Identification

Summary

Ravulizumab is a monoclonal antibody used to treat paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, and myasthenia gravis.

Brand Names
Ultomiris
Generic Name
Ravulizumab
DrugBank Accession Number
DB11580
Background

Ravulizumab is a potent and selective complement 5 (C5) inhibitor. It is a humanized monoclonal IgG2/4 kappa antibody produced in Chinese hamster ovary (CHO) cells.4 Ravulizumab was engineered from eculizumab, another complement inhibitor, to increase the duration of action and reduce the frequency of drug administration.1 It works by blocking terminal complement-mediated inflammation, cell activation, and cell lysis in blood disorders associated with destruction of red blood cells, thrombosis, and impaired bone marrow function.2

Ravulizumab was first approved by the FDA on December 21, 2018, for the treatment of paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome in children and adults.2 It was later approved by the European Commission on July 2, 2019 for the same indications.6 Ravulizumab is also used to treat myasthenia gravis.4 Ravulizumab is currently being investigated for the treatment of Coronavirus disease (COVID-19)-induced microvasculature injury and endothelial damage leading to thrombotic microangiopathy (TMA) causing acute kidney injury (AKI).7

Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Monoclonal antibody (mAb)
Protein Chemical Formula
C6430H9888N1696O2028S48
Protein Average Weight
148000.0 Da (approximate)
Sequences
>A Chain
XVQLVQSGAEVKKPGASVKVSCKASGHIFSNYWIQWVRQAPGQGLEWMGEILPGSGHTEY
TENFKDRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARYFFGSSPNWYFDVWGQGTLVTV
SSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ
SSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPAPPVAGPS
VFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNST
YRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMT
KNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQE
GNVFSCSVLHEALHSHYTQKSLSLSLG
>B Chain
XVQLVQSGAEVKKPGASVKVSCKASGHIFSNYWIQWVRQAPGQGLEWMGEILPGSGHTEY
TENFKDRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARYFFGSSPNWYFDVWGQGTLVTV
SSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ
SSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPAPPVAGPS
VFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNST
YRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMT
KNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQE
GNVFSCSVLHEALHSHYTQKSLSLSLG
>C Chain
DIQMTQSPSSLSASVGDRVTITCGASENIYGALNWYQQKPGKAPKLLIYGATNLADGVPS
RFSGSGSGTDFTLTISSLQPEDFATYYCQNVLNTPLTFGQGTKVEIKRTVAAPSVFIFPP
SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT
LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
>D Chain
DIQMTQSPSSLSASVGDRVTITCGASENIYGALNWYQQKPGKAPKLLIYGATNLADGVPS
RFSGSGSGTDFTLTISSLQPEDFATYYCQNVLNTPLTFGQGTKVEIKRTVAAPSVFIFPP
SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT
LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
References:
  1. KEGG Drug: Ravulizumab [Link]
Download FASTA Format
Synonyms
  • Ravulizumab
  • ravulizumab-cwvz
External IDs
  • ALXN-1210
  • ALXN1210

Pharmacology

Indication

Ravulizumab is indicated for the treatment of adult and pediatric patients one month of age and older with paroxysmal nocturnal hemoglobinuria (PNH).4

It is also indicated for the treatment of adult and pediatric patients one month of age and older with atypical hemolytic uremic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy (TMA). However, the FDA advises against the use of ravulizumab for the treatment of patients with Shiga toxin E. coli related hemolytic uremic syndrome (STEC-HUS).4

Ravulizumab is also indicated for treatment of adult patients with generalized myasthenia gravis (gMG) who are anti-acetylcholine receptor (AChR) antibody-positive.4

The European Commission approved ravulizumab for the treatment of paroxysmal nocturnal haemoglobinuria (PNH) in adults and children with a body weight of 10 kg or more with the following conditions: have hemolysis with clinical symptoms indicative of high disease activity or be clinically stable after having been treated with eculizumab for at least the past six months. Ravulizumab is also indicated for the treatment of hemolytic uremic syndrome (aHUS) in patients with a body weight of 10 kg or more who are either complement inhibitor treatment-naïve or have received eculizumab for at least 3 months and have evidence of response to eculizumab.5

