Lumacaftor

Identification

Summary

Lumacaftor is a protein chaperone used in combination with ivacaftor for the treatment of cystic fibrosis in patients who are homozygous for the F508del mutation in the CFTR gene.

Brand Names

Orkambi

Generic Name

Lumacaftor

DrugBank Accession Number

DB09280

Background

Lumacaftor is a drug used in combination with Ivacaftor as the fixed dