Iptacopan

Identification

Summary

Iptacopan is a factor B inhibitor used to treat paroxysmal nocturnal hemoglobinuria.

Brand Names
Fabhalta
Generic Name
Iptacopan
DrugBank Accession Number
DB16200
Background

Iptacopan is a small-molecule factor B inhibitor previously investigated as a potential treatment for the rare blood disease paroxysmal nocturnal hemoglobinuria (PNH) by inhibiting the complement factor B.1 Factor B is a positive regulator of the alternative complement pathway, where it activates C3 convertase and subsequently C5 convertase.2 This is of particular importance to PNH, where one of the disease hallmarks is the mutation of the PIGA gene. Due to this mutation, all progeny erythrocytes will lack the glycosyl phosphatidylinositol–anchored proteins that normally anchor 2 membrane proteins, CD55 and CD59, that protect blood cells against the alternative complement pathway.3 Additionally, iptacopan has the benefit of targeting factor B, which only affect the alternative complement pathway, leaving the classic and lectin pathway untouched for the body to still mount adequate immune responses against pathogens.2

On December 6th, 2023, Iptacopan under the brand name Fabhalta was approved by the FDA for the treatment of adults with PNH. This approval was based on favorable results obtained from the phase III APPL-PNH and APPOINT-PNH studies, where 82.3% and 77.5% of patients experienced a sustained hemoglobin improvement without transfusions respectively.5

Type
Small Molecule
Groups
Approved, Investigational
Structure
Weight
Average: 422.525
Monoisotopic: 422.220557454
Chemical Formula
C25H30N2O4
Synonyms
  • 4-((2S,4S)-4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl) benzoic acid
  • BENZOIC ACID, 4-((2S,4S)-4-ETHOXY-1-((5-METHOXY-7-METHYL-1H-INDOL-4-YL)METHYL)-2-PIPERIDINYL)-
  • Iptacopan
External IDs
  • LNP 023
  • LNP-023
  • LNP023
  • NVP-LNP023
  • NVP-LNP023-NX

Pharmacology

Indication

Iptacopan is indicated for the treatment of adults with paroxysmal nocturnal hemoglobinuria.4

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Treatment ofParoxysmal nocturnal haemoglobinuria (pnh)••••••••••••••••••••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

Inhibition of the alternative complement pathway biomarkers, in vitro alternative pathway assay, and plasma Bb (fragment Bb of Factor B), started approximately 2 hours after a single iptacopan dose in healthy volunteers.4

In paroxysmal nocturnal hemoglobinuria (PNH) patients receiving concomitant anti-C5 treatment and iptacopan 200 mg twice daily, the in vitro alternative pathway assay and plasma Bb decreased from baseline by 54.1% and 56.1%, respectively, on the first observation on Day 8. In treatment-naive PNH patients, these same biomarkers decreased from baseline by 78.4% and 58.9%, respectively, on the first observation after 4 weeks of treatment with iptacopan 200 mg twice daily.4

In PNH patients on concomitant anti-C5 treatment and FABHALTA 200 mg twice daily, the mean PNH red blood cell (RBC) clone size was 54.8% at baseline and increased to 89.2% after 13 weeks; the proportion of PNH Type II + III RBCs with C3 deposition was 12.4% at baseline and decreased to 0.2% after 13 weeks. In treatment-naive PNH patients, the mean PNH RBC clone size was 49.1% at baseline and increased to 91.1% after 12 weeks; there were negligible PNH Type II + III RBCs with C3 deposition in this population due to the predominance of IVH.4

Iptacopan reduces serum LDH levels. In PNH patients previously treated with eculizumab, all patients treated with FABHALTA 200 mg twice daily achieved a reduction of LDH levels to < 1.5 times the upper limit of normal (ULN) at 13 weeks. In treatment-naive PNH patients, iptacopan 200 mg twice daily reduced LDH by > 60% compared to baseline after 12 weeks and maintained the effect through the end of the study at 2 years.4

In a QTc clinical study in healthy volunteers, single supra-therapeutic iptacopan doses up to 1,200 mg (which provided greater than 4-fold peak concentration of the MRHD) showed no effect on cardiac repolarization or QT interval.4

Mechanism of action

Iptacopan binds to Factor B of the alternative complement pathway and regulates the cleavage of C3, the generation of downstream effectors, and the amplification of the terminal pathway. In paroxysmal nocturnal hemoglobinuria, intravascular hemolysis (IVH) is mediated by the downstream membrane attack complex (MAC), while extravascular hemolysis (EVH) is facilitated by C3b opsonization. Iptacopan acts proximally in the alternative pathway of the complement cascade to control both C3b-mediated EVH and terminal complement-mediated IVH.4

