Identification

Name
Emapalumab
Accession Number
DB14724
Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Monoclonal antibody (mAb)
Description

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, 2018.1,5 The approval of emapalumab was followed by the designation of orphan drug, priority review and breakthrough therapy.5 As well, emapalumab was given the status of PRIME by the EMA.7

Protein chemical formula
C6430H9898N1718O2038S46
Protein average weight
154400.0 Da
Sequences
Not Available
Synonyms
  • emapalumab-lzsg
External IDs
NI-0501
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
GamifantInjection50 mg/10mLIntravenousNovImmune SA2018-11-202021-11-30Us
GamifantInjection10 mg/2mLIntravenousNovImmune SA2018-11-202021-11-30Us
GamifantInjection50 mg/10mLIntravenousSWEDISH ORPHAN BIOVITRUM AB (PUBL)2019-05-17Not applicableUs
GamifantInjection10 mg/2mLIntravenousSWEDISH ORPHAN BIOVITRUM AB (PUBL)2019-05-17Not applicableUs
Additional Data Available
  • Application Number
    Application Number

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

    Learn more
  • Product Code
    Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

    Learn more
Categories
UNII
3S252O2Z4X
CAS number
1709815-23-5

Pharmacology

Indication

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.5

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.1 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.5

Associated Conditions
Pharmacodynamics

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.6 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.8

Mechanism of action

Emapalumab acts by binding and neutralizing interferon-gamma.1 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.7 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.3

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.2

TargetActionsOrganism
AInterferon gamma
neutralizer
Humans
Additional Data Available
Adverse Effects

Comprehensive structured data on known drug adverse effects with statistical prevalence. MedDRA and ICD10 ids are provided for adverse effect conditions and symptoms.

Learn more
Additional Data Available
Contraindications

Structured data covering drug contraindications. Each contraindication describes a scenario in which the drug is not to be used. Includes restrictions on co-administration, contraindicated populations, and more.

Learn more
Additional Data Available
Blackbox Warnings

Structured data representing warnings from the black box section of drug labels. These warnings cover important and dangerous risks, contraindications, or adverse effects.

Learn more
Absorption

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.Label

Volume of distribution

The central and peripheral volume of distribution of emapalumab are 4.2 and 5.6 L, respectively.Label

Protein binding

Monoclonal antibodies are usually not required to have protein binding studies.Label

Metabolism

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.4

Route of elimination

Emapalumab presents a target-mediated clearance that is dependent on interferon-gamma production.Label

Half life

Emapalumab elimination half-life is of approximately 22 days in healthy subjects and it ranges between 2.5-18.9 in HLH patients.Label

Clearance

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.Label

Toxicity

There are no reported effects in male or female reproductive organs after an 8- or 13-week repeat-dose toxicity study in animals.Label

Affected organisms
  • Humans
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
(R)-warfarinThe metabolism of (R)-warfarin can be increased when combined with Emapalumab.
(S)-WarfarinThe metabolism of (S)-Warfarin can be increased when combined with Emapalumab.
2-MethoxyethanolThe risk or severity of adverse effects can be increased when 2-Methoxyethanol is combined with Emapalumab.
4-hydroxycoumarinThe metabolism of 4-hydroxycoumarin can be increased when combined with Emapalumab.
4-MethoxyamphetamineThe metabolism of 4-Methoxyamphetamine can be increased when combined with Emapalumab.
5-methoxy-N,N-dimethyltryptamineThe metabolism of 5-methoxy-N,N-dimethyltryptamine can be increased when combined with Emapalumab.
6-O-benzylguanineThe metabolism of 6-O-benzylguanine can be increased when combined with Emapalumab.
8-azaguanineThe metabolism of 8-azaguanine can be increased when combined with Emapalumab.
8-chlorotheophyllineThe metabolism of 8-chlorotheophylline can be increased when combined with Emapalumab.
9-(N-methyl-L-isoleucine)-cyclosporin AThe risk or severity of adverse effects can be increased when 9-(N-methyl-L-isoleucine)-cyclosporin A is combined with Emapalumab.
Additional Data Available
  • Extended Description
    Extended Description

    Extended description of the mechanism of action and particular properties of each drug interaction.

    Learn more
  • Severity
    Severity

    A severity rating for each drug interaction, from minor to major.

    Learn more
  • Evidence Level
    Evidence Level

    A rating for the strength of the evidence supporting each drug interaction.

