Identification

Summary

Avacopan is an orally bioavailable complement 5a receptor (C5aR) antagonist for the treatment of severe anti-neutrophil cytoplasmic (auto)antibody (ANCA)-associated vasculitis.

Brand Names
Tavneos
Generic Name
Avacopan
DrugBank Accession Number
DB15011
Background

Anti-neutrophil cytoplasmic (auto)antibody (ANCA)-associated vasculitis (AAV) is a rare (estimated incidence of 3 cases per 100,000 per year) form of "pauci-immune" systemic small-vessel vasculitis typified by the presence of ANCAs in the serum.1,2,8 The full spectrum of AAV includes granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), eosinophilic granulomatosis with polyangiitis (EGPA), and drug-induced AAV. AAV may be associated with necrotizing and crescentic glomerulonephritis (NCGN).1,2 Despite complex pathophysiology, studies over the past ~2 decades have identified a key role for the alternative complement pathway and, in particular, the interaction between the anaphylatoxin fragment C5a and its cognate C5aR receptor in AAV.2,3,4,5 Avacopan (formerly CCX168) is an allosteric C5aR antagonist indicated for use in AAV.5,7,9

Avacopan was granted FDA approval on October 8, 2021, and is currently marketed under the name TAVNEOS by ChemoCentryx, Inc.9

Type
Small Molecule
Groups
Approved, Investigational
Structure
Thumb
Weight
Average: 581.656
Monoisotopic: 581.266540031
Chemical Formula
C33H35F4N3O2
Synonyms
  • Avacopan
External IDs
  • CCX168

Pharmacology

Indication

Avacopan is indicated for the adjunctive treatment of adult patients with severe active anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (granulomatosis with polyangiitis and microscopic polyangiitis; GPA/MPA) in combination with standard therapy including glucocorticoids. Avacopan does not eliminate the need for glucocorticoids.9

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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Pharmacodynamics

Avacopan is a complement 5a receptor (C5aR) antagonist that blocks C5a-induced upregulation of C11b (integrin alpha M) on neutrophils and inhibits C5a-mediated neutrophil activation and migration. Avacopan has been associated with hypersensitivity reactions, including angioedema, and hepatotoxicity, as evidenced by elevated liver transaminases. Likely due to its effect on the complement pathway, avacopan has also been associated with hepatitis B virus reactivation and serious infections, which should be monitored for as appropriate.9

Mechanism of action

Anti-neutrophil cytoplasmic (auto)antibody (ANCA)-associated vasculitis (AAV) is considered a "pauci-immune" form of systemic small-vessel vasculitis accompanied by the presence of ANCAs in the serum. The full spectrum of AAV includes granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), eosinophilic granulomatosis with polyangiitis (EGPA), and drug-induced AAV. AAV may be associated with necrotizing and crescentic glomerulonephritis (NCGN). Of the various known ANCAs, the major antigens are myeloperoxidase (MPO) and proteinase 3 (PR3/myeloblastin).1,2

The pathophysiology giving rise to AAV is complex, though a working model has been proposed. An initial trigger, such as infection, causes differentiation of naive T cells into TH17 helper T cells that induce the release from macrophages of pro-inflammatory cytokines (e.g., TNF-α and IL-1β), which prime neutrophils. Concurrently, the anaphylatoxin C5a is produced through activation of the alternative complement pathway, which also primes neutrophils through binding to the C5a receptor (C5aR; CD88). Primed neutrophils undergo physiological changes, including upregulating the display of ANCA antigens on their surface. Circulating ANCAs bind to displayed ANCA antigens on the surface of neutrophils; simultaneously, the Fc region of these ANCAs is recognized by Fcγ receptors on other neutrophils, resulting in excessive neutrophil activation. Activated neutrophils form NETs (neutrophil extracellular traps), which induce tissue damage and vasculitis. MPO/PR3 in NETs induces further ANCA production through dendritic cell- and CD4+ T cell-mediated activation of B cells, further exacerbating the condition.1,2

A role for complement was not initially considered in AAV due to a lack of excessive complement or immunoglobulin deposition in AAV lesions.2,3 However, extensive molecular studies confirmed a significant role for the alternative complement pathway, acting through C3 and C5, in the pathogenesis of AAV.2,3,4,5 The C5a fragment, generated by C5 cleavage, can bind to both the C5aR and C5a-like receptor (C5L2) on the surface of neutrophils; C5aR binding is associated with AAV while C5L2 binding has a protective effect.4,5 As the alternative complement pathway is self-sustaining in the absence of down-regulation by specific proteins, it is likely a significant driver of AAV. Furthermore, neutrophils activated by C5a release reactive oxygen species, properdin, and other molecules that stimulate the complement pathway leading to the production of more C5a in a vicious cycle.1,2

