Gamifant Drug Information
Generic name: EMAPALUMAB-LZSG
Interferon gamma Blocker [EPC]
Uses of Gamifant
is indicated for the treatment of: adult and pediatric patients with primary hemophagocytic lymphohistiocytosis (HLH) with refractory, recurrent or progressive disease or intolerance with conventional HLH therapy. adult and pediatric patients with 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. GAMIFANT is an interferon gamma (IFNγ) neutralizing antibody indicated for the treatment of: adult and pediatric patients with primary hemophagocytic lymphohistiocytosis (HLH) with refractory, recurrent or progressive disease or intolerance with conventional HLH therapy. adult and pediatric patients with 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.
Dosage & Administration of Gamifant
Side Effects of Gamifant
Clinical Trial Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Primary HLH The safety data described in this section reflect exposure to GAMIFANT in which 34 patients with untreated primary HLH and previously treated patients with primary HLH ( NCT01818492 ) received GAMIFANT at a starting dose of 1 mg/kg every 3 days with dose increases up to 10 mg/kg . The median duration of treatment with GAMIFANT was 59 days (range: 4 to 245 days) and the median cumulative dose was 25 mg/kg (range: 4 to 254 mg/kg). The median age of study population was 1 year (range: 0.1 to 13 years), 53% were female, and 65% were Caucasian. 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 two (6%) of patients and included septic shock and gastrointestinal hemorrhage. Disseminated histoplasmosis led to drug discontinuation in one patient.
The most commonly reported adverse reactions (≥20%) were infections, hypertension, infusion-related reactions, and pyrexia. Adverse reactions reported in ≥10% of patients during treatment with GAMIFANT are presented in Table 4. Table 4 : Adverse Reactions Reported in 10% of Patients with Primary HLH Adverse Reactions GAMIFANT (%) (N = 34) Infections a 56 Hypertension b 41 Infusion-related reactions c 27 Pyrexia 24 Hypokalemia 15 Constipation 15 Rash 12 Abdominal pain 12 Cytomegalovirus infection 12 Diarrhea 12 Lymphocytosis 12 Cough 12 Irritability 12 Tachycardia 12 Tachypnea 12 a Includes viral, bacterial, fungal, and infections in which no pathogen was identified b Includes secondary hypertension c Includes events of drug eruption, pyrexia, rash, erythema, and hyperhidrosis Additional selected adverse reactions (all grades) that were reported in less than 10% of patients treated with GAMIFANT included: vomiting, acute kidney injury, asthenia, bradycardia, dyspnea, gastro-intestinal hemorrhage, epistaxis, and peripheral edema. HLH/MAS The safety of GAMIFANT was evaluated in two open-label clinical studies in patients with HLH/MAS in Stills disease, including sJIA . The pooled safety data from these two studies included 39 patients who received an initial dose of 6 mg/kg followed by 3 mg/kg every 3 days until Day 16, and then twice weekly thereafter.
The median duration of treatment with GAMIFANT was 29 days (range: 7 to 220 days) and the median cumulative dose was 33 mg/kg (range: 12 to 175 mg/kg). 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. Pneumonia led to drug discontinuation in one patient (3%). The most common adverse reactions (≥20%) were viral infections, including cytomegalovirus infection or reactivation, and rash. Adverse reactions reported in ≥ 10% of patients in the pooled safety analysis up to Week 8 during treatment with GAMIFANT are presented in Table 5. Table 5: Adverse Reactions Reported in ≥10% of Patients with HLH/MAS in Still's disease Adverse Reactions GAMIFANT (%) (N = 39) Viral infection a Cytomegalovirus infection or reactivation 44 36 Rash b 21 Anemia c 18 Leukopenia d 15 Thrombosis 15 Bacterial infection 13 Headache 13 Hyperglycemia 13 Infusion-related reactions e 13 Abdominal pain 10 Hypertension 10 Pyrexia 10 Thrombocytopenia 10 a Includes: Cytomegalovirus infection reactivation, Cytomegalovirus infection, Adenovirus test positive, Cytomegalovirus test positive, BK polyomavirus test positive, Respirovirus test positive, Parainfluenzae virus infection, COVID-19, Rhinovirus infection, gastroenteritis Rotavirus, Adenovirus infection, Human herpesvirus 6 infection reactivation, Adenovirus reactivation b Includes: rash maculo-papular, rash erythematous, rash pruritic, urticaria c Includes: anemia macrocytic, and hypochromic anemia d Includes: granulocytopenia, neutropenia e Infusion-related reactions were defined as any event reported to have occurred within 24 hours after the start of infusion and assessed as related to study treatment
Warnings & Cautions for Gamifant
Infections
GAMIFANT may increase the risk of fatal and serious infections to include specific pathogens favored by IFNγ neutralization, including mycobacteria, herpes zoster virus, and Histoplasma capsulatum. Do not administer GAMIFANT in patients with infections caused by these pathogens 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.
The reported infections were viral (41%), bacterial (35%), fungal (9%), and the pathogen was not identified in 15% of cases. 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. The reported infections were viral (44%), bacterial (13%), fungal (3%) and the pathogen was not identified in (13%) of patients.
In the GAMIFANT clinical trials, additional infections were reported in patients treated with GAMIFANT including herpes zoster (2.4%) and mycobacterial infections (2.4%). Evaluate patients for tuberculosis risk factors and test for latent infection (PPD testing, PCR, or IFNγ release assay) 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 to mitigate the risk to patients 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. Infusion-related reactions were defined as any event reported to have occurred within 24 hours after the start of infusion and assessed as related to GAMIFANT. In the GAMIFANT clinical trials, additional infusion-related reactions that were reported in less than 3% of patients treated with GAMIFANT included: malaise, sinus tachycardia, feeling hot, and acute respiratory failure. Monitor patients for infusion-related reactions which can be severe.
Interrupt the infusion for infusion reactions and institute appropriate medical management prior to continuing infusion at a slower rate.
Drug Interactions with Gamifant
Effect of
GAMIFANT on Cytochrome P450 Substrates The formation of CYP450 enzymes may be suppressed by increased levels of cytokines (such as IFNγ) during chronic inflammation. By neutralizing IFNγ, use of GAMIFANT may normalize CYP450 activities which may reduce the efficacy of drugs that are CYP450 substrates due to increased metabolism. Upon initiation or discontinuation of concomitant GAMIFANT, monitor for reduced efficacy and adjust dosage of CYP450 substrate drugs as appropriate.
Pregnancy Safety for Gamifant
Pregnancy Risk Summary There are no available data on GAMIFANT use in pregnant women to inform a drug-associated risk of adverse developmental outcomes. In an animal reproduction study, a murine surrogate anti-mouse IFNγ antibody administered to pregnant mice throughout gestation crossed the placental barrier, and no fetal harm was observed (see Data ). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data In a mouse embryo-fetal development study, a murine surrogate anti-mouse IFNγ antibody was administered every 3-4 days throughout organogenesis and late gestation at doses of 0, 30, 75 or 150 mg/kg/occasion. The surrogate antibody was detected in the plasma of all treated pregnant mice and their corresponding fetuses.
No maternal toxicity occurred and there was no evidence of teratogenicity or effects on embryo-fetal survival or growth.
Pediatric Use of Gamifant
Pediatric Use Safety and effectiveness of GAMIFANT have been established in pediatric patients with primary HLH that is reactivated or refractory to conventional therapies and with HLH/MAS in Still’s Disease (including sJIA) with an inadequate response to glucocorticoids. Use of GAMIFANT is supported by 3 single-arm trials which included 57 pediatric patients: 27 with primary HLH and 30 with HLH/MAS in Still’s disease. These studies included pediatric patients in the following age groups: 5 patients newborn to 6 months, 13 patients 6 months to 2 years, 27 patients from 2 years to <12 years, and 12 patients from 12 years to <17 years.
Overdosage Information for Gamifant
Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdose management recommendations.
Clinical Studies of Gamifant
Primary Hemophagocytic Lymphohistiocytosis
The efficacy of GAMIFANT was evaluated in a multicenter, open-label, single-arm trial NI-0501-04 ( NCT01818492 ) in 27 pediatric patients with suspected or confirmed primary Hemophagocytic lymphohistiocytosis (HLH) with either refractory, recurrent, or progressive disease during conventional HLH therapy or who were intolerant of conventional HLH therapy. Patients were required to fulfill the following criteria for enrollment: primary HLH based on a molecular diagnosis or family history consistent with primary HLH or five out of the 8 criteria fulfilled: fever, splenomegaly, cytopenias affecting 2 of 3 lineages in the peripheral blood (hemoglobin < 9, platelets < 100 x 10 9 /L, neutrophils < 1 x 10 9 /L), hypertriglyceridemia (fasting triglycerides > 3 mmol/L or ≥265 mg/dL) and/or hypofibrinogenemia (≤1.5 g/L), hemophagocytosis in bone marrow, spleen, or lymph nodes with no evidence of malignancy, low or absent NK-cell activity, ferritin ≥500 mcg/L, soluble CD25 ≥2400 U/mL. Patients had to have evidence of active disease as assessed by the treating physician. Patients had to fulfill one of the following criteria as assessed by the treating physician: having not responded or not achieved a satisfactory response or not maintained a satisfactory response to conventional HLH therapy, or intolerance to conventional HLH treatments.
