Emapalumab – Uses, Dosage, Side Effects, Interaction

Emapalumab is an interferon-gamma-blocking antibody used to treat primary hemophagocytic lymphohistiocytosis.

Emapalumab, also known as NI-0501, is a fully human monoclonal antibody that targets interferon-gamma. Emapalumab development was sponsored by NovImmune SA, further developed by Sobi, and FDA-approved on November 20, 2018.^[rx,rx] The approval of emapalumab was followed by the designation of an orphan drug, priority review, and breakthrough therapy.^[rx] As well, emapalumab was given the status of PRIME by the EMA.^[rx]

Mechanism of action

Emapalumab acts by binding and neutralizing interferon-gamma.^[rx] The specific interaction between emapalumab and interferon-gamma produces an inhibition in the interaction between interferon-gamma and its cognate receptor on T-cells which produces the neutralizing activity.^[rx] It is important to consider that emapalumab inhibits both free and IFNGR1-bound interferon-gamma as well as the interaction with IFNGR1 and IFNGR2 at the cell surface.^[rx]

HLH is an immune dysregulation syndrome in which several cytokines are involved but it has been reported that interferon-gamma plays a pivotal role in the development of this disease as studies have shown a vast increase in the interferon-gamma levels in HLH patients.^[rx]

In phase 2/3 clinical? trials, emapalumab administered concomitantly with dexamethasone reported an overall response in 63% of the patients. The overall response was defined as the achievement of complete or partial response or HLH improvement.^[rx] In this trial and as proof of interferon-gamma neutralization, there was registered a sharp decrease in serum CXCL9 and to avoid QT prolongation in the presence of low doses of emapalumab.^[rx]

Indications

• Emapalumab is indicated for the treatment of pediatric and adult patients with primary hemophagocytic lymphohistiocytosis (HLH) with refractory?, recurrent?, or progressive disease or intolerance to conventional HLH therapy.^[rx]
• The HLH condition is a hyperinflammatory status characterized by the overwhelming activation of normal T lymphocytes and macrophages which can lead to disturbances in the hematology profile and even death. As part of the condition profile, there have been reports proving a massive overexpression of interferon-gamma which is thought to drive the immune hyperactivation leading to organ failure.^[rx] This condition is usually developed and presents the symptomatic profile within the first months or years of life. These symptoms consist of fever, enlarged liver or spleen, and a lower number of blood cells.^[rx]
• Progressive, refractory, primary intolerance with conventional therapy, recurrent Hemophagocytic Lymphohistiocytosis
• Emapalumab is used to treat primary hemophagocytic lymphohistiocytosis (HLH) with refractory, recurrent, or progressive disease or intolerance with conventional HLH therapy.
• For the treatment of primary hemophagocytic lymphohistiocytosis (HLH) with refractory, recurrent, or progressive disease or intolerance with conventional HLH therapy

Use in Cancer

Emapalumab-lzsg is approved to treat:

• Hemophagocytic lymphohistiocytosis (HLH) is inherited. It is used in adults and children (newborn and older) whose disease is refractory (does not respond to treatment), has recurred, has gotten worse, or cannot be treated with other therapies for HLH.

Emapalumab-lzsg is also being studied in the treatment of other conditions.

Contraindications

• active tuberculosis?
• shingles
• a type of fungal? lung infection? called histoplasmosis
• an infection due to a fungus
• pneumonia? with a fungus called Pneumocystis jirovecii

Dosage?

Strengths: lzsg 5 mg/mL

Histiocytosis

• Initial dose: 1 mg/kg IV over 1 hour 2 times a week (every 3 to 4 days)
• Doses after the initial dose may be increased stepwise to 10 mg/kg based on clinical and laboratory criteria (see Dose Adjustments).
• Duration of therapy: Until hematopoietic stem cell transplantation (HSCT) is performed or unacceptable toxicity; discontinue when a patient no longer requires treatment of HLH.

Premedication/Concomitant Medication:

• For patients who are not receiving baseline? dexamethasone: Begin dexamethasone at a daily dose of at least 5 to 10 mg/m2 the day before initiation of this drug.
• For patients who were receiving baseline dexamethasone: They may continue their regular dose provided the dose is at least 5 mg/m2.
• Dexamethasone can be tapered according to the judgment of the physician.
• Test for latent? TB? using the purified protein derivative (PPD) or IFNy release assay and evaluate patients for TB risk factors.
• Administer TB prophylaxis to patients at risk, or known to have a positive PPD test result or positive IFNy release assay.
• Administer prophylaxis for herpes zoster, Pneumocystis jirovecii, and fungal infections prior to therapy initiation.
• During therapy monitor for TB, adenovirus, EBV, and CMV every 2 weeks and as clinically indicated.

Pediatric Dose for Histiocytosis

• Initial dose: 1 mg/kg IV over 1 hour 2 times a week (every 3 to 4 days)
• Doses after the initial dose may be increased stepwise to 10 mg/kg based on clinical and laboratory criteria (see Dose Adjustments).
• Duration of therapy: Until hematopoietic stem cell transplantation (HSCT) is performed or unacceptable toxicity; discontinue when a patient no longer requires treatment of HLH.