TargetActionsOrganism
AComplement factor B
inhibitor
Humans
Absorption

Following oral administration, iptacopan reached peak plasma concentrations approximately 2 hours post-dose. At the recommended dosing regimen of 200 mg twice daily, a steady state is achieved in approximately 5 days with minor accumulation (1.4-fold).4

Based on a food-effect study in healthy volunteers, a high-fat meal did not affect the exposure of iptacopan to a clinically meaningful degree.4

Volume of distribution

After administration of iptacopan 200 mg twice daily, the apparent volume of distribution at steady state was approximately 288 L.4

Protein binding

Iptacopan showed concentration-dependent plasma protein binding due to binding to the target Factor B in the systemic circulation. Iptacopan was 75% to 93% protein-bound in vitro at the relevant clinical plasma concentrations.4

Metabolism

Metabolism is a predominant elimination pathway for iptacopan with approximately 50% of the dose attributed to oxidative pathways. Metabolism of iptacopan includes N-dealkylation, O-deethylation, oxidation, and dehydrogenation, mostly driven by CYP2C8 (98%) with a small contribution from CYP2D6 (2%). Iptacopan undergoes Phase 2 metabolism through glucuronidation by UGT1A1, UGT1A3, and UGT1A8. In plasma, iptacopan was the major component, accounting for 83% of the drug-related species. Two acyl glucuronides were the only metabolites detected in plasma and were minor, accounting for 8% and 5% of the drug-related species. Iptacopan metabolites are not pharmacologically active.4

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Route of elimination

In a human study, following a single 100 mg oral dose of [14C]-iptacopan, the mean total excretion of radioactivity (iptacopan and metabolites) was 71.5% in the feces and 24.8% in the urine, for a total mean excretion of >96% of the dose. Specifically, 17.9% of the dose was excreted as parent iptacopan in the urine, and 16.8% of the dose was excreted as parent iptacopan in feces.4

Half-life

The half-life (t1/2) of iptacopan at steady state is approximately 25 hours after administration of 200 mg twice daily.4

Clearance

The clearance of iptacopan at steady state is 7.96 L/h after administration of 200 mg twice daily.4

Adverse Effects
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Toxicity

Available data from clinical trials with iptacopan use in pregnant women are insufficient to identify a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. There are risks to the mother and fetus associated with untreated paroxysmal nocturnal hemoglobinuria (PNH) in pregnancy. The use of iptacopan in pregnant women or women planning to become pregnant may be considered following an assessment of the risks and benefits. PNH in pregnancy is associated with adverse maternal outcomes, including worsening cytopenias, thrombosis, infections, bleeding, miscarriages, increased maternal mortality, and adverse fetal outcomes, including fetal death and premature delivery.4

In animal reproduction studies, oral administration of iptacopan to pregnant rats and rabbits during organogenesis at exposures 4 to 6 times the human exposure (based on AUC) at the maximum recommended human dose (MRHD) of 200 mg twice daily did not induce embryo or fetal toxicity.4

Iptacopan was not genotoxic or mutagenic in a battery of in vitro and in vivo assays.4

Carcinogenicity studies conducted with oral administration of iptacopan in RasH2 transgenic mice with doses up to 1,000 mg/kg/day for 6 months and in rats with doses up to 750 mg/kg/day for 2 years did not identify any carcinogenic potential. The highest exposure to iptacopan in rats corresponds to ~9 times the MRHD based on AUC.4

In a fertility study in male rats, iptacopan did not adversely impact fertility up to the highest tested dose of 750 mg/kg/day, which corresponds to 4 times the MRHD based on AUC. Reversible effects on the male reproductive system (testicular tubular degeneration and cellular debris in epididymis) were observed in repeatdose toxicity studies with oral administration in dogs at doses ≥ 2 times the MRHD based on AUC, with no clear effects on sperm numbers, morphology, or motility. In a fertility and early embryonic developmental study in female rats, oral administration of iptacopan caused increased pre-and post-implantation losses when given at the highest dose of 1,000 mg/kg/day orally, which corresponds to ~11 times the MRHD based on AUC.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.
DrugInteraction
AbataceptThe metabolism of Iptacopan can be increased when combined with Abatacept.
AbirateroneThe metabolism of Iptacopan can be decreased when combined with Abiraterone.
AcebutololThe metabolism of Iptacopan can be decreased when combined with Acebutolol.
AcetaminophenThe metabolism of Iptacopan can be decreased when combined with Acetaminophen.
AdagrasibThe metabolism of Iptacopan can be decreased when combined with Adagrasib.
Food Interactions
No interactions found.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Iptacopan hydrochloride monohydrateXW5CK7C6YH2447007-60-3JUWBBUFSAGEROP-VVJLZRNGSA-N
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
FabhaltaCapsule200 mg/1OralNovartis Pharmaceuticals Corporation2023-12-05Not applicableUS flag

