Ravulizumab

Identification

Name

Ravulizumab

Accession Number

DB11580

Description

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

References:

METHOD FOR SIMULTANEOUS QUANTIFICATION OF ALXN1210 AND ECULIZUMAB IN HUMAN SERUM OR URINE: International Publication Number WO 2018/183449 A1 [File]

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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.

Associated Conditions

Paroxysmal Nocturnal Haemoglobinuria (PNH)

Contraindications & Blackbox Warnings

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Pharmacodynamics

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	inhibitor	Humans

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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Toxicity

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.

Affected organisms

Humans and other mammals

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
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Abatacept	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.
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.
Altretamine	The risk or severity of adverse effects can be increased when Altretamine is combined with Ravulizumab.
Amsacrine	The risk or severity of adverse effects can be increased when Amsacrine is combined with Ravulizumab.

Additional Data Available

Extended Description

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

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Severity

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

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Evidence Level

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

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Action

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

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Food Interactions

Not Available

Products

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End
Unlock Additional Data
Ultomiris	Solution, concentrate	300 mg/3mL	Intravenous	Alexion Pharmaceuticals Inc.	2018-12-21	Not applicable
Ultomiris	Solution	10 mg	Intravenous	Alexion Pharma Gmbh	Not applicable	Not applicable
Ultomiris	Solution, concentrate	300 mg/30mL	Intravenous	Alexion Pharmaceuticals Inc.	2018-12-21	Not applicable
Ultomiris	Solution, concentrate	1100 mg/11mL	Intravenous	Alexion Pharmaceuticals Inc.	2018-12-21	Not applicable

Additional Data Available

Application Number

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

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Product Code

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

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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

RxNav: 2107316
Wikipedia: Ravulizumab

FDA label

Download (1.29 MB)

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
4	Not Yet Recruiting	Treatment	Paroxysmal Nocturnal Haemoglobinuria (PNH)	1
4	Recruiting	Treatment	Coronavirus Disease 2019 (COVID‑19)	1
3	Active Not Recruiting	Treatment	Atypical Hemolytic Uremic Syndrome (aHUS)	2
3	Active Not Recruiting	Treatment	Generalized Myasthenia Gravis	1
3	Active Not Recruiting	Treatment	Paroxysmal Nocturnal Haemoglobinuria (PNH)	2
3	Not Yet Recruiting	Treatment	Acute Kidney Injury (AKI) / Coronavirus Disease 2019 (COVID‑19) / Thrombotic Microangiopathies	1
3	Not Yet Recruiting	Treatment	Paroxysmal Nocturnal Haemoglobinuria (PNH)	1
3	Recruiting	Treatment	Acute Lung Injury (ALI) / Acute Respiratory Distress Syndrome (ARDS) / Coronavirus Disease 2019 (COVID‑19) / COVID-19 Severe Pneumonia / Viral Pneumonia	1
3	Recruiting	Treatment	Amyotrophic Lateral Sclerosis (ALS)	1
3	Recruiting	Treatment	Neuromyelitis Optica / Neuromyelitis Optica Spectrum Disorder	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Injection, solution, concentrate	Intravenous	300 MG
Solution	Intravenous	10 mg
Solution, concentrate	Intravenous	1100 mg/11mL
Solution, concentrate	Intravenous	300 mg/3mL
Solution, concentrate	Intravenous	300 mg/30mL

Prices

Not Available

Patents

Not Available

Properties

State: Solid
Experimental Properties: Not Available

Targets

Details1. Complement C5

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