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General Description:

Emapalumab, identified by CAS number 1709815-23-5, is a notable compound with significant therapeutic applications. 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. The approval of emapalumab was followed by the designation of orphan drug, priority review and breakthrough therapy. As well, emapalumab was given the status of PRIME by the EMA.

Indications:

This drug is primarily indicated for: 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. 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. This condition is usually developed and present 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. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Emapalumab undergoes metabolic processing primarily in: Monoclonal antibodies are thought to be internalized in endothelial cells bound to Fc receptor and rescued from metabolism by recycling. Later, they are degraded in the reticuloendothelial system to small peptides and amino acids which can be used for de-novo protein synthesis. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Emapalumab are crucial for its therapeutic efficacy: In clinical pharmacokinetic studies, a dose of 1 mg/kg of emapalumab was administered which generated a peak concentration at steady state of 44 mcg/ml and a median steady-state concentration of 25 mcg/ml. The serum concentration of emapalumab increases proportionally between a dose of 1-3 mg/kg and the steady-state is attained by the 7th infusion. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Emapalumab is an important consideration for its dosing schedule: Emapalumab elimination half-life is of approximately 22 days in healthy subjects and it ranges between 2.5-18.9 in HLH patients. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Emapalumab exhibits a strong affinity for binding with plasma proteins: Monoclonal antibodies are usually not required to have protein binding studies. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Emapalumab from the body primarily occurs through: Emapalumab presents a target-mediated clearance that is dependent on interferon-gamma production. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Emapalumab is distributed throughout the body with a volume of distribution of: The central and peripheral volume of distribution of emapalumab are 4.2 and 5.6 L, respectively. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Emapalumab is a critical factor in determining its safe and effective dosage: Emapalumab clearance is reported to be 0.007 L/h in healthy subjects. This clearance rate can vary in HLH patients depending on the production of interferon-gamma. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Emapalumab exerts its therapeutic effects through: 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 achievement of a complete or partial response or HLH improvement. In this trial and as a 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. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Emapalumab functions by: Emapalumab acts by binding and neutralizing interferon-gamma. 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. 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. 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. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Emapalumab belongs to the None, classified under the direct parent group Peptides. This compound is a part of the Organic Compounds, falling under the Organic Acids superclass, and categorized within the Carboxylic Acids and Derivatives class, specifically within the Amino Acids, Peptides, and Analogues subclass.

Categories:

Emapalumab is categorized under the following therapeutic classes: Agents reducing cytokine levels, Amino Acids, Peptides, and Proteins, Antibodies, Antibodies, Monoclonal, Antineoplastic and Immunomodulating Agents, Blood Proteins, Globulins, Immunoglobulins, Immunoproteins, Immunosuppressive Agents, Interferon gamma Antagonists, Interferon gamma Blocker, Interferon-gamma, Lymphohistiocytosis, Hemophagocytic, Proteins, Selective Immunosuppressants, Serum Globulins. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.

Experimental Properties:

Further physical and chemical characteristics of Emapalumab include:

• Water Solubility: 50 mg/ml
• Melting Point: 78 ºC
• Boiling Point: Fab and Fc domains denaturates at 60 and 70 ºC respectively
• Isoelectric Point: 6.6 - 7.2
• Molecular Weight: 154400.0
• Molecular Formula: C6430H9898N1718O2038S46