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Associated Conditions
Contraindications & Blackbox Warnings
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Pharmacodynamics

Ravulizumab is a potent long-acting complement inhibitor of C5, which is a key complement protein involved in inflammatory and thrombotic pathways.1 It has a long duration of action and fast onset of action. In a clinical study of adult and pediatric patients with paroxysmal nocturnal hemoglobinuria, completion inhibition of free C5 - determined as the serum concentration of less than 0.5 mcg/mL - was observed by the end of the first ravulizumab infusion: this effect was sustained throughout the entire 26-week treatment period. In patients with atypical hemolytic uremic syndrome, inhibition of C5 was observed in 93% of the patients in the study. C5 inhibition by ravulizumab is exposure-dependent.4

Mechanism of action

Complement system activation plays an important role in innate and acquired immunity. Paroxysmal nocturnal hemoglobinuria (PNH) is a hematopoietic stem cell disorder characterized by hemolytic anemia, bone marrow failure, and thrombosis. It is caused by a genetic mutation, leading to complement-mediated hemolysis and deficiencies in glycosylphosphatidylinositol (GPI)-linked proteins such as those involved in fibrinolysis.2 Atypical hemolytic uraemic syndrome (aHUS) is a type of thrombotic microangiopathy also caused by complement dysregulation. It is associated with thrombocytopenia, microangiopathic hemolytic anemia, and end-organ damage.3

Ravulizumab inhibits the terminal complement pathway by binding to C5 with high affinity: this inhibits the cleavage of C5 to C5a, which is a pro-inflammatory and pro-thrombotic anaphylatoxin, and C5b, an initiating subunit of the terminal complement complex (C5b-9), which promotes cell lysis. Since the generation of C5b is blocked, the formation of C5b-9 is also inhibited by ravulizumab.1,4 Ravulizumab inhibits terminal complement-mediated intravascular hemolysis in patients with PNH and complement-mediated thrombotic microangiopathy (TMA) in patients with aHUS.4

TargetActionsOrganism
AComplement C5
inhibitor
Humans
Absorption

In children with paroxysmal nocturnal hemoglobinuria who are complement inhibitor-naïve, the mean Cmax was 733 mcg/mL following the loading dose and 1490 mcg/mL following the maintenance dose. In children who were previously treated with eculizumab, the mean Cmax was 885 mcg/mL following the loading dose and 1705 mcg/mL following the maintenance dose.4

In adults with paroxysmal nocturnal hemoglobinuria who are complement inhibitor-naïve, the mean Cmax was 771 mcg/mL following the loading dose and 1379 mcg/mL following the maintenance dose. In adults who were previously treated with eculizumab, the mean Cmax was 843 mcg/mL following the loading dose and 1386 mcg/mL following the maintenance dose.4

In children with atypical hemolytic uremic syndrome and a body weight of less than 20 kg, the mean Cmax was 656 mcg/mL following the loading dose and 1467 mcg/mL following the maintenance dose. In children with a body weight ranging from 20 to 40 kg, the mean Cmax was 600 mcg/mL following the loading dose and 1863 mcg/mL following the maintenance dose. In adults with a body weight greater than 40 kg, the mean Cmax was 754 mcg/mL following the loading dose and 1458 mcg/mL following the maintenance dose.4

Tmax is expected at the end of infusion (EOI) or soon after EOI. Therapeutic steady-state drug concentrations are reached after the first dose.5

Volume of distribution

The mean (%CV) volume of distribution at steady state was 5.30 (17.9) L in patients with paroxysmal nocturnal hemoglobinuria and 5.22 (35.4) L in patients with atypical hemolytic uremic syndrome.4

Protein binding

There is no information on the protein binding of ravulizumab.

Metabolism

Ravulizumab is expected to be metabolized in the same manner as any endogenous immunoglobulin gamma monoclonal antibody: it undergoes degradation into small peptides and amino acids via catabolic pathways. Ravulizumab contains only natural occurring amino acids and has no known active metabolites.5

Route of elimination

There is no information on the route of elimination of ravulizumab.

Half-life

The mean (%CV) terminal elimination half-life of ravulizumab is 49.6 (18.3) days in patients with paroxysmal nocturnal hemoglobinuria and 51.8 (31.3) days in patients with atypical hemolytic uremic syndrome.4

Clearance

The mean (%CV) clearance of ravulizumab is 0.08 (28.1) L/day in patients with paroxysmal nocturnal hemoglobinuria and 0.08 (53.3) L/day in patients with atypical hemolytic uremic syndrome.4

Adverse Effects
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Toxicity

There is no information on the LD50 value of ravulizumab.

No case of ravulizumab overdose has been reported to date. Patients who experience overdose should have immediate interruption of their infusion and be closely monitored.5

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
AbataceptThe risk or severity of adverse effects can be increased when Abatacept is combined with Ravulizumab.
AbciximabThe risk or severity of adverse effects can be increased when Abciximab is combined with Ravulizumab.
AdalimumabThe risk or severity of adverse effects can be increased when Adalimumab is combined with Ravulizumab.
Adenovirus type 7 vaccine liveThe risk or severity of infection can be increased when Adenovirus type 7 vaccine live is combined with Ravulizumab.
AducanumabThe risk or severity of adverse effects can be increased when Ravulizumab is combined with Aducanumab.
AldesleukinThe risk or severity of adverse effects can be increased when Aldesleukin is combined with Ravulizumab.
AlefaceptThe risk or severity of adverse effects can be increased when Alefacept is combined with Ravulizumab.
AlemtuzumabThe risk or severity of adverse effects can be increased when Alemtuzumab is combined with Ravulizumab.
AlirocumabThe risk or severity of adverse effects can be increased when Alirocumab is combined with Ravulizumab.
Allogeneic processed thymus tissueThe therapeutic efficacy of Allogeneic processed thymus tissue can be decreased when used in combination with Ravulizumab.
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Food Interactions
No interactions found.

Products

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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
UltomirisInjection, solution, concentrate1100 mgIntravenousAlexion Europe Sas2021-03-17Not applicableEU flag
UltomirisInjection, solution, concentrate10 mg / mLIntravenousAlexion Pharma GmbhNot applicableNot applicableCanada flag
UltomirisInjection, solution, concentrate300 mg/30mLIntravenousAlexion Pharmaceuticals Inc.2018-12-21Not applicableUS flag
UltomirisInjection, solution, concentrate300 mgIntravenousAlexion Europe Sas2021-03-17Not applicableEU flag
UltomirisInjection, solution, concentrate1100 mg/11mLIntravenousAlexion Pharmaceuticals Inc.2018-12-21Not applicableUS flag
UltomirisInjection, solution, concentrate300 mgIntravenousAlexion Europe Sas2021-02-11Not applicableEU flag
UltomirisInjection, solution, concentrate300 mg/3mLIntravenousAlexion Pharmaceuticals Inc.2018-12-21Not applicableUS flag

Categories

ATC Codes
L04AA43 — Ravulizumab
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
C3VX249T6L
CAS number
1803171-55-2

References

Synthesis Reference

Method for simultaneous quantification of alxn1210 and eculizumab in human serum or urine: WO20 8183449A1, Ryan Pelto, Meng Chen