Avacopan (CCX168) is a specific C5aR receptor allosteric antagonist that inhibits C5a-mediated neutrophil activation both in vitro and in vivo.5,6,7 By inhibiting the C5a/C5aR axis, avacopan should have minimal effects on the formation of the membrane attack complex (which includes C5b) and therefore little effect on the innate immune response in treated patients.2,3

TargetActionsOrganism
AC5a anaphylatoxin chemotactic receptor 1
antagonist
Humans
Absorption

In AAV patients receiving 30 mg avacopan twice daily, avacopan had a Cmax of 349 ± 169 ng/mL and an AUC0-12hr of 3466 ± 1921 ng*h/mL. On this dosing scheme, steady-state plasma concentrations are reached by 13 weeks with a roughly 4-fold accumulation. Co-administration of 30 mg with a high-fat meal increased the Cmax by ~8%, the AUC by ~72%, and delayed the Tmax by four hours (from two hours).9

Volume of distribution

Avacopan has an apparent volume of distribution of 345 L.9

Protein binding

Avacopan and its M1 metabolite are more than 99.9% bound to plasma proteins.9

Metabolism

Avacopan is metabolized primarily by CYP3A4. The major circulating M1 metabolite, a mono-hydroxylated form of avacopan, represents ~12% of drug plasma levels and acts as a C5aR antagonist with similar efficacy to avacopan itself.9

Route of elimination

Avacopan is mainly eliminated in feces, with smaller amounts present in the urine. Following oral administration of the radiolabeled drug, roughly 77% (7% as unchanged avacopan) was recovered in feces while 10% (<0.1% unchanged) was recovered in urine.9

Half-life

A single 30 mg dose of avacopan given with food to healthy subjects resulted in mean elimination half-lives of 97.6 and 55.6 hours for avacopan and its M1 metabolite, respectively.9

Clearance

Avacopan has an estimated total apparent body clearance (CL/F) of 16.3 L/h.9

Adverse Effects
Adverseeffects
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Toxicity

Animal studies have not revealed any mutagenic potential of avacopan and no impairment of fertility at doses up to 1000 mg/kg/day. Avacopan is not mutagenic based on the Ames test.9

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
AbametapirThe serum concentration of Avacopan can be increased when it is combined with Abametapir.
AbemaciclibThe metabolism of Abemaciclib can be decreased when combined with Avacopan.
AbirateroneThe metabolism of Avacopan can be decreased when combined with Abiraterone.
AcalabrutinibThe metabolism of Acalabrutinib can be decreased when combined with Avacopan.
AcenocoumarolThe metabolism of Acenocoumarol can be decreased when combined with Avacopan.
AlbendazoleThe metabolism of Albendazole can be decreased when combined with Avacopan.
AlectinibThe metabolism of Alectinib can be decreased when combined with Avacopan.
AlpelisibThe metabolism of Alpelisib can be decreased when combined with Avacopan.
AminophyllineThe metabolism of Aminophylline can be decreased when combined with Avacopan.
AmiodaroneThe metabolism of Avacopan can be decreased when combined with Amiodarone.
Interactions
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Food Interactions
  • Take with food.

Products

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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
TavneosCapsule10 mg/1OralChemoCentryx, Inc.2021-10-18Not applicableUS flag

Categories

Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as 1-benzoylpiperidines. These are compounds containing a piperidine ring substituted at the 1-position with a benzoyl group.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Benzene and substituted derivatives
Sub Class
Benzoyl derivatives
Direct Parent
1-benzoylpiperidines
Alternative Parents
N-benzoylpiperidines / Phenylpiperidines / 2-halobenzoic acids and derivatives / Trifluoromethylbenzenes / o-Toluamides / Anilides / Benzamides / Piperidinecarboxamides / Aniline and substituted anilines / N-arylamides
show 15 more
Substituents
1-benzoylpiperidine / 2-halobenzoic acid or derivatives / 3-piperidinecarboxamide / Alkyl fluoride / Alkyl halide / Amine / Amino acid or derivatives / Anilide / Aniline or substituted anilines / Aromatic heteromonocyclic compound
show 37 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
Not Available
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
O880NM097T
CAS number
1346623-17-3
InChI Key
PUKBOVABABRILL-YZNIXAGQSA-N
InChI
InChI=1S/C33H35F4N3O2/c1-20-12-15-25(19-27(20)33(35,36)37)39-31(41)26-10-6-18-40(32(42)29-21(2)7-5-11-28(29)34)30(26)22-13-16-24(17-14-22)38-23-8-3-4-9-23/h5,7,11-17,19,23,26,30,38H,3-4,6,8-10,18H2,1-2H3,(H,39,41)/t26-,30-/m0/s1
IUPAC Name
(2R,3S)-2-[4-(cyclopentylamino)phenyl]-1-(2-fluoro-6-methylbenzoyl)-N-[4-methyl-3-(trifluoromethyl)phenyl]piperidine-3-carboxamide
SMILES
CC1=CC=C(NC(=O)[C@H]2CCCN([C@H]2C2=CC=C(NC3CCCC3)C=C2)C(=O)C2=C(F)C=CC=C2C)C=C1C(F)(F)F

