GAMIFANT Solution for injection Ref.[10208] Active ingredients: Emapalumab

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.

The pharmacokinetics of emapalumab-lzsg were evaluated in healthy adult subjects and in patients with primary 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 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 4.2 and 5.6 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.

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

In patients, the total clearance of emapalumab-lzsg was significantly influenced by the production of IFNγ, demonstrating target mediated clearance of emapalumab-lzsg.

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 (2 to 82 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 56 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.

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.

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 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 × 10⁹/L, neutrophils <1 × 10⁹/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 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 Capsulatum). 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 3.

Table 3. HLH Mutations in Patients with Primary HLH with Prior Therapy:

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 × 10⁹cells/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 >1 × 10⁹/L, platelets >100 × 10⁹/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 4. Overall Response Rate at End of Treatment:

CI = confidence interval
* 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%.

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.