General References
  1. Ladwig PM, Willrich MAV: Ravulizumab: Characterization and quantitation of a new C5 inhibitor using isotype specific affinity purification and high-resolution mass spectrometry. J Mass Spectrom Adv Clin Lab. 2021 Aug 12;21:10-18. doi: 10.1016/j.jmsacl.2021.08.002. eCollection 2021 Aug. [Article]
  2. Stern RM, Connell NT: Ravulizumab: a novel C5 inhibitor for the treatment of paroxysmal nocturnal hemoglobinuria. Ther Adv Hematol. 2019 Sep 10;10:2040620719874728. doi: 10.1177/2040620719874728. eCollection 2019. [Article]
  3. Syed YY: Ravulizumab: A Review in Atypical Haemolytic Uraemic Syndrome. Drugs. 2021 Apr;81(5):587-594. doi: 10.1007/s40265-021-01481-6. [Article]
  4. FDA Approved Drug Products: ULTOMIRIS (ravulizumab-cwvz) injection, for intravenous use [Link]
  5. EMA Summary of Product Characteristics: Ultomiris (ravulizumab) intravenous infusion [Link]
  6. European Medicines Agency Medicines: Ultomiris (ravulizumab) [Link]
  7. ClinicalTrials.gov: Ravulizumab and COVID-19 (NCT04570397) [Link]
RxNav
2107316
Wikipedia
Ravulizumab
FDA label
Download (1.29 MB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4Active Not RecruitingTreatmentParoxysmal Nocturnal Haemoglobinuria (PNH)1
4RecruitingTreatmentCoronavirus Disease 2019 (COVID‑19)1
3Active Not RecruitingTreatmentAtypical Hemolytic Uremic Syndrome (aHUS)2
3Active Not RecruitingTreatmentMyasthenia Gravis, Generalized1
3Active Not RecruitingTreatmentNeuromyelitis Optica (NMO) / Neuromyelitis Optica Spectrum Disorders1
3Active Not RecruitingTreatmentParoxysmal Nocturnal Haemoglobinuria (PNH)4
3Active Not RecruitingTreatmentThrombotic Microangiopathies1
3RecruitingTreatmentAcute Kidney Injury (AKI) / Coronavirus Disease 2019 (COVID‑19) / Thrombotic Microangiopathies1
3RecruitingTreatmentParoxysmal Nocturnal Haemoglobinuria (PNH)2
3RecruitingTreatmentThrombotic Microangiopathies2

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, solution, concentrateIntravenous10 mg / mL
Injection, solution, concentrateIntravenous1100 MG
Injection, solution, concentrateIntravenous1100 mg/11mL
Injection, solution, concentrateIntravenous300 mg/3mL
Injection, solution, concentrateIntravenous300 mg/30mL
Injection, solution, concentrateIntravenous300 MG
Prices
Not Available
Patents
Not Available

Properties

State
Liquid
Experimental Properties
Not Available

Targets

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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Receptor binding
Specific Function
Activation of C5 by a C5 convertase initiates the spontaneous assembly of the late complement components, C5-C9, into the membrane attack complex. C5b has a transient binding site for C6. The C5b-C...
Gene Name
C5
Uniprot ID
P01031
Uniprot Name
Complement C5
Molecular Weight
188303.705 Da
References
  1. Ladwig PM, Willrich MAV: Ravulizumab: Characterization and quantitation of a new C5 inhibitor using isotype specific affinity purification and high-resolution mass spectrometry. J Mass Spectrom Adv Clin Lab. 2021 Aug 12;21:10-18. doi: 10.1016/j.jmsacl.2021.08.002. eCollection 2021 Aug. [Article]
  2. Stern RM, Connell NT: Ravulizumab: a novel C5 inhibitor for the treatment of paroxysmal nocturnal hemoglobinuria. Ther Adv Hematol. 2019 Sep 10;10:2040620719874728. doi: 10.1177/2040620719874728. eCollection 2019. [Article]
  3. FDA Approved Drug Products: ULTOMIRIS (ravulizumab-cwvz) injection, for intravenous use [Link]
  4. Ravulizumab FDA Label [File]

Drug created at April 17, 2016 22:44 / Updated at April 28, 2022 23:24