Ravulizumab
Identification
- Summary
Ravulizumab is a monoclonal antibody used to treat paroxysmal nocturnal hemoglobinuria.
- Brand Names
- Ultomiris
- Generic Name
- Ravulizumab
- DrugBank Accession Number
- DB11580
- Background
Ravulizumab is considered a long-acting complement 5 (C5) inhibitor that has been undergoing clinical trials for the treatment of paroxysmal nocturnal haemoglobinuria (PNH) as of 4 February, 2016. A drug similar to ravulizumab (ALXN1210), called eculizumab, is currently approved for the treatment of PNH in 46 countries under the brand name Soliris®. Ravulizumab is considered by Alexion Pharmaceuticals Inc. to be a "next-generation" eculizumab molecule. Ravulizumab was subsequently approved by the US FDA in December of 2018 for a variety of beneficial characteristics that make it an advanced, next-generation agent in comparison to eculizumab 3. In particular, ravulizumab is currently the first and only long-acting C5 complement inhibitor that can be administered every eight weeks for the treatment of adult patients with PNH whereas eculizumab is a bi-weekly treatment 3,Label. Moreover, virtually all of the phase 3 trial results for ravulizumab have demonstrated the equivalent efficacy and safety established by eculizumab and that patients transition safely and effectively from using eculizumab to ravulizumab 3. Subsequently, whereas PNH patients may have needed to previously plan their lives rather strictly around the bi-weekly infusion administrations of eculizumab, with ravulizumab such patients can find a more relaxed dosing schedule of only six or seven infusions over an entire year 3,Label.
Just as the US FDA permitted a timely and expedited approval of ravulizumab ahead of the Prescription Drug User Fee Act (PDUFA) date of February 18, 2019 following the use of a rare disease priority review voucher by Ultomiris (ravulizumab) developer Alexion for many of the aforementioned beneficial treatment reasons, regulatory authorities in the European Union (EU) and Japan have currently accepted and are reviewing applications for the approval of Ultomiris (ravulizumab) as a treatment for adults with PNH as well 3.
- Type
- Biotech
- Groups
- Approved, Investigational
- Biologic Classification
- Protein Based Therapies
Monoclonal antibody (mAb) - Protein Chemical Formula
- Not Available
- Protein Average Weight
- Not Available
- Sequences
>Light Chain DIQMTQSPSSLSASVGDRVTITCGASENIYGALNWYQQKPGKAPKLLIYGATNLADGVPS RFSGSGSGTDFTLTISSLQPEDFATYYCQNVLNTPLTFGQGTKVEIKRTVAAPSVFIFPP SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
>Heavy Chain QVQLVQSGAEVKKPGASVKVSCKASGHIFSNYWIQWVRQAPGQGLEWMGEILPGSGHTEY TENFKDRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARYFFGSSPNWYFDVWGQGTLVTV SSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ SSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPAPPVAGPS VFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNST YRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMT KNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQE GNVFSCSVLHEALHSHYTQKSLSLSLGK
Download FASTA FormatReferences:
- METHOD FOR SIMULTANEOUS QUANTIFICATION OF ALXN1210 AND ECULIZUMAB IN HUMAN SERUM OR URINE: International Publication Number WO 2018/183449 A1 [File]
- Synonyms
- Ravulizumab
- ravulizumab-cwvz
- External IDs
- ALXN-1210
- ALXN1210
Pharmacology
- Indication
Ravulizumab is indicated for the treatment of adult patients with paroxysmal nocturnal hemoglobinuria (PNH) Label.
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- Contraindications & Blackbox Warnings
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Immediate and complete inhibition of serum-free complement protein C5 (concentration of less than 0.5 mcg/mL) was observed by the end of the first ravulizumab infusion and sustained throughout the entire 26-week treatment period in all patients, both complement-inhibitor naïve and previously treated with eculizumab Label.
The extent and duration of the pharmacodynamic response in patients with PNH were exposure dependent for ravulizumab Label. Free C5 levels of <0.5 mcg/mL were correlated with maximal intravascular hemolysis control and complete terminal complement inhibition Label.
Complete terminal complement inhibition following initiation of ravulizumab treatment led to normalization of serum LDH by week 4 in complement-inhibitor naïve patients and maintained LDH normalization in patients previously treated with eculizumab Label.