Patients with active infections caused by specific pathogens favored by IFNγ neutralization were excluded from the trial (e.g., mycobacteria and Histoplasma c apsulatum ). Patients received prophylaxis for herpes zoster, Pneumocystis jirovecii, and fungal infections. Twenty-seven patients enrolled and received treatment in the study and twenty patients (74%) completed the study. Seven patients (26%) were prematurely withdrawn.
Twenty-two patients (81%) enrolled onto the open-label extension study which monitored patients for up to 1 year after HSCT or after the last GAMIFANT infusion (NI-0501-05; NCT02069899 ). The study treatment duration was up to 8 weeks after which patients could continue treatment on the extension study. All patients received an initial starting dose of GAMIFANT of 1 mg/kg every 3 days. Subsequent doses could be increased to a maximum of 10 mg/kg based on clinical and laboratory parameters interpreted as unsatisfactory response.
Forty-four percent of patients remained at a dose of 1 mg/kg, 30% of patients increased to 3-4 mg/kg and 26% of patients increased to 6-10 mg/kg. The median time to dose increase was 27 days (range: 3-31 days) with 22% of patients requiring a dose increase in the first week of treatment. All patients received dexamethasone as background HLH treatment with doses between 5 to 10 mg/m 2 /day.
Cyclosporine A was continued if administered prior to screening. Patients receiving methotrexate and glucocorticoids administered intrathecally at baseline could continue these treatments. In Study NI-0501-04, the median patient age was 1 year (0.2 to 13). Fifty-nine percent of the patients were female, 63% were Caucasian, 11% were Asian, and 11% were Black.
A genetic mutation known to cause HLH was present in 82% of patients. The most frequent causative mutations were FHL3-UNC13D (MUNC 13-4) (26%), FHL2-PRF1 (19%), and Griscelli Syndrome type 2 (19%). The HLH mutations in the population enrolled are described in Table 6 Table 6: HLH Mutations in Patients with Primary HLH with Prior Therapy GAMIFANT (N=27) HLH Genetic Confirmation 22 FHL3-UNC13D 7 FHL2-PRF1 5 Griscelli Syndrome type 2 (RAB27A) 5 FHL5-STXBP2 (UNC18B) 2 FHL4-STX11 1 X-linked Lymphoproliferative Disorder 1 1 X-linked Lymphoproliferative Disorder 2 1 All patients received previous HLH treatments. Patients received a median of 3 prior agents before enrollment into the trial.
Prior regimens included combinations of the following agents: dexamethasone, etoposide, cyclosporine A, and anti-thymocyte globulin. At baseline entry into the study, 78% of patients had elevated ferritin levels, thrombocytopenia (70% with platelet count of < 100 x 10 9 cells/L), hypertriglyceridemia (67%) with triglyceride level >3 mmol/L. Central nervous system findings were present in 37% of patients. Forty-one percent of patients had active infections not due to specific pathogens favored by IFNγ neutralization at the time of GAMIFANT initiation.
The efficacy of GAMIFANT was based upon overall response rate (ORR) at the end of treatment, defined as achievement of either a complete or partial response or HLH improvement. ORR was evaluated using an algorithm that included the following objective clinical and laboratory parameters: fever, splenomegaly, central nervous system symptoms, complete blood count, fibrinogen and/or D-dimer, ferritin, and soluble CD25 (also referred to as soluble interleukin-2 receptor) levels. Complete response was defined as normalization of all HLH abnormalities (i.e., no fever, no splenomegaly, neutrophils >1x10 9 /L, platelets >100x10 9 /L, ferritin <2,000 µg/L, fibrinogen >1.50 g/L, D-dimer <500 µg/L, normal CNS symptoms, no worsening of sCD25 >2-fold baseline). Partial response was defined as normalization of ≥3 HLH abnormalities.