References

Synthesis Reference

Christopher Lange, Viengkham Malathong, Venkat Reddy Mali, Jeffrey McMahon, Darren J. McMurtrie, Sreenivas Punna, Howard S. Roth, Rajinder Singh, Yu Wang, Ju Yang, Penglie Zhang, "Immunomodulator compounds." U.S. Patent US10919852B2, issued May 9, 2019.

General References
  1. Nakazawa D, Masuda S, Tomaru U, Ishizu A: Pathogenesis and therapeutic interventions for ANCA-associated vasculitis. Nat Rev Rheumatol. 2019 Feb;15(2):91-101. doi: 10.1038/s41584-018-0145-y. [Article]
  2. Brilland B, Garnier AS, Chevailler A, Jeannin P, Subra JF, Augusto JF: Complement alternative pathway in ANCA-associated vasculitis: Two decades from bench to bedside. Autoimmun Rev. 2020 Jan;19(1):102424. doi: 10.1016/j.autrev.2019.102424. Epub 2019 Nov 15. [Article]
  3. Xiao H, Schreiber A, Heeringa P, Falk RJ, Jennette JC: Alternative complement pathway in the pathogenesis of disease mediated by anti-neutrophil cytoplasmic autoantibodies. Am J Pathol. 2007 Jan;170(1):52-64. doi: 10.2353/ajpath.2007.060573. [Article]
  4. Schreiber A, Xiao H, Jennette JC, Schneider W, Luft FC, Kettritz R: C5a receptor mediates neutrophil activation and ANCA-induced glomerulonephritis. J Am Soc Nephrol. 2009 Feb;20(2):289-98. doi: 10.1681/ASN.2008050497. Epub 2008 Dec 10. [Article]
  5. Xiao H, Dairaghi DJ, Powers JP, Ertl LS, Baumgart T, Wang Y, Seitz LC, Penfold ME, Gan L, Hu P, Lu B, Gerard NP, Gerard C, Schall TJ, Jaen JC, Falk RJ, Jennette JC: C5a receptor (CD88) blockade protects against MPO-ANCA GN. J Am Soc Nephrol. 2014 Feb;25(2):225-31. doi: 10.1681/ASN.2013020143. Epub 2013 Oct 31. [Article]
  6. Bekker P, Dairaghi D, Seitz L, Leleti M, Wang Y, Ertl L, Baumgart T, Shugarts S, Lohr L, Dang T, Miao S, Zeng Y, Fan P, Zhang P, Johnson D, Powers J, Jaen J, Charo I, Schall TJ: Characterization of Pharmacologic and Pharmacokinetic Properties of CCX168, a Potent and Selective Orally Administered Complement 5a Receptor Inhibitor, Based on Preclinical Evaluation and Randomized Phase 1 Clinical Study. PLoS One. 2016 Oct 21;11(10):e0164646. doi: 10.1371/journal.pone.0164646. eCollection 2016. [Article]
  7. Liu H, Kim HR, Deepak RNVK, Wang L, Chung KY, Fan H, Wei Z, Zhang C: Orthosteric and allosteric action of the C5a receptor antagonists. Nat Struct Mol Biol. 2018 Jun;25(6):472-481. doi: 10.1038/s41594-018-0067-z. Epub 2018 Jun 4. [Article]
  8. Jayne D: Complement inhibition in ANCA vasculitis. Nephrol Ther. 2019 Nov;15(6):409-412. doi: 10.1016/j.nephro.2019.04.001. Epub 2019 Oct 17. [Article]
  9. FDA Approved Drug Products: TAVNEOS (avacopan) capsules [Link]
ChemSpider
52083514
RxNav
2572100
ChEMBL
CHEMBL3989871
PDBe Ligand
EFD
Wikipedia
Avacopan
PDB Entries
6c1r

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3CompletedTreatmentANCA-Associated Vasculitis (AAV)1
2Active Not RecruitingTreatmentAcne Inversa / Hidradenitis Suppurativa (HS)1
2CompletedTreatmentANCA-Associated Vasculitis (AAV)1
2CompletedTreatmentComplement 3 Glomerulopathy (C3G)1
2CompletedTreatmentImmunoglobulin A Nephropathy1
2CompletedTreatmentVasculitis1
2TerminatedTreatmentAtypical Hemolytic Uremic Syndrome (aHUS)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
CapsuleOral10 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US8906938No2009-12-212029-12-21US flag
US8445515No2011-02-032031-02-03US flag

