Identification

Summary

Ropeginterferon alfa-2b is a mono-pegylated type I interferon used to treat polycythemia vera.

Brand Names
Besremi
Generic Name
Ropeginterferon alfa-2b
DrugBank Accession Number
DB15119
Background

Polycythemia vera (PV) is the most common Philadelphia chromosome-negative myeloproliferative neoplasm (MPN), characterized by increased hematocrit and platelet/leukocyte counts, an increased risk for hemorrhage and thromboembolic events, and a long-term propensity for myelofibrosis and leukemia.1,2 Interferon alfa-2b has been used for decades to treat PV but requires frequent dosing and is not tolerated by all patients.2 Ropeginterferon alfa-2b is a next-generation mono-pegylated type I interferon produced from proline-IFN-α-2b in Escherichia coli that has high tolerability and a long half-life.4,6 Ropeginterferon alfa-2b has shown efficacy in PV in in vitro and in vivo models and clinical trials.3,4

Ropeginterferon alfa-2b was approved by the FDA on November 12, 2021, and is currently marketed under the trademark BESREMi by PharmaEssentia Corporation.6

Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Interferons
Protein Structure
Protein Chemical Formula
C16H29N3O6(C2H4O)n(C2H4O)n
Protein Average Weight
60000.0 Da (approximate)
Sequences
Not Available
Synonyms
  • Ropeginterferon alfa-2b
External IDs
  • AOP2014

Pharmacology

Indication

Ropeginterferon alfa-2b is indicated for the treatment of adult patients with polycythemia vera.6

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Associated Conditions
Contraindications & Blackbox Warnings
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Pharmacodynamics

Ropeginterferon alfa-2b acts through the interferon-alpha/beta receptor to initiate downstream JAK/STAT signalling leading to its therapeutic effects. Like other interferon alfa products, ropeginterferon alfa-2b may cause various toxicities, including endocrine, cardiovascular, pulmonary, ophthalmologic, dental/periodontal, renal, and dermatological toxicity. In addition, interferon alfa has been associated with hepatotoxicity, including increases in serum ALT, AST, GGT, and bilirubin; ropeginterferon alfa-2b is contraindicated in patients with moderate to severe (Child-Pugh B or C) hepatic impairment. Pancreatitis and colitis, including fatal ulcerative/hemorrhagic/ischemic colitis, have occurred in patients treated with interferon alfa. Significant toxicity of any kind may require treatment discontinuation. Interferon alfa treatment has decreased peripheral blood counts, including thrombocytopenia and leukopenia, and altered lipid levels, including hyperlipidemia, hypertriglyceridemia, and dyslipidemia. Hypersensitivity reactions, including anaphylaxis, may occur; ropeginterferon alfa-2b is contraindicated in hypersensitive patients and those with known hypersensitivity to other interferons. Life-threatening or fatal neuropsychiatric reactions may occur, including in patients without prior history; ropeginterferon alfa-2b is contraindicated in patients with a history of severe psychiatric disorders. Finally, ropeginterferon alfa-2b can cause fetal harm and should be used with caution in females of reproductive potential.6

Mechanism of action

Polycythemia vera (PV) is the most common Philadelphia chromosome-negative myeloproliferative neoplasm (MPN), which also includes essential thrombocytopenia and myelofibrosis.1,2 PV is characterized by increased hematocrit and platelet/leukocyte counts, an increased risk for hemorrhage and thromboembolic events, and a long-term propensity for myelofibrosis and leukemia. The main driver mutation, JAK2 V617F, is present in >95% of PV patients and results in constitutive JAK/STAT signalling; other exon 12 mutations in JAK2 may also result in PV. PV results in clonal hematopoietic stem cells, such that they form endogenous erythroid colonies (EECs) in vitro.1

Interferon alfa-2b has been used for decades in PV despite the lack of formal approval.2 Although the mechanism of action is unclear, interferon alfa-2b is known to bind the interferon-alpha/beta receptor (IFNAR) and activate downstream JAK/STAT signalling.2,6 The overall result is a series of anti-proliferative, anti-angiogenic, pro-apoptotic, and immunomodulatory effects, including augmenting T-cell, macrophage, and natural killer cells.2 Interestingly, in vitro studies have revealed that ropeginterferon alfa-2b is specific to some extent for JAK2-mutant EECs, a result that is in line with the reduced allelic burden observed in clinical trials.3,4 Partial and complete molecular and hematological responses have been achieved with ropeginterferon alfa-2b.4

TargetActionsOrganism
AInterferon alpha/beta receptor (IFNAR)
binder
Humans
Absorption