- Mechanism of action
Paroxysmal nocturnal hemoglobinuria (PNH) is a chronic, progressive, debilitating and life-threatening ultra-rare blood disorder characterized by hemolysis (destruction of red blood cells) that is mediated by the uncontrolled activation of the complement system, a component of the body’s immune system 1.
Ravulizumab is subsequently a terminal complement inhibitor that specifically binds to the particular complement protein C5 with high affinity, thereby inhibiting its cleavage to C5a (the proinflammatory anaphylatoxin) and C5b (the initiating subunit of the terminal complement complex [C5b-9]) and preventing the generation of the terminal complement complex C5b9 Label. Ravulizumab inhibits terminal complement-mediated intravascular hemolysis in patients with PNH Label.
Target Actions Organism UComplement C5 inhibitorHumans - Absorption
It has been demonstrated that mean ravulizumab Cmax and AUC∞ increase in a dose-proportional manner and that a single 400 mg intravenous dose of ravulizumab administered to subjects reach or exceed the threshold level of 100 µg/mL 2.
- Volume of distribution
The mean (SD) volume of distribution at steady state was 5.34 (0.92) L Label.
- Protein binding
Readily accessible data regarding the protein binding of ravulizumab is not available.
- Metabolism
Monoclonal antibody agents like ravulizumab are not expected to generate toxic metabolites as they generally undergo proteolysis to their constituent amino acids [F94].
- Route of elimination
Monoclonal antibody agents like ravulizumab are generally not eliminated via hepatic, renal, or biliary routes [F94].
- Half-life
The mean (SD) terminal elimination half-life of ravulizumab in patients with PNH was recorded as 49.7 (8.9) days Label.
- Clearance
The mean (SD) clearance of ravulizumab in patients with PNH was recorded as being 0.08 (0.022) L/day respectively Label.
- Adverse Effects
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Although PNH in pregnancy is associated with adverse maternal outcomes, including worsening cytopenias, thrombotic events, infections, bleeding, miscarriages, increased maternal mortality, and adverse fetal outcomes like fetal death and premature delivery, there are no available data on ravulizumab use in pregnant women to inform a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes Label.
Although there are currently no human reproductive studies, human immunoglobulins like ravulizumab are known to cross the human placental barrier, and thus may potentially cause terminal complement inhibition in the fetal circulation Label.
There are no data on the presence of ravulizumab in human milk, the effect on the breastfed child, or the effect on milk production Label. Since many medicinal products and immunoglobulins are secreted into human milk, and because of the potential for serious adverse reactions in a nursing child, breastfeeding should be discontinued during treatment and for 8 months after the final dose Label.
The safety and efficacy of ravulizumab in pediatric patients and geriatric use have not yet been established Label.
Genotoxicity studies have not been conducted with ravulizumab Label.
Effects of ravulizumab upon fertility have not been studied in animals Label. Intravenous injections of male and female mice with a murine anti-C5 antibody at up to 0.8-2.2 times the equivalent of the clinical dose of ravulizumab had no adverse effects on mating or fertility Label.
- 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.
Drug Interaction Integrate drug-drug
interactions in your softwareAbatacept The risk or severity of adverse effects can be increased when Abatacept is combined with Ravulizumab. Abciximab The risk or severity of adverse effects can be increased when Abciximab is combined with Ravulizumab. Adalimumab The risk or severity of adverse effects can be increased when Adalimumab is combined with Ravulizumab. Adenovirus type 7 vaccine live The risk or severity of infection can be increased when Adenovirus type 7 vaccine live is combined with Ravulizumab. Aducanumab The risk or severity of adverse effects can be increased when Ravulizumab is combined with Aducanumab. Aldesleukin The risk or severity of adverse effects can be increased when Aldesleukin is combined with Ravulizumab. Alefacept The risk or severity of adverse effects can be increased when Alefacept is combined with Ravulizumab. Alemtuzumab The risk or severity of adverse effects can be increased when Alemtuzumab is combined with Ravulizumab. Alirocumab The risk or severity of adverse effects can be increased when Alirocumab is combined with Ravulizumab. Allogeneic processed thymus tissue The therapeutic efficacy of Allogeneic processed thymus tissue can be decreased when used in combination with Ravulizumab. 
