NAV

Zilucoplan

Identification

Summary

Zilucoplan is a complement inhibitor used to treat generalized myasthenia gravis in anti-acetylcholine receptor (AChR) antibody-positive adults.

Brand Names
Zilbrysq
Generic Name
Zilucoplan
DrugBank Accession Number
DB15636
Background

Zilucoplan is a 15 amino-acid, synthetic macrocyclic peptide. It is a complement inhibitor that works to prevent the activation of C5, which is a complement protein involved in the innate immune system to initiate inflammatory responses.1 On October 17, 2023, zilucoplan gained its first FDA approval for the treatment of generalized myasthenia gravis.5 It was also later approved by the EMA on December 4, 2023, as an add-on treatment for the same condition.7

Type
Small Molecule
Groups
Approved
Structure
Similar Structures
Weight
Average: 3562.229
Monoisotopic: 3559.969439148
Chemical Formula
C172H278N24O55
Synonyms
  • N2-ACETYL-L-LYSYL-L-VALYL-L-.ALPHA.-GLUTAMYL-L-ARGINYL-L-PHENYLALANYL-L-.ALPHA.-ASPARTYL-N-METHYL-L-.ALPHA.-ASPARTYL-3-METHYL-L-VALYL-L-TYROSYL-3-(1H-PYRROLO(2,3-B)PYRIDIN-3-YL)-L-ALANYL-L-.ALPHA.-GLUTAMYL-L-TYROSYL-L-PROLYL-(2S)-2-CYCLOHEXYLGLYCYL-N6-(3
  • POLY(OXY-1,2-ETHANEDIYL), .ALPHA.-(2-(((4S)-4-CARBOXY-1-OXO-4-(1-OXOHEXADECYL)BUTYL)AMINO)ETHYL)-.OMEGA.-HYDROXY-, 15-ETHER WITH N-ACETYL-L-LYSYL-L-VALYL-L-.ALPHA.-GLUTAMYL-L-ARGINYL-L-PHENYLALANYL-L-.ALPHA.-ASPARTYL-N-METHYL-L-.ALPHA.-ASPARTYL-3-METHYL-
  • Zilucoplan
External IDs
  • RA101495
  • WHO 10602
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Pharmacology

Indication

Zilucoplan is indicated as the main treatment or add-on treatment to standard therapy for generalized myasthenia gravis (gMG) in adult patients who are anti-acetylcholine receptor (AChR) antibody-positive by the FDA and EMA respectively.4,6

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Treatment ofGeneralized myasthenia gravis••••••••••••••••••••••••••••••••••• •••••••• •••••••• •••••••••••••••••
Adjunct therapy in treatment ofMyasthenia gravis••••••••••••••••••••••••••••••••••• •••••••• •••••••• •••••••••••••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

In clinical trials consisting of anti-AChR antibody-positive adults with gMG, zilucoplan improved the signs and symptoms of myasthenia gravis, including muscle weakness.4 In vitro, it blocked the activation of C5 clinical variants.1 Zilucoplan causes complement inhibition in a dose-dependent manner: In clinical trials, complement inhibition of 97.5% by zilucoplan was observed by the end of the first week and persisted throughout the 12-week treatment period.4

Mechanism of action

The complement system is part of the innate immune system and is critical in inflammatory reactions in response to pathogenic bacteria. Activation pathways of the complement system involve the cleavage of the complement protein C5 by C5 convertases to form C5a, a potent anaphylatoxin, and C5b.1,3 Cleavage of C5 also recruits C6, C7, C8, and C9. C5b binds to C6 1,2 to yield the terminal complement complex C5b9, a hydrophilic pore that spans the cell membrane. C5b9 causes an influx of water and ions, resulting in osmotic lysis of the targeted cell.1,3 The terminal complement cascade has been implicated in the pathophysiology of various inflammatory and autoimmune disorders, including gMG. gMG is an autoimmune disorder characterized by pathogenic autoantibodies that bind to AChRs. Accumulated MAC on the postsynaptic plasma membrane of the neuromuscular junction leads to muscle weakness and damage.3

