ)-neutralizing antibody indicated for the treatment of adult and pediatric (newborn and older) patients with:

  • Primary hemophagocytic lymphohistiocytosis (HLH) with refractory, recurrent, or progressive disease or intolerance with conventional HLH therapy.
  • HLH/macrophage activation syndrome (MAS) in known or suspected Still’s disease, including systemic Juvenile Idiopathic Arthritis (sJIA), with an inadequate response or intolerance to glucocorticoids, or with recurrent MAS.

IMPORTANT SAFETY INFORMATION

Infections

Gamifant may increase the risk of fatal and serious infections with pathogens including mycobacteria, herpes zoster virus, and histoplasma capsulatum. Do not administer Gamifant in patients with these infections until appropriate treatment has been initiated.

In patients with primary HLH receiving Gamifant in clinical trials, serious infections such as sepsis, pneumonia, bacteremia, disseminated histoplasmosis, necrotizing fasciitis, viral infections, and perforated appendicitis were observed in 32% of patients.

In patients with HLH/MAS in Still’s disease receiving Gamifant in clinical trials, serious infections such as pneumonia, cytomegalovirus infection, cytomegalovirus infection reactivation, and sepsis were observed in 13% of patients.

Evaluate patients for tuberculosis risk factors and test for latent infection prior to initiating Gamifant. Administer tuberculosis prophylaxis to patients at risk for tuberculosis or known to have a positive purified protein derivative (PPD) test result.

Consider prophylaxis for herpes zoster, Pneumocystis jirovecii, and fungal infection while receiving Gamifant. Employ surveillance testing during treatment with Gamifant.

Closely monitor patients receiving Gamifant for signs or symptoms of infection, promptly initiate a complete diagnostic workup appropriate for an immunocompromised patient, and initiate appropriate antimicrobial therapy.

Increased Risk of Infection With Use of Live Vaccines

Do not administer live or live attenuated vaccines to patients receiving Gamifant and for at least 4 weeks after the last dose of Gamifant. The safety of immunization with live vaccines during or following Gamifant therapy has not been studied.

Infusion-Related Reactions

Infusion-related reactions in patients with primary HLH, including drug eruption, pyrexia, rash, erythema, and hyperhidrosis, were reported with Gamifant treatment in 27% of patients. In one-third of these patients, the infusion-related reaction occurred during the first infusion.

Infusion-related reactions in patients with HLH/MAS in Still’s disease, including pyrexia, headache, paresthesia, bone pain, pruritic rash, and peripheral coldness, were reported with Gamifant treatment in 13% of patients. Infusion-related reactions were reported as mild in 8% of patients and as moderate in 5% of patients.

Monitor patients for infusion-related reactions, which can be severe. Interrupt the infusion for infusion reactions and institute appropriate medical management before continuing infusion at a slower rate.

Adverse Reactions

Primary HLH

Serious adverse reactions were reported in 53% of patients. The most common serious adverse reactions (≥3%) included infections, gastrointestinal hemorrhage, and multiple organ dysfunction. Fatal adverse reactions occurred in 2 (6%) of patients and included septic shock and gastrointestinal hemorrhage.

The most common adverse reactions were (≥10%) for Gamifant included infection (56%), hypertension (41%), infusion-related reactions (27%), pyrexia (24%), hypokalemia (15%), constipation (15%), rash (12%), abdominal pain (12%), CMV infection (12%), diarrhea (12%), lymphocytosis (12%), cough (12%), irritability (12%), tachycardia (12%), and tachypnea (12%).

HLH/MAS

Serious adverse reactions were reported in 12 patients (31%), with the most common serious adverse reaction being pneumonia (5%). Fatal adverse reactions occurred in two patients (5%) and included multiple organ dysfunction and circulatory shock.

The most common adverse reactions (≥10%) for Gamifant included viral infection (44%), rash (21%), anemia (18%), leukopenia (15%), thrombosis (15%), bacterial infections (13%), headache (13%), hyperglycemia (13%), infusion-related reactions (13%), abdominal pain (10%), hypertension (10%), pyrexia (10%), and thrombocytopenia (10%).