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- No interactions found.
Products
Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Ultomiris Injection, solution, concentrate 300 mg Intravenous Alexion Europe Sas 2021-03-17 Not applicable EU 
Ultomiris Injection, solution, concentrate 300 mg/3mL Intravenous Alexion Pharmaceuticals Inc. 2018-12-21 Not applicable US 
Ultomiris Injection, solution, concentrate 300 mg Intravenous Alexion Europe Sas 2021-02-11 Not applicable EU Ultomiris Injection, solution, concentrate 10 mg / mL Intravenous Alexion Pharma Gmbh Not applicable Not applicable Canada 
Ultomiris Injection, solution, concentrate 1100 mg Intravenous Alexion Europe Sas 2021-03-17 Not applicable EU Ultomiris Injection, solution, concentrate 300 mg/30mL Intravenous Alexion Pharmaceuticals Inc. 2018-12-21 Not applicable US Ultomiris Injection, solution, concentrate 1100 mg/11mL Intravenous Alexion Pharmaceuticals Inc. 2018-12-21 Not applicable US
Categories
- ATC Codes
- L04AA43 — Ravulizumab
- Drug Categories
- Amino Acids, Peptides, and Proteins
- Antibodies
- Antibodies, Monoclonal
- Antibodies, Monoclonal, Humanized
- Antineoplastic and Immunomodulating Agents
- Blood Proteins
- Complement Inactivating Agents
- Complement Inactivator Proteins
- Globulins
- Immunoglobulins
- Immunologic Factors
- Immunoproteins
- Immunosuppressive Agents
- Immunotherapy
- Proteins
- Selective Immunosuppressants
- Serum Globulins
- 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
- Alexion Receives Early FDA Approval for ULTOMIRIS™ (Ravulizumab-cwvz) in Adults with Paroxysmal Nocturnal Hemoglobinuria (PNH) [Link]
- First in Human Single-Ascending Dose Study: Safety, Biomarker, Pharmacokinetics and Exposure-Response Relationships of ALXN1210, a Humanized Monoclonal Antibody to C5, with Marked Half-Life Extension and Potential for Significantly Longer Dosing Intervals / Blood 2015 125:4777 [Link]
- Ravulizumab FDA Approval Press Release [File]
- External Links
- 2107316
- Wikipedia
- Ravulizumab
- FDA label
- Download (1.29 MB)
Clinical Trials
- Clinical Trials
Phase Status Purpose Conditions Count 4 Active Not Recruiting Treatment Paroxysmal Nocturnal Haemoglobinuria (PNH) 1 4 Recruiting Treatment Coronavirus Disease 2019 (COVID‑19) 1 3 Active Not Recruiting Treatment Amyotrophic Lateral Sclerosis (ALS) 1 3 Active Not Recruiting Treatment Atypical Hemolytic Uremic Syndrome (aHUS) 2 3 Active Not Recruiting Treatment Myasthenia Gravis, Generalized 1 3 Active Not Recruiting Treatment Neuromyelitis Optica (NMO) / Neuromyelitis Optica Spectrum Disorders 1 3 Active Not Recruiting Treatment Paroxysmal Nocturnal Haemoglobinuria (PNH) 2 3 Not Yet Recruiting Treatment Thrombotic Microangiopathies 1 3 Recruiting Treatment Acute Kidney Injury (AKI) / Coronavirus Disease 2019 (COVID‑19) / Thrombotic Microangiopathies 1 3 Recruiting Treatment Paroxysmal Nocturnal Haemoglobinuria (PNH) 2
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Injection, solution, concentrate Intravenous 10 mg / mL Injection, solution, concentrate Intravenous 1100 mg/11mL Injection, solution, concentrate Intravenous 1100 MG Injection, solution, concentrate Intravenous 300 mg/3mL Injection, solution, concentrate Intravenous 300 mg/30mL Injection, solution, concentrate Intravenous 300 MG - Prices
- Not Available
- Patents
- Not Available
Properties
- State
- Solid
- Experimental Properties
- Not Available
Targets
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- 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
- Ravulizumab FDA Label [File]
Drug created on April 17, 2016 22:44 / Updated on May 21, 2021 10:22