HLH improvement was defined as ≥3 HLH abnormalities improved by at least 50% from baseline. Table 7: Overall Response Rate at End of Treatment GAMIFANT (N=27) Overall Response Rate N (%) 17 (95% CI) p-value† 0.013 Overall Response by Category Complete response, n (%) 7 Partial response 8 HLH improvement 2 †p-value based on Exact Binomial Test at a one-sided significance level of 2.5% comparing proportion of patients with overall response to hypothesized null hypothesis of 40%. CI = confidence interval The median duration of first response, defined as time from achievement of first response to loss of first response, is not reached (range: 4-56+ days). Seventy percent (19/27) of patients proceeded to HSCT.
Hemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome (MAS) in Still’s disease (including sJIA)
The efficacy of GAMIFANT was evaluated in two open-label, single arm, multicenter studies which enrolled a total of 39 patients with hemophagocytic lymphohistiocytosis (HLH)/macrophage activation syndrome (MAS) in Still’s disease, including systemic Juvenile Idiopathic Arthritis (sJIA), with an inadequate response to high-dose glucocorticoid treatment. In each study, patients were required to fulfill the following criteria for enrollment: confirmed or suspected diagnosis of sJIA or AOSD; a diagnosis of active MAS with ferritin >684 ng/mL and any 2 of these 4 laboratory criteria: platelet count ≤181×10 9 /L, AST >48 U/L, triglycerides >156 mg/dL, or fibrinogen levels ≤360 mg/dL; an inadequate response to high-dose IV glucocorticoids. Patients with active infections caused by specific pathogens favored by IFNγ neutralization were excluded from the trial (e.g., mycobacteria and Histoplasma capsulatum ). In each study, GAMIFANT was administered at an initial dose of 6 mg/kg, followed by at least 3 mg/kg every 3 days until Day 16, and then twice weekly thereafter.
Glucocorticoids and anakinra (<4 mg/kg/d) could be co-administered for the treatment of Still’s disease. Pooled Data The pooled analysis includes all patients from Study NI-0501-06 ( NCT03311854 ) and Study NI-0501-14 ( NCT05001737 ). These two studies enrolled 39 patients who received GAMIFANT, and 37 patients completed the studies (95%). The majority of patients were female (80%) and the median age was 12.0 years (range: 0.9 to 64 years). The racial distribution was White (74%), Asian (10%), Black or African American (5%), and Other (3%), with 3 patients not reporting race (8%). Ethnicity was only collected in Study NI-0501-14 in which 88% reported Not Hispanic or Latino with 3 patients not reporting ethnicity (12%). At baseline, patients had elevated ferritin levels (median 6833 µg/L), elevated ALT (median 259 U/L), and elevated LDH (median 954 U/L). The efficacy of GAMIFANT was based on complete response (CR), a composite endpoint consisting of clinical resolution of MAS signs and symptoms (a visual analogue scale (VAS), of ≤1 cm ) and the following 7 laboratory parameter endpoints: WBC count and platelet count above the lower limit of normal (LLN), LDH, AST and ALT below 1.5×the upper limit of normal (ULN), fibrinogen >100 mg/dL, and ferritin levels decreased ≥80% from values at screening or baseline (whichever was higher) or <2000 ng/mL, whichever was lower (see Table 8). Table 8 – Pooled Efficacy Results Composite endpoint and individual components at Week 8 n/N % of patients 95% CI a Complete response (CR) 21/39 53.8 37.2,
Clinical
MAS remission (VAS ≤ 1 cm) b 32/39 82.1 66.5,
Ferritin reduction to < 2000 ng/mL or an 80% decrease c 33/39
84.6 69.5,
Platelet count above the
LLN 34/39 87.2 72.6,
ALT below 1.5×
ULN 34/39 87.2 72.6,
AST below 1.5×ULN 37/39 94.9 82.7, 99.4 Fibrinogen > 100 mg/dL 35/39
89.7 75.8,
WBC above the
LLN 36/39 92.3 79.1,
LDH below 1.5×ULN 26/39 66.7 49.8, 80.9 a Clopper-Pearson confidence interval is
presented: two-sided 95% confidence interval b Clinical MAS remission was assessed using a visual analogue scale (VAS) where 0 cm referred to no clinical signs or symptoms of MAS and 10 cm referred to the worst possible clinical signs and symptoms of MAS c 80% decrease calculated from values at screening or baseline (whichever was highest) or < 2000 ng/mL, whichever was lowest
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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