References

  1. Morimoto A, Nakazawa Y, Ishii E. Hemophagocytic lymphohistiocytosis: pathogenesis, diagnosis, and management. Pediatr Int. 2016;58(9):817-825. doi:10.1111/ped.13064
  2. Di Cola I, Ruscitti P, Giacomelli R, Cipriani P. The pathogenic role of interferons in the hyperinflammatory response on adult-onset Still's disease and macrophage activation syndrome: paving the way towards new therapeutic targets. J Clin Med. 2021;10(6):1164. doi:10.3390/jcm10061164
  3. Prencipe G, Caiello I, Pascarella A, et al. Neutralization of IFN-γ reverts clinical and laboratory features in a mouse model of macrophage activation syndrome. J Allergy Clin Immunol. 2018;141(4):1439-1449. doi:10.1016/j.jaci.2017.07.021
  4. Dustin ML. The immunological synapse. Cancer Immunol Res. 2014;2(11):1023-1033. doi:10.1158/2326-6066.CIR-14-0161
  5. Wissinger E. CD8+ t cells. Imperial College London, UK. British Society for Immunology. Accessed March 29, 2024. https://www.immunology.org/public-information/bitesized-immunology/c%C3%A9lulas/cd8-t-ce
  6. Westburg. T-Cell Mediated Cytotoxicity. Accessed March 29, 2024. https://www.westburg.eu/immunotherapy-for-cancer/active-immunotherapy/t-cell-mediated-cytotoxicity
  7. Price B, Lines J, Lewis D, Holland N. Haemophagocytic lymphohistiocytosis: a fulminant syndrome associated with multiorgan failure and high mortality that frequently masquerades as sepsis and shock. S Afr Med J. 2014;104(6):401-406. doi:10.7196/samj.7810
  8. Young HA, Hodge DL. Interferon-γ. In: Henry HL, Norman AW, eds. Encyclopedia of Hormones. Academic Press. 2003:391-397. doi:10.1016/B0-12-341103-3/00151-0
  9. Arango Duque G, Descoteaux A. Macrophage cytokines: involvement in immunity and infectious diseases. Front Immunol. 2014;5:491. doi:10.3389/fimmu.2014.00491
  10. Lin FC, Karwan M, Saleh B, et al. IFN-γ causes aplastic anemia by altering hematopoietic stem/progenitor cell composition and disrupting lineage differentiation. Blood. 2014;124(25):3699-3708. doi:10.1182/blood-2014-01-549527
  11. Liao W, Florén CH. Tumor necrosis factor up-regulates expression of low-density lipoprotein receptors on HepG2 cells. Hepatology. 1993;17(5):898-907.
  12. Valade S, Joly BS, Veyradier A, et al. Coagulation disorders in patients with severe hemophagocytic lymphohistiocytosis. PLoS One. 2021;16(8):e0251216. doi:10.1371/journal.pone.0251216
  13. Recalcati S, Invernizzi P, Arosio P, Cairo G. New functions for an iron storage protein: the role of ferritin in immunity and autoimmunity. J Autoimmun. 2008;30(1-2):84-89. doi:10.1016/j.jaut.2007.11.003
  14. Brusko TM, Wasserfall CH, Hulme MA, Cabrera R, Schatz D, Atkinson MA. Influence of membrane CD25 stability on T lymphocyte activity: implications for immunoregulation. PLoS One. 2009;4(11):e7980. doi:10.1371/journal.pone.0007980
  15. Crayne CB, Albeituni S, Nichols KE, Cron RQ. The immunology of macrophage activation syndrome. Front Immunol . 2019;10:119. doi:10.3389/fimmu.2019.00119
  16. Jordan MB, Allen CE, Weitzman S, Filipovich AH, McClain KL. How I treat hemophagocytic lymphohistiocytosis. Blood. 2011;118(15):4041-4052. doi:10.1182/blood-2011-03-278127
  17. Sepulveda FE, de Saint Basile G. Hemophagocytic syndrome: primary forms and predisposing conditions. Curr Opin Immunol. 2017;49:20-26. doi:10.1016/j.coi.2017.08.004
  18. Gamifant (emapalumab-lszg) prescribing information. Stockholm, Sweden: Sobi, Inc. 2022.
  1. HOME
  2. Primary HLH
  3. IFNγ in primary HLH

IFNγ is a key cytokine in the immune system1,2

Interferon gamma (IFNγ) is the only type II interferon and plays an important role in cell communication during immune responses. During innate immune responses, IFNγ helps eliminate intracellular pathogens by activating macrophages and natural killer (NK) cells. During adaptive immune responses, IFNγ is responsible for both the differentiation and overproliferation of activated T cells.1,2