Categories

Drug Categories
Classification
Not classified
Affected organisms
Not Available

Chemical Identifiers

UNII
8E05T07Z6W
CAS number
1644670-37-0
InChI Key
RENRQMCACQEWFC-UGKGYDQZSA-N
InChI
InChI=1S/C25H30N2O4/c1-4-31-19-10-12-27(22(14-19)17-5-7-18(8-6-17)25(28)29)15-21-20-9-11-26-24(20)16(2)13-23(21)30-3/h5-9,11,13,19,22,26H,4,10,12,14-15H2,1-3H3,(H,28,29)/t19-,22-/m0/s1
IUPAC Name
4-[(2S,4S)-4-ethoxy-1-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]piperidin-2-yl]benzoic acid
SMILES
CCO[C@H]1CCN(CC2=C(OC)C=C(C)C3=C2C=CN3)[C@@H](C1)C1=CC=C(C=C1)C(O)=O

References

General References
  1. James AD, Kulmatycki K, Poller B, Romeo AA, Van Lier JJ, Klein K, Pearson D: Absorption, Distribution, Metabolism, and Excretion of [(14)C]iptacopan in Healthy Male Volunteers and in In Vivo and In Vitro Studies. Drug Metab Dispos. 2023 Jul;51(7):873-883. doi: 10.1124/dmd.123.001290. Epub 2023 Jun 12. [Article]
  2. Rizk DV, Rovin BH, Zhang H, Kashihara N, Maes B, Trimarchi H, Perkovic V, Meier M, Kollins D, Papachristofi O, Charney A, Barratt J: Targeting the Alternative Complement Pathway With Iptacopan to Treat IgA Nephropathy: Design and Rationale of the APPLAUSE-IgAN Study. Kidney Int Rep. 2023 Feb 9;8(5):968-979. doi: 10.1016/j.ekir.2023.01.041. eCollection 2023 May. [Article]
  3. Lindorfer MA, Pawluczkowycz AW, Peek EM, Hickman K, Taylor RP, Parker CJ: A novel approach to preventing the hemolysis of paroxysmal nocturnal hemoglobinuria: both complement-mediated cytolysis and C3 deposition are blocked by a monoclonal antibody specific for the alternative pathway of complement. Blood. 2010 Mar 18;115(11):2283-91. doi: 10.1182/blood-2009-09-244285. Epub 2010 Jan 12. [Article]
  4. FDA Approved Drug Products: FABHALTA® (iptacopan) capsules, for oral use [Link]
  5. Novartis Wins FDA Approval for Oral Monotherapy for Rare Blood Disorder [Link]
ChemSpider
75533872
RxNav
2671061
ChEMBL
CHEMBL4594448
ZINC
ZINC000223246892
PDBe Ligand
JGQ
Wikipedia
Iptacopan
PDB Entries
6rav

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3Active Not RecruitingTreatmentImmunoglobulin A Nephropathy1
3CompletedTreatmentParoxysmal Nocturnal Hemoglobinuria (PNH)2
3Not Yet RecruitingTreatmentAtypical Hemolytic Uremic Syndrome (aHUS)2
3RecruitingTreatmentAtypical Hemolytic Uremic Syndrome (aHUS)1
3RecruitingTreatmentC3G1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
CapsuleOral200 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US9682968No2014-07-142034-07-14US flag
US11603363No2021-05-252041-05-25US flag

