Gamifant

Description for Gamifant

Emapalumab-lzsg is an interferon gamma (IFNγ) blocking antibody. Emapalumab-lzsg is produced in Chinese Hamster Ovary cells by recombinant DNA technology. Emapalumab-lzsg is an IgG1 immunoglobulin with a molecular weight of approximately 148 kDa.

GAMIFANT (emapalumab-lzsg) injection for intravenous use is a sterile, preservative-free, clear to slightly opalescent, colorless to slightly yellow solution provided in single-dose vials that require dilution prior to intravenous infusion.

Each vial contains 10 mg/2 mL or 50 mg/10 mL emapalumab-lzsg at a concentration of 5 mg/mL. Each mL also contains the following inactive ingredients: L-Histidine (1.55 mg), L-Histidine monohydrochloride, monohydrate (3.14 mg), Polysorbate 80 (0.05 mg), sodium chloride (7.30 mg), and Water for Injection, USP.

ADVERSE REACTIONS

The following adverse reactions are described elsewhere in the labeling:

• Infections [see Warnings and Precautions (5.1)]
• Increased Risk of Infection with Use of Live Vaccines [see Warnings and Precautions (5.2)]
• Infusion-Related Reactions [see Warnings and Precautions (5.3)]

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 [see Dosage and Administration ( 2.1) and Clinical Studies ( 14)]. 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)
Infectionsa	56
Hypertensionb	41
Infusion-related reactionsc	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
aIncludes viral, bacterial, fungal, and infections in which no pathogen was identified bIncludes secondary hypertension cIncludes 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 Still's disease, including sJIA [see Clinical Studies (14.2)].

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 infectiona   Cytomegalovirus infection or reactivation	44 36
Rashb	21
Anemiac	18
Leukopeniad	15
Thrombosis	15
Bacterial infection	13
Headache	13
Hyperglycemia	13
Infusion-related reactionse	13
Abdominal pain	10
Hypertension	10
Pyrexia	10
Thrombocytopenia	10
aIncludes: 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 bIncludes: rash maculo-papular, rash erythematous, rash pruritic, urticaria cIncludes: anemia macrocytic, and hypochromic anemia dIncludes: granulocytopenia, neutropenia eInfusion-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

Drug Interactions for 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.

Warnings for Gamifant

Included as part of the PRECAUTIONS section.

Precautions 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.

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 [see Dosage and Administration ( 2.2)].

Consider prophylaxis for Herpes Zoster, Pneumocystis jirovecii , and fungal infection to mitigate the risk to patients while receiving GAMIFANT [see Dosage and Administration ( 2.3)]. 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 prior to continuing infusion at a slower rate.

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity or genotoxicity studies have been conducted with emapalumab-lzsg.

No studies have been conducted to evaluate the effects of emapalumab-lzsg on fertility; however, no adverse effects on male or female reproductive organs were observed in the 8- or 13-week repeat-dose toxicity studies in cynomolgus monkeys.

OVERDOSAGE

Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdose management recommendations.

Contraindications for Gamifant

No information provided

Clinical Pharmacology for Gamifant

Mechanism of Action

Emapalumab-lzsg is a monoclonal antibody that binds to and neutralizes interferon gamma (IFNγ). Nonclinical data suggest that IFNγ plays a pivotal role in the pathogenesis of HLH by being hypersecreted.

Pharmacodynamics

IFNγ Inhibition

Emapalumab-lzsg reduces the plasma concentrations of CXCL9, a chemokine induced by IFNγ.

Cardiac Electrophysiology

At a dose of 3 mg/kg GAMIFANT does not prolong the QT interval to any clinically relevant extent.

Pharmacokinetics

The pharmacokinetics of emapalumab-lzsg were evaluated in healthy adult subjects and in patients with HLH.

Following a 1 mg/kg emapalumab-lzsg dose, median steady state peak concentration was 44 mcg/mL, which was 2.9 times higher than after the first dose. The median steady state trough concentration was 25 mcg/mL, which was 4.3 times higher than after the first dose. Emapalumab-lzsg AUC increases slightly more than proportionally between 1 and 3 mg/kg doses, and less than proportionally at 3, 6, and 10 mg/kg doses.

Emapalumab-lzsg exhibits target-mediated-like clearance dependent on IFNγ production, which can vary between and within patients as a function of time and can affect the recommended dosage [see Dosage and Administration ( 2.2)]. Emapalumab-lzsg steady state is achieved by the 7th infusion when the IFNγ production is moderate. At high IFNγ production, steady-state is reached earlier due to a shorter half-life.

Distribution

The central and peripheral volumes of distribution in a subject with body weight of 70 kg are 2.8 and 4.4 L, respectively.

Elimination

Emapalumab-lzsg elimination half-life is approximately 22 days in healthy subjects and ranged from 2.5 to 18.9 days in HLH patients.

In patients with HLH, the elimination half-life of emapalumab-lzsg was significantly influenced by the amount of IFNγ within the patient, demonstrating a target mediated clearance-like mechanism. The elimination half-life of emapalumab-lzsg is reduced as the concentration of IFNy increases.

Emapalumab-lzsg clearance is approximately 0.007 L/h in healthy subjects.

Metabolism

The metabolic pathway of emapalumab-lzsg has not been characterized. Like other protein therapeutics, GAMIFANT is expected to be degraded into small peptides and amino acids via catabolic pathways.

Specific Populations

Body weight (3 to 80 kg) was a significant covariate of emapalumab-lzsg pharmacokinetics, supporting body weight-based dosing.

No clinically significant differences in the pharmacokinetics of emapalumab-lzsg were observed based on age (0.02 to 64 year), sex (53% Females), race (71.4% Caucasian, 12.2% Asian and 8.2% Black), renal impairment including dialysis, or hepatic impairment (mild, moderate, and severe).

Drug Interaction Studies

No drug-drug interaction studies have been conducted with GAMIFANT.

Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other emapalumab products may be misleading.

The immunogenicity of emapalumab-lzsg has been evaluated using an

electrochemiluminescence-based immunoassay (ECLIA). Treatment-emergent anti-drug antibodies (ADAs) were detected in 1/33 (3%) of patients in the primary HLH clinical trial. The ADAs in this patient were found to have neutralizing ability. Treatment-emergent ADAs were detected in 5/35 patients (14%) in the two HLH/MAS clinical trials. None of the ADAs in these 5 patients were found to have neutralizing ability. No evidence of an altered pharmacokinetic, safety or efficacy profile was identified in primary HLH or HLH/MAS patients who developed antibodies to emapalumab-lzsg.

Patient Information for Gamifant

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Infections

Inform patients and their caregivers of the risk of developing infections during treatment with GAMIFANT, and to report any symptoms of infection [see Warnings and Precautions ( 5.1)].

Vaccinations

Advise patients and their caregivers that the patient should not receive live or live attenuated vaccines during GAMIFANT treatment [see Warnings and Precautions ( 5.2)].

Infusion-Related Reactions

Advise patients and their caregivers of the potential for developing infusion-related reactions during treatment with GAMIFANT [see Warnings and Precautions ( 5.3)].