In primary hemophagocytic lymphohistiocytosis (HLH), the immune system is dysregulated—and IFNγ contributes directly to disease pathogenesis.1,3

Genetic mutations disrupt immune function4-6

In healthy individuals, antigen-presenting cells (APCs) are recognized by cytotoxic CD8+ T cells, which bind to them to release perforin and granzymes into the immunological synapse space. Perforin creates pores in the target cell's plasma membrane, allowing the cytotoxic granzymes to enter and initiate lysis. In primary HLH, genetic mutations prevent perforin pore formation needed for cell lysis.4-6

Graphic showing perforin and granzyme function

See how IFNγ activates a vicious cycle of hyperinflammation1

Click through to see how IFNγ-activated macrophages trigger the downstream release of proinflammatory cytokines—including additional IFNγ—perpetuating hypercytokinemia and hyperinflammation in an aggressive continuum.1

IFNγ drives the uncontrolled release of cytokines, which result in the rapidly progressive and life-threatening symptoms of primary HLH.

  • Stage 1 of 5
  • Stage 2 of 5
  • Stage 3 of 5
  • Stage 4 of 5 Binding to the Macrophage
  • Stage 5 of 5 The Cytokine Storm
Graphical steps of IFNγ activating a macrophage to release cytokines. Genetic trigger highlighted Graphical steps of IFNγ activating a macrophage to release cytokines. Genetic trigger highlighted

For more information about the critical role of IFNγ in primary HLH, download this guide.

IFNγ Guide

Damaging effects of downstream CYTOKINES

See how IFNγ triggers clinical and laboratory manifestations of disease.

Signs and symptoms
Drivers
Fever9
  • Activated macrophages release pyrogenic IL-6, IL-1, and TNF-α
Cytopenia10
  • Activated macrophages can lead to the destruction of bone marrow
  • Decreased stem cell proliferation and hypercytokinemia result in cytopenia
Hypertriglyceridemia9,11
  • Activated macrophages release TNF-α
  • TNF-α stimulates hepatic lipid synthesis
Hypofibrinogenemia12
  • IFNγ stimulates macrophages to release plasminogen activator
  • Plasminogen activator produces plasmin, the predominant enzyme responsible for fibrinolysis
Hyperferritinemia9,13
  • Activated macrophages release TNF-α, which upregulates ferritin synthesis in hepatocytes and other macrophages
Elevated soluble CD25 (sCD25)14
  • sCD25 levels are elevated during T cell activation and production of IFNγ
Hepatosplenomegaly9
  • Activated macrophages release IL-6 and TNF-α
  • Increased acute inflammatory response, lymphocyte infiltration, and activation
Elevated liver enzymes9
  • IL-1β, IL-6, and TNF-α released from IFNγ-activated macrophages drive acute-phase protein production in liver
  • Activated hepatic macrophages can also cause liver damage
Hemophagocytosis15
  • Overactive macrophages lead to hemophagocytosis in the liver, spleen, and bone marrow

The critical role of IFNγ

The critical role of IFNγ

IFNγ was found to be essential for the development of HLH-like pathology. In murine models, inhibition of this cytokine led to an improvement of known features of HLH, including2,3:

  • Increased blood cell counts
    (hemoglobin, platelets, and/or neutrophils)
  • Significant reduction of triglyceride and ferritin levels
  • Normalization of histopathological features of the spleen
  • Reduction of macrophage activation, as evidenced by the reduction of hemophagocytosis in the liver

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  2. Testing for Primary HLH

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  2. Treatment

Looking for more?

Discover the storm

Primary hemophagocytic lymphohistiocytosis (HLH) is a rare hyperinflammatory condition that mostly affects children, but can also occur in adults and teenagers.16,17

Gamifant controls the inflammatory symptoms of primary HLH by neutralizing IFNγ.18

Dosing and Administration

Gamifant is given as an intravenous infusion twice per week until the patient no longer requires therapy for the treatment of HLH or until hematopoietic stem cell transplantation (HSCT) is performed.18

ORDERING GAMIFANT

Contact your Sobi Health Systems Director to understand Gamifant ordering options. Connect with your Reimbursement Manager for your individual patient's insurance coverage policy and reimbursement pathway.

Help through the storm

Here you’ll find tools and resources to help your patients and their families.