In patients with polycythemia vera on a two-week dosing interval, the estimated steady-state Cmin was 1.4-12 ng/mL, Cmax was 4.4-31 ng/mL, and AUC was 1011-7809 ng*h/mL. The estimated geometric mean (%CV) of the absorption rate constant if 0.12 day-1 (27%) and the estimated steady-state Cmax occurs between 2-5 days.6

Volume of distribution

Ropeginterferon alfa-2b has an estimated geometric mean apparent volume of distribution (%CV) of 4.8 L (21%) in polycythemia vera patients.6

Protein binding

Not Available

Metabolism

Ropeginterferon alfa-2b is expected to be catabolized by various proteolytic enzymes.5

Route of elimination

Ropeginterferon alfa-2b is expected to be eliminated predominantly by hepatic metabolism.5

Half-life

Ropeginterferon alfa-2b administered to polycythemia vera patients over a dose range of 100-500 μg has a half-life of approximately seven days.6

Clearance

Ropeginterferon alfa-2b administered to polycythemia vera patients over a dose range of 100-500 μg has a clearance of 1.7-2.5 L/h.6

Adverse Effects
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Toxicity

Ropeginterferon alfa-2b overdose may present with influenza-like symptoms or other adverse reactions. As there is no known antidote, symptomatic and supportive care should be administered in the result of an overdose. Ropeginterferon alfa-2b is not mutagenic in standard assays but has not been tested for carcinogenic potential.6

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
1,2-BenzodiazepineThe risk or severity of neuropsychiatric effects can be increased when Ropeginterferon alfa-2b is combined with 1,2-Benzodiazepine.
AbataceptThe risk or severity of adverse effects can be increased when Abatacept is combined with Ropeginterferon alfa-2b.
AbciximabThe risk or severity of bleeding can be increased when Abciximab is combined with Ropeginterferon alfa-2b.
AcebutololThe metabolism of Acebutolol can be decreased when combined with Ropeginterferon alfa-2b.
AcenocoumarolThe metabolism of Acenocoumarol can be decreased when combined with Ropeginterferon alfa-2b.
AcetaminophenThe metabolism of Acetaminophen can be decreased when combined with Ropeginterferon alfa-2b.
AcetazolamideThe risk or severity of neuropsychiatric effects can be increased when Ropeginterferon alfa-2b is combined with Acetazolamide.
AcetophenazineThe risk or severity of neuropsychiatric effects can be increased when Ropeginterferon alfa-2b is combined with Acetophenazine.
Acetylsalicylic acidThe risk or severity of bleeding can be increased when Acetylsalicylic acid is combined with Ropeginterferon alfa-2b.
AcyclovirThe metabolism of Acyclovir can be decreased when combined with Ropeginterferon alfa-2b.
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Food Interactions
No interactions found.

Products

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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
BesremiInjection, solution500 ?g/0.5mlSubcutaneousAop Orphan Pharmaceuticals Gmb H2020-12-16Not applicableEU flag
BesremiInjection, solution250 ?g/0.5mlSubcutaneousAop Orphan Pharmaceuticals Gmb H2020-12-16Not applicableEU flag
BesremiInjection, solution250 ?g/0.5mlSubcutaneousAop Orphan Pharmaceuticals Gmb H2021-03-03Not applicableEU flag
BESREMiInjection500 ug/1mLSubcutaneousPharmaEssentia USA2021-11-12Not applicableUS flag

Categories

ATC Codes
L03AB15 — Ropeginterferon alfa-2b
Drug Categories
Chemical TaxonomyProvided by Classyfire
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
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
981TME683S
CAS number
1335098-50-4