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.000219 mg/mLALOGPS
logP6.82ALOGPS
logP7.59ChemAxon
logS-6.4ALOGPS
pKa (Strongest Acidic)14.05ChemAxon
pKa (Strongest Basic)4.98ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area61.44 Å2ChemAxon
Rotatable Bond Count7ChemAxon
Refractivity158.6 m3·mol-1ChemAxon
Polarizability58.26 Å3ChemAxon
Number of Rings5ChemAxon
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

Targets

Drugtargets2
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insights and accelerate drug research.
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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antagonist
General Function
Receptor for the chemotactic and inflammatory peptide anaphylatoxin C5a (PubMed:1847994, PubMed:8182049, PubMed:7622471, PubMed:9553099, PubMed:10636859, PubMed:15153520, PubMed:29300009). The ligand interacts with at least two sites on the receptor: a high-affinity site on the extracellular N-terminus, and a second site in the transmembrane region which activates downstream signaling events (PubMed:8182049, PubMed:7622471, PubMed:9553099). Receptor activation stimulates chemotaxis, granule enzyme release, intracellular calcium release and superoxide anion production (PubMed:10636859, PubMed:15153520).
Specific Function
Complement component c5a binding
Gene Name
C5AR1
Uniprot ID
P21730
Uniprot Name
C5a anaphylatoxin chemotactic receptor 1
Molecular Weight
39335.065 Da
References
  1. Xiao H, Dairaghi DJ, Powers JP, Ertl LS, Baumgart T, Wang Y, Seitz LC, Penfold ME, Gan L, Hu P, Lu B, Gerard NP, Gerard C, Schall TJ, Jaen JC, Falk RJ, Jennette JC: C5a receptor (CD88) blockade protects against MPO-ANCA GN. J Am Soc Nephrol. 2014 Feb;25(2):225-31. doi: 10.1681/ASN.2013020143. Epub 2013 Oct 31. [Article]
  2. Bekker P, Dairaghi D, Seitz L, Leleti M, Wang Y, Ertl L, Baumgart T, Shugarts S, Lohr L, Dang T, Miao S, Zeng Y, Fan P, Zhang P, Johnson D, Powers J, Jaen J, Charo I, Schall TJ: Characterization of Pharmacologic and Pharmacokinetic Properties of CCX168, a Potent and Selective Orally Administered Complement 5a Receptor Inhibitor, Based on Preclinical Evaluation and Randomized Phase 1 Clinical Study. PLoS One. 2016 Oct 21;11(10):e0164646. doi: 10.1371/journal.pone.0164646. eCollection 2016. [Article]
  3. Liu H, Kim HR, Deepak RNVK, Wang L, Chung KY, Fan H, Wei Z, Zhang C: Orthosteric and allosteric action of the C5a receptor antagonists. Nat Struct Mol Biol. 2018 Jun;25(6):472-481. doi: 10.1038/s41594-018-0067-z. Epub 2018 Jun 4. [Article]
  4. FDA Approved Drug Products: TAVNEOS (avacopan) capsules [Link]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
Inhibitor
Inducer
Curator comments
Both avacopan and its M1 metabolite may induce and inhibit CYP3A4.
General Function
Vitamin d3 25-hydroxylase activity
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 performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. FDA Approved Drug Products: TAVNEOS (avacopan) capsules [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inhibitor
Curator comments
Avacopan itself does not inhibit CYP2C9, though its M1 metabolite does.
General Function
Steroid hydroxylase activity
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
CYP2C9
Uniprot ID
P11712
Uniprot Name
Cytochrome P450 2C9
Molecular Weight
55627.365 Da
References
  1. FDA Approved Drug Products: TAVNEOS (avacopan) capsules [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inducer
Curator comments
Avacopan itself does not induce CYP1A2, though its M1 metabolite does.
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. FDA Approved Drug Products: TAVNEOS (avacopan) capsules [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inducer
Curator comments
Avacopan itself does not induce CYP2B6, though its M1 metabolite does.
General Function
Steroid hydroxylase activity
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
CYP2B6
Uniprot ID
P20813
Uniprot Name
Cytochrome P450 2B6
Molecular Weight
56277.81 Da
References
  1. FDA Approved Drug Products: TAVNEOS (avacopan) capsules [Link]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
Curator comments
Avacopan is not itself a substrate of P-gp. Rather, the avacopan M1 metabolite is a P-gp substrate.
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da
References
  1. FDA Approved Drug Products: TAVNEOS (avacopan) capsules [Link]

Drug created at May 20, 2019 14:42 / Updated at October 30, 2021 04:07