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.00578 mg/mLALOGPS
logP4.08ALOGPS
logP1.4Chemaxon
logS-4.9ALOGPS
pKa (Strongest Acidic)3.7Chemaxon
pKa (Strongest Basic)8.75Chemaxon
Physiological Charge0Chemaxon
Hydrogen Acceptor Count5Chemaxon
Hydrogen Donor Count2Chemaxon
Polar Surface Area74.79 Å2Chemaxon
Rotatable Bond Count7Chemaxon
Refractivity121.95 m3·mol-1Chemaxon
Polarizability47.52 Å3Chemaxon
Number of Rings4Chemaxon
Bioavailability1Chemaxon
Rule of FiveYesChemaxon
Ghose FilterYesChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleYesChemaxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-0a6r-0029200000-924dcc9e35d5d3e4daab
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-00ai-0009200000-b37fb47f0a8a287d8558
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-05fr-0004900000-61dada916d5bf2088c07
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-001i-0009100000-5ffe9610ec7cb40899ab
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-0m9c-0759200000-9694645dad781774209e
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-004i-5895100000-5033cb46243b8eedf7d7
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
Not Available

Targets

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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Serine-type endopeptidase activity
Specific Function
Factor B which is part of the alternate pathway of the complement system is cleaved by factor D into 2 fragments: Ba and Bb. Bb, a serine protease, then combines with complement factor 3b to genera...
Gene Name
CFB
Uniprot ID
P00751
Uniprot Name
Complement factor B
Molecular Weight
85532.325 Da
References
  1. FDA Approved Drug Products: FABHALTA® (iptacopan) capsules, for oral use [Link]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
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
CYP2C8
Uniprot ID
P10632
Uniprot Name
Cytochrome P450 2C8
Molecular Weight
55824.275 Da
References
  1. FDA Approved Drug Products: FABHALTA® (iptacopan) capsules, for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic...
Gene Name
CYP2D6
Uniprot ID
P10635
Uniprot Name
Cytochrome P450 2D6
Molecular Weight
55768.94 Da
References
  1. FDA Approved Drug Products: FABHALTA® (iptacopan) capsules, for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Steroid binding
Specific Function
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isoform glucuronidates bilirubin IX-alpha to form both the...
Gene Name
UGT1A1
Uniprot ID
P22309
Uniprot Name
UDP-glucuronosyltransferase 1-1
Molecular Weight
59590.91 Da
References
  1. FDA Approved Drug Products: FABHALTA® (iptacopan) capsules, for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Retinoic acid binding
Specific Function
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. Isoform 2 lacks transferase activity but acts as a negative reg...
Gene Name
UGT1A3
Uniprot ID
P35503
Uniprot Name
UDP-glucuronosyltransferase 1-3
Molecular Weight
60337.835 Da
References
  1. FDA Approved Drug Products: FABHALTA® (iptacopan) capsules, for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Steroid binding
Specific Function
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. Isoform 2 lacks transferase activity but acts as a negative reg...
Gene Name
UGT1A8
Uniprot ID
Q9HAW9
Uniprot Name
UDP-glucuronosyltransferase 1-8
Molecular Weight
59741.035 Da
References
  1. FDA Approved Drug Products: FABHALTA® (iptacopan) capsules, for oral use [Link]

Carriers

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Binder
General Function
Toxic substance binding
Specific Function
Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloid...
Gene Name
ALB
Uniprot ID
P02768
Uniprot Name
Serum albumin
Molecular Weight
69365.94 Da
References
  1. James AD, Kulmatycki K, Poller B, Romeo AA, Van Lier JJ, Klein K, Pearson D: Absorption, Distribution, Metabolism, and Excretion of [(14)C]iptacopan in Healthy Male Volunteers and in In Vivo and In Vitro Studies. Drug Metab Dispos. 2023 Jul;51(7):873-883. doi: 10.1124/dmd.123.001290. Epub 2023 Jun 12. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Binder
General Function
Not Available
Specific Function
Functions as transport protein in the blood stream. Binds various ligands in the interior of its beta-barrel domain. Also binds synthetic drugs and influences their distribution and availability in...
Gene Name
ORM1
Uniprot ID
P02763
Uniprot Name
Alpha-1-acid glycoprotein 1
Molecular Weight
23511.38 Da
References
  1. James AD, Kulmatycki K, Poller B, Romeo AA, Van Lier JJ, Klein K, Pearson D: Absorption, Distribution, Metabolism, and Excretion of [(14)C]iptacopan in Healthy Male Volunteers and in In Vivo and In Vitro Studies. Drug Metab Dispos. 2023 Jul;51(7):873-883. doi: 10.1124/dmd.123.001290. Epub 2023 Jun 12. [Article]

Drug created at December 15, 2020 18:15 / Updated at February 20, 2024 04:50