Premedication/Concomitant Medication:

• For patients who are not receiving baseline dexamethasone: Begin dexamethasone at a daily dose of at least 5 to 10 mg/m2 the day before initiation of this drug.
• For patients who were receiving baseline dexamethasone: They may continue their regular dose provided the dose is at least 5 mg/m2.
• Dexamethasone can be tapered according to the judgment of the physician.
• Test for latent TB using the purified protein derivative (PPD) or IFNy release assay and evaluate patients for TB risk factors.
• Administer TB prophylaxis to patients at risk, or known to have a positive PPD test result or positive IFNy release assay.
• Administer prophylaxis for herpes zoster, Pneumocystis jirovecii, and fungal infections prior to therapy initiation.
• During therapy monitor for TB, adenovirus, EBV, and CMV every 2 weeks and as clinically indicated.

Dose Adjustments

Dose Modification Based on Response:

• Day 1: Starting dose of 1 IV mg/kg
• Increase the dose to 3 mg/kg IV on Day 3 for unsatisfactory improvement
• Increase the dose to 6 mg/kg IV on Day 6 onwards for unsatisfactory improvement
• Increase dose to 10 mg/kg IV from Day 9 onwards

NOTE: UNSATISFACTORY IMPROVEMENT ON DAY 3 AND DAY 6 IS DEFINED AS ASSESSED BY A HEALTHCARE PROVIDER AND AT LEAST ONE OF THE FOLLOWING:
FEVER: Persistent or recurring
PLATELET? COUNT:

• If the baseline is less than 50,000/mm3 and no improvement to greater than 50,000/mm3
• If the baseline is greater than 50,000/mm3 and less than 30% improvement
• If the baseline is greater than 100,000/mm3 and decreases to less than 100,000/mm3

NEUTROPHIL? COUNT:

• If the baseline is less than 500/mm3 and no improvement to greater than 500/mm3
• If a baseline is greater than 500 to 1000/mm3 and decreases to less than 500/mm3 -If the baseline is 1000 to 1500/mm3 and decreases to less than 1000/ mm3

FERRITIN (ng/mL):

• If the baseline is 3000 ng/mL or greater and less than a 20% decrease
• If the baseline is less than 3000 ng/mL and any increase to greater than 3000 ng/mL SPLENOMEGALY: Any worsening

COAGULOPATHY? (both D-Dimer? and Fibrinogen must apply):

• D-Dimer: If abnormal at baseline and no improvement
• Fibrinogen (mg/dL): If baseline levels are 100 mg/dL or less and no improvement
• If baseline levels are greater than 100 mg/dL) and any decrease to less than 100 mg/dL

NOTE: UNSATISFACTORY IMPROVEMENT ON DAY 9 IS DEFINED AS:

• Assessment? by a healthcare provider that based on initial signs of response, a further increase in the dose can be of benefit.

Administration advice:

• Administer diluted solution IV over 1 hour through an IV line containing a sterile, non-pyrogenic, low-protein binding 0.2-micron in-line filter.
• Do not infuse this drug concomitantly with other agents and do not add any other product to the infusion bag or syringe.

Side Effects

The Most Common

• constipation?
• nose bleeds
• fast, slow, or irregular heartbeat
• fast breathing
• muscle cramps
• numbness? and tingling?
• bloody or black, tarry stools
• vomiting? blood or brown material that resembles coffee grounds
• decreased urination
• swelling? in the hands, feet, ankles, or lower legs

More common

• Agitation
• back pain?
• black, tarry stools
• bloating or swelling of the face, arms, hands, lower legs, or feet
• bloody stools
• blurred vision
• chest pain, discomfort, or tightness
• chills
• confusion
• cough
• decreased awareness or responsiveness
• decreased urine
• depression
• difficult or labored breathing
• dry mouth
• fast, pounding, or irregular heartbeat or pulse
• feeling of warmth
• fever
• headache
• hoarseness
• hostility
• increased thirst
• irritability
• lightheadedness, dizziness, or fainting
• loss of appetite
• loss of consciousness
• lower back or side pain
• mood changes
• muscle pain, cramps, or twitching
• nausea
• nervousness
• nosebleed
• numbness or tingling in the hands, feet, or lips
• painful or difficult urination
• pounding in the ears
• rapid weight gain
• rapid, shallow breathing
• redness of the face, neck, arms and occasionally, upper chest
• seizures
• severe sleepiness
• slow heartbeat
• swollen glands
• unusual drowsiness, dullness, tiredness, weakness, or feeling of sluggishness
• unusual weight gain or loss
• vomiting
• vomiting of blood or material that looks like coffee grounds

Rare

• fever, chills, night sweats;
• loss of appetite, weight loss;
• feeling very tired;
• warmth, redness, or painful sores on your skin;
• cough, trouble breathing;
• mouth and throat ulcers;
• cough with bloody mucus; or
• any other new or worsening signs of infection.
• fever; or
• increased blood pressure.

Drug Interaction

Pregnancy and Lactation

US FDA pregnancy category: Not assigned.

Pregnancy

The manufacturer makes no recommendation regarding use during pregnancy. There are no available data on the use of this drug in pregnant women to inform a drug-associated risk of adverse developmental outcomes. In animal studies, a murine surrogate anti-mouse antibody administered to pregnant mice throughout gestation crossed the placental barrier, and no fetal harm was observed.

Lactation

Safety has not been established.
Excreted into human milk: Unknown
Excreted into animal milk: Data not available
The effects in the nursing infant are unknown. Available data suggest that only limited amounts of therapeutic antibodies are found in breast milk and they do not enter the neonatal and infant circulations in substantial amounts.

References