    Learn more
  • Action
    Action

    An effect category for each drug interaction. Know how this interaction affects the subject drug.

    Learn more
Food Interactions
Not Available

References

General References
  1. Kaplon H, Reichert JM: Antibodies to watch in 2018. MAbs. 2018 Feb/Mar;10(2):183-203. doi: 10.1080/19420862.2018.1415671. Epub 2018 Jan 16. [PubMed:29300693]
  2. Avau A, Matthys P: Therapeutic Potential of Interferon-gamma and Its Antagonists in Autoinflammation: Lessons from Murine Models of Systemic Juvenile Idiopathic Arthritis and Macrophage Activation Syndrome. Pharmaceuticals (Basel). 2015 Nov 25;8(4):793-815. doi: 10.3390/ph8040793. [PubMed:26610523]
  3. Zuber B, Rudstrom K, Ehrnfelt C, Ahlborg N: Epitope Mapping of Neutralizing Monoclonal Antibodies to Human Interferon-gamma Using Human-Bovine Interferon-gamma Chimeras. J Interferon Cytokine Res. 2016 Sep;36(9):542-51. doi: 10.1089/jir.2016.0017. Epub 2016 Jun 23. [PubMed:27336613]
  4. Tabrizi MA, Tseng CM, Roskos LK: Elimination mechanisms of therapeutic monoclonal antibodies. Drug Discov Today. 2006 Jan;11(1-2):81-8. doi: 10.1016/S1359-6446(05)03638-X. [PubMed:16478695]
  5. FDA news [Link]
  6. Clinical trials [Link]
  7. NHS [Link]
  8. American Society of Hematology [Link]
External Links
RxNav
2104603
Wikipedia
Emapalumab
ATC Codes
L04AA39 — Emapalumab
FDA label
Download (521 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedNot AvailableHealthy Volunteers1
2RecruitingTreatmentJuvenile Idiopathic Arthritis (JIA) / Lymphohistiocytosis, Hemophagocytic / Macrophage Activation Syndrome1
2, 3Active Not RecruitingTreatmentPrimary Haemophagocytic Lymphohistiocytosis / Primary Hemophagocytic Lymphohistiocytosis1
2, 3RecruitingTreatmentHemophagocytic Lymphohistiocytoses1
2, 3RecruitingTreatmentNovel Coronavirus Infectious Disease (COVID-19)1
3RecruitingTreatmentHaemophagocytic Lymphohistiocytosis / Primary Hemophagocytic Hymphohistiocytosis1
Not AvailableRecruitingOtherLymphohistiocytosis, Hemophagocytic1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
InjectionIntravenous10 mg/2mL
InjectionIntravenous50 mg/10mL
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)78 ºCJi-Hee, et al. Front Immunol, 7:394 (2016)
boiling point (°C)Fab and Fc domains denaturates at 60 and 70 ºC respectivelyArnoldus W. et al. (2000). Biophysical Journal. Vol 78. 394-404
water solubility50 mg/mlHuman IgG purified. Product Information
isoelectric point6.6 - 7.2Jin, et al. Electrophoresis. Sep;23(19):3385-91. (2002).

Taxonomy

Description
Not Available
Kingdom
Organic Compounds
Super Class
Organic Acids
Class
Carboxylic Acids and Derivatives
Sub Class
Amino Acids, Peptides, and Analogues
Direct Parent
Peptides
Alternative Parents
Not Available
Substituents
Not Available
Molecular Framework
Not Available
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Neutralizer
General Function
Interferon-gamma receptor binding
Specific Function
Produced by lymphocytes activated by specific antigens or mitogens. IFN-gamma, in addition to having antiviral activity, has important immunoregulatory functions. It is a potent activator of macrop...
Gene Name
IFNG
Uniprot ID
P01579
Uniprot Name
Interferon gamma
Molecular Weight
19348.165 Da
References
  1. Kaplon H, Reichert JM: Antibodies to watch in 2018. MAbs. 2018 Feb/Mar;10(2):183-203. doi: 10.1080/19420862.2018.1415671. Epub 2018 Jan 16. [PubMed:29300693]

Drug created on November 29, 2018 10:57 / Updated on March 01, 2020 21:55

Logo pink
Are you a
new drug developer?
Contact us to learn more about our customized products and solutions.
Logo pink
Stay in the know!
As part of our commitment to providing the most up-to-date drug information, we will be releasing #DrugBankUpdates with our newly added curated drug pages.
#DrugBankUpdates