The exact mechanism of zilucoplan in gMG has not been fully elucidated. Zilucoplan binds to the complement protein C5 with high affinity to inhibit its cleavage to C5a and C5b, preventing the generation of C5b9.4

TargetActionsOrganism
AComplement C5
inhibitor
Humans
Absorption

Following single and multiple daily subcutaneous administration of 0.3 mg/kg zilucoplan, time to reach peak plasma concentrations (Tmax) ranged from three to six hours. Following daily subcutaneous dosing of 0.3 mg/kg zilucoplan for 14 days in healthy subjects, both the peak plasma concentration and exposure (AUCtau) increased by approximately 3-fold.4

After daily repeated subcutaneous administration of 0.3 mg/kg zilucoplan, plasma concentrations of zilucoplan were consistent, with steady state trough concentrations being reached by four weeks of treatment with zilucoplan through 12 weeks.4

Volume of distribution

The mean volume of distribution at steady state was 3.51 L in the population pharmacokinetics analysis for adult patients with gMG.4

Protein binding

Zilucoplan and its two major metabolites, RA103488 and RA102758, are more than 99% bound to plasma proteins.4

Metabolism

Zilucoplan is expected to be degraded into small peptides and amino acids via catabolic pathways. RA103488 and RA102758 are two major metabolites detected in plasma. RA103488 is formed by CYP4F2-mediated metabolism and has comparable pharmacological activity to its parent compound; however, since RA103488 is present at much lower concentrations compared to zilucoplan, its contribution to the pharmacological action of zilucoplan is expected to be low. RA102758, formed by protease-mediated degradation, is pharmacologically inactive. The AUCs of both metabolites were approximately 10% of the parent AUC.4

Route of elimination

Less than 1% of zilucoplan and its metabolites are excreted in urine and feces.4

Half-life

The mean plasma terminal half-life of zilucoplan was approximately 172 hours (7 to 8 days).4

Clearance

No information is available.

Adverse Effects
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Toxicity

There is no information available regarding the acute toxicity (LD50) or overdose of zilucoplan.4

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.
Not Available
Food Interactions
No interactions found.

Products

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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
ZilbrysqInjection, solution40 mg/1mLSubcutaneousUCB, Inc.2024-01-03Not applicableUS flag
ZilbrysqInjection, solution40 mg/1mLSubcutaneousUCB, Inc.2024-01-03Not applicableUS flag
ZilbrysqInjection, solution40 mg/1mLSubcutaneousUCB, Inc.2024-01-03Not applicableUS flag

