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

3D

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MOLSDF3D-SDFPDBSMILESInChI

Similar Structures

Structure for Iptacopan (DB16200)

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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

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Pharmacology

Indication

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

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Associated Conditions

Indication Type	Indication	Combined Product Details	Approval Level	Age Group	Patient Characteristics	Dose Form
Treatment of	Paroxysmal nocturnal haemoglobinuria (pnh)		••••••••••••	•••••		•••••••

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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

Target	Actions	Organism
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

Hover over products below to view reaction partners

• Iptacopan
  • M2 iptacopan
    • M9 iptacopan
  • M8 iptacopan
  • M6 iptacopan
  • M1 iptacopan

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 (t_1/2) 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.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drug	Interaction
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Abatacept	The metabolism of Iptacopan can be increased when combined with Abatacept.
Abiraterone	The metabolism of Iptacopan can be decreased when combined with Abiraterone.
Acebutolol	The metabolism of Iptacopan can be decreased when combined with Acebutolol.
Acetaminophen	The metabolism of Iptacopan can be decreased when combined with Acetaminophen.
Adagrasib	The metabolism of Iptacopan can be decreased when combined with Adagrasib.

Food Interactions

No interactions found.

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Product Ingredients

Ingredient	UNII	CAS	InChI Key
Iptacopan hydrochloride monohydrate	XW5CK7C6YH	2447007-60-3	JUWBBUFSAGEROP-VVJLZRNGSA-N

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Fabhalta	Capsule	200 mg/1	Oral	Novartis Pharmaceuticals Corporation	2023-12-05	Not applicable

Categories

Drug Categories

• Cytochrome P-450 CYP2C8 Substrates
• Cytochrome P-450 CYP2D6 Substrates
• Cytochrome P-450 Substrates
• UGT1A1 Substrates
• UGT1A3 substrates

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]

External Links

ChemSpider

75533872

RxNav

2671061

ChEMBL

CHEMBL4594448

ZINC

ZINC000223246892

PDBe Ligand

JGQ

Wikipedia

Iptacopan

PDB Entries

6rav

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
3	Active Not Recruiting	Treatment	Immunoglobulin A Nephropathy	1
3	Completed	Treatment	Paroxysmal Nocturnal Haemoglobinuria (PNH)	2
3	Not Yet Recruiting	Treatment	Atypical Hemolytic Uremic Syndrome(aHUS)	1
3	Recruiting	Treatment	Atypical Hemolytic Uremic Syndrome(aHUS)	2
3	Recruiting	Treatment	C3G	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Capsule	Oral	200 mg/1

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)	Region
US9682968	No	2014-07-14	2034-07-14
US11603363	No	2021-05-25	2041-05-25

Properties

State

Solid

Experimental Properties

Not Available

Predicted Properties

Property	Value	Source
Water Solubility	0.00578 mg/mL	ALOGPS
logP	4.08	ALOGPS
logP	1.4	Chemaxon
logS	-4.9	ALOGPS
pKa (Strongest Acidic)	3.7	Chemaxon
pKa (Strongest Basic)	8.75	Chemaxon
Physiological Charge	0	Chemaxon
Hydrogen Acceptor Count	5	Chemaxon
Hydrogen Donor Count	2	Chemaxon
Polar Surface Area	74.79 Å2	Chemaxon
Rotatable Bond Count	7	Chemaxon
Refractivity	121.95 m3·mol-1	Chemaxon
Polarizability	47.52 Å3	Chemaxon
Number of Rings	4	Chemaxon
Bioavailability	1	Chemaxon
Rule of Five	Yes	Chemaxon
Ghose Filter	Yes	Chemaxon
Veber's Rule	No	Chemaxon
MDDR-like Rule	Yes	Chemaxon

Predicted ADMET Features

Not Available

Spectra

Mass Spec (NIST)

Not Available

Spectra

Spectrum	Spectrum Type	Splash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)	Predicted LC-MS/MS	splash10-0a6r-0029200000-924dcc9e35d5d3e4daab
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	splash10-00ai-0009200000-b37fb47f0a8a287d8558
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	splash10-05fr-0004900000-61dada916d5bf2088c07
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	splash10-001i-0009100000-5ffe9610ec7cb40899ab
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	splash10-0m9c-0759200000-9694645dad781774209e
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	splash10-004i-5895100000-5033cb46243b8eedf7d7
Predicted 1H NMR Spectrum	1D NMR	Not Applicable
Predicted 13C NMR Spectrum	1D NMR	Not Applicable

Chromatographic Properties

Collision Cross Sections (CCS)

Not Available

Targets

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Details1. Complement factor B

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]

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