References

General References
  1. Bartalucci N, Guglielmelli P, Vannucchi AM: Polycythemia vera: the current status of preclinical models and therapeutic targets. Expert Opin Ther Targets. 2020 Jul;24(7):615-628. doi: 10.1080/14728222.2020.1762176. Epub 2020 May 18. [Article]
  2. How J, Hobbs G: Use of Interferon Alfa in the Treatment of Myeloproliferative Neoplasms: Perspectives and Review of the Literature. Cancers (Basel). 2020 Jul 18;12(7). pii: cancers12071954. doi: 10.3390/cancers12071954. [Article]
  3. Verger E, Soret-Dulphy J, Maslah N, Roy L, Rey J, Ghrieb Z, Kralovics R, Gisslinger H, Grohmann-Izay B, Klade C, Chomienne C, Giraudier S, Cassinat B, Kiladjian JJ: Ropeginterferon alpha-2b targets JAK2V617F-positive polycythemia vera cells in vitro and in vivo. Blood Cancer J. 2018 Oct 4;8(10):94. doi: 10.1038/s41408-018-0133-0. [Article]
  4. Gisslinger H, Zagrijtschuk O, Buxhofer-Ausch V, Thaler J, Schloegl E, Gastl GA, Wolf D, Kralovics R, Gisslinger B, Strecker K, Egle A, Melchardt T, Burgstaller S, Willenbacher E, Schalling M, Them NC, Kadlecova P, Klade C, Greil R: Ropeginterferon alfa-2b, a novel IFNalpha-2b, induces high response rates with low toxicity in patients with polycythemia vera. Blood. 2015 Oct 8;126(15):1762-9. doi: 10.1182/blood-2015-04-637280. Epub 2015 Aug 10. [Article]
  5. EMA Approved Products: Besremi (ropeginterferon alfa-2b ) solution for injection [Link]
  6. FDA Approved Drug Products: BESREMi (ropeginterferon alfa-2b-njft) injection [Link]
RxNav
2587059
Wikipedia
Ropeginterferon_alfa-2b

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3Active Not RecruitingPreventionChronic Myeloid Leukemia in Remission1
3CompletedOtherPolycythemia Vera (PV)1
3CompletedTreatmentChronic Hepatitis C Virus (HCV) Infection1
3CompletedTreatmentPolycythemia Vera (PV)2
3RecruitingTreatmentEssential Thrombocythemia (ET)1
3RecruitingTreatmentPolycythemia Vera (PV)1
2Active Not RecruitingTreatmentPolycythemia Vera (PV)2
2Active Not RecruitingTreatmentPrimary Myelofibrosis (PMF) / Secondary Myelofibrosis1
2CompletedTreatmentPolycythemia Vera (PV)1
2Not Yet RecruitingTreatmentEssential Thrombocythemia (ET)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
InjectionSubcutaneous500 ug/1mL
Injection, solutionSubcutaneous250 MCG/0.5ML
Injection, solutionSubcutaneous250 ?g/0.5ml
Injection, solutionSubcutaneous500 ?g/0.5ml
Injection, solutionSubcutaneous500 MCG/0.5ML
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available

Targets

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Kind
Protein group
Organism
Humans
Pharmacological action
Yes
Actions
Binder
Curator comments
Although the exact mechanism of action remains unclear, ropeginterferon alfa-2b binds the interferon alfa/beta receptor to induce downstream JAK-STAT signalling.
General Function
Type i interferon receptor activity
Specific Function
Associates with IFNAR2 to form the type I interferon receptor. Receptor for interferons alpha and beta. Binding to type I IFNs triggers tyrosine phosphorylation of a number of proteins including JA...

Components:
References
  1. FDA Approved Drug Products: BESREMi (ropeginterferon alfa-2b-njft) injection [Link]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inhibitor
General Function
Steroid hydroxylase activity
Specific Function
Exhibits a high coumarin 7-hydroxylase activity. Can act in the hydroxylation of the anti-cancer drugs cyclophosphamide and ifosphamide. Competent in the metabolic activation of aflatoxin B1. Const...
Gene Name
CYP2A6
Uniprot ID
P11509
Uniprot Name
Cytochrome P450 2A6
Molecular Weight
56501.005 Da
References
  1. FDA Approved Drug Products: BESREMi (ropeginterferon alfa-2b-njft) injection [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inhibitor
Curator comments
Inhibition of CYP1A2 is not reported across all sources.
General Function
Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP1A2
Uniprot ID
P05177
Uniprot Name
Cytochrome P450 1A2
Molecular Weight
58293.76 Da
References
  1. Delaporte E, Renton KW: Cytochrome P4501A1 and cytochrome P4501A2 are downregulated at both transcriptional and post-transcriptional levels by conditions resulting in interferon-alpha/beta induction. Life Sci. 1997;60(10):787-96. doi: 10.1016/s0024-3205(97)00006-4. [Article]
  2. EMA Approved Products: Besremi (ropeginterferon alfa-2b ) solution for injection [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inhibitor
Curator comments
Inhibition of CYP2D6 is not reported across all sources.
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic...
Gene Name
CYP2D6
Uniprot ID
P10635
Uniprot Name
Cytochrome P450 2D6
Molecular Weight
55768.94 Da
References
  1. EMA Approved Products: Besremi (ropeginterferon alfa-2b ) solution for injection [Link]

Drug created at May 20, 2019 14:51 / Updated at December 03, 2021 07:35