Categories

Drug Categories
Classification
Not classified
Affected organisms
Not Available

Chemical Identifiers

UNII
YG391PK0CC
CAS number
1841136-73-9
InChI Key
JDXCOXKBIGBZSK-PSNKNOTQSA-N
InChI
InChI=1S/C172H278N24O55/c1-9-10-11-12-13-14-15-16-17-18-19-20-27-44-146(202)182-136(170(226)227)53-56-144(200)177-64-67-229-69-71-231-73-75-233-77-79-235-81-83-237-85-87-239-89-91-241-93-95-243-97-99-245-101-103-247-105-107-249-109-111-251-113-112-250-110-108-248-106-104-246-102-100-244-98-96-242-94-92-240-90-88-238-86-84-236-82-80-234-78-76-232-74-72-230-70-68-228-66-59-145(201)175-60-31-29-41-135(169(224)225)186-165(220)152(126-37-25-22-26-38-126)193-162(217)142-43-34-65-196(142)168(223)140(116-125-47-51-129(199)52-48-125)190-157(212)133(54-57-148(204)205)184-161(216)139(117-127-120-180-154-130(127)39-32-62-178-154)188-159(214)138(115-124-45-49-128(198)50-46-124)189-166(221)153(172(5,6)7)194-163(218)143(119-150(208)209)195(8)167(222)141-118-147(203)176-61-30-28-40-131(181-122(4)197)158(213)192-151(121(2)3)164(219)185-134(55-58-149(206)207)156(211)183-132(42-33-63-179-171(173)174)155(210)187-137(160(215)191-141)114-123-35-23-21-24-36-123/h21,23-24,32,35-36,39,45-52,62,120-121,126,131-143,151-153,198-199H,9-20,22,25-31,33-34,37-38,40-44,53-61,63-119H2,1-8H3,(H,175,201)(H,176,203)(H,177,200)(H,178,180)(H,181,197)(H,182,202)(H,183,211)(H,184,216)(H,185,219)(H,186,220)(H,187,210)(H,188,214)(H,189,221)(H,190,212)(H,191,215)(H,192,213)(H,193,217)(H,194,218)(H,204,205)(H,206,207)(H,208,209)(H,224,225)(H,226,227)(H4,173,174,179)/t131-,132-,133-,134-,135-,136-,137-,138-,139-,140-,141-,142-,143-,151-,152-,153+/m0/s1
IUPAC Name
(2S)-2-[(2S)-2-{[(2S)-1-[(2S)-2-[(2S)-2-[(2S)-2-[(2S)-2-[(2S)-2-[(2S)-2-{1-[(2S,5S,8S,11S,14S,22S)-11-benzyl-8-(3-carbamimidamidopropyl)-5-(2-carboxyethyl)-22-acetamido-3,6,9,12,16,23-hexaoxo-2-(propan-2-yl)-1,4,7,10,13,17-hexaazacyclotricosan-14-yl]-N-methylformamido}-3-carboxypropanamido]-3,3-dimethylbutanamido]-3-(4-hydroxyphenyl)propanamido]-3-{1H-pyrrolo[2,3-b]pyridin-3-yl}propanamido]-4-carboxybutanamido]-3-(4-hydroxyphenyl)propanoyl]pyrrolidin-2-yl]formamido}-2-cyclohexylacetamido]-6-{1-[(4S)-4-carboxy-4-hexadecanamidobutanamido]-3,6,9,12,15,18,21,24,27,30,33,36,39,42,45,48,51,54,57,60,63,66,69,72-tetracosaoxapentaheptacontan-75-amido}hexanoic acid
SMILES
CCCCCCCCCCCCCCCC(=O)N[C@@H](CCC(=O)NCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCC(=O)NCCCC[C@H](NC(=O)[C@@H](NC(=O)[C@@H]1CCCN1C(=O)[C@H](CC1=CC=C(O)C=C1)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC1=CNC2=NC=CC=C12)NC(=O)[C@H](CC1=CC=C(O)C=C1)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)N(C)C(=O)[C@@H]1CC(=O)NCCCC[C@H](NC(C)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC2=CC=CC=C2)C(=O)N1)C(C)(C)C)C1CCCCC1)C(O)=O)C(O)=O

References

General References
  1. Tang GQ, Tang Y, Dhamnaskar K, Hoarty MD, Vyasamneni R, Vadysirisack DD, Ma Z, Zhu N, Wang JG, Bu C, Cong B, Palmer E, Duda PW, Sayegh C, Ricardo A: Zilucoplan, a macrocyclic peptide inhibitor of human complement component 5, uses a dual mode of action to prevent terminal complement pathway activation. Front Immunol. 2023 Aug 9;14:1213920. doi: 10.3389/fimmu.2023.1213920. eCollection 2023. [Article]
  2. Menon D, Bril V: Pharmacotherapy of Generalized Myasthenia Gravis with Special Emphasis on Newer Biologicals. Drugs. 2022 Jun;82(8):865-887. doi: 10.1007/s40265-022-01726-y. Epub 2022 May 31. [Article]
  3. Howard JF Jr, Vissing J, Gilhus NE, Leite MI, Utsugisawa K, Duda PW, Farzaneh-Far R, Murai H, Wiendl H: Zilucoplan: An Investigational Complement C5 Inhibitor for the Treatment of Acetylcholine Receptor Autoantibody-Positive Generalized Myasthenia Gravis. Expert Opin Investig Drugs. 2021 May;30(5):483-493. doi: 10.1080/13543784.2021.1897567. Epub 2021 Apr 1. [Article]
  4. FDA Approved Drug Products: ZILBRYSQ (zilucoplan) injection, for subcutaneous use [Link]
  5. PR Newswire: UCB announces U.S. FDA approval of ZILBRYSQ® (zilucoplan) for the treatment of adults with generalized myasthenia gravis [Link]
  6. EMA Approved Drug Products: Zilbrysq (zilucoplan) solution for injection [Link]
  7. UCB announces European Commission approval of ZILBRYSQ[®]▼ (zilucoplan) for the treatment of adults with generalized Myasthenia Gravis [Link]
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RxNav
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Wikipedia
Zilucoplan

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3Active Not RecruitingTreatmentGeneralized Myasthenia Gravis2
3CompletedTreatmentCoronavirus Disease 2019 (COVID‑19)1
3CompletedTreatmentGeneralized Myasthenia Gravis1
2CompletedTreatmentCoronavirus Disease 2019 (COVID‑19)1
2CompletedTreatmentGeneralized Myasthenia Gravis1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, solutionSubcutaneous40 mg/1mL
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US11752190No2015-06-122035-06-12US flag
US11014965No2015-06-122035-06-12US flag
US10435438No2015-06-122035-06-12US flag
US10208089No2015-06-122035-06-12US flag
US10106579No2015-06-122035-06-12US flag
US10835574No2015-06-122035-06-12US flag
US11535650No2015-06-122035-06-12US flag
US10562934No2015-06-122035-06-12US flag

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.00999 mg/mLALOGPS
logP2.08ALOGPS
logP-0.72Chemaxon
logS-5.6ALOGPS
pKa (Strongest Acidic)2.73Chemaxon
pKa (Strongest Basic)11.9Chemaxon
Physiological Charge-4Chemaxon
Hydrogen Acceptor Count59Chemaxon
Hydrogen Donor Count28Chemaxon
Polar Surface Area1074.38 Å2Chemaxon
Rotatable Bond Count141Chemaxon
Refractivity922.42 m3·mol-1Chemaxon
Polarizability397.1 Å3Chemaxon
Number of Rings8Chemaxon
Bioavailability0Chemaxon
Rule of FiveNoChemaxon
Ghose FilterNoChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleYesChemaxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available
Chromatographic Properties
Collision Cross Sections (CCS)
Not Available

Targets

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Details1. Complement C5
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. Wilkinson T, Dixon R, Page C, Carroll M, Griffiths G, Ho LP, De Soyza A, Felton T, Lewis KE, Phekoo K, Chalmers JD, Gordon A, McGarvey L, Doherty J, Read RC, Shankar-Hari M, Martinez-Alier N, O'Kelly M, Duncan G, Walles R, Sykes J, Summers C, Singh D: ACCORD: A Multicentre, Seamless, Phase 2 Adaptive Randomisation Platform Study to Assess the Efficacy and Safety of Multiple Candidate Agents for the Treatment of COVID-19 in Hospitalised Patients: A structured summary of a study protocol for a randomised controlled trial. Trials. 2020 Jul 31;21(1):691. doi: 10.1186/s13063-020-04584-9. [Article]
  2. FDA Approved Drug Products: ZILBRYSQ (zilucoplan) injection, for subcutaneous use [Link]

Enzymes

Details1. Leukotriene-B(4) omega-hydroxylase 1
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Not Available
Specific Function
Not Available
Gene Name
CYP4F2
Uniprot ID
P78329
Uniprot Name
Phylloquinone omega-hydroxylase CYP4F2
Molecular Weight
59852.825 Da
References
  1. FDA Approved Drug Products: ZILBRYSQ (zilucoplan) injection, for subcutaneous use [Link]

Drug created at March 07, 2020 20:17 / Updated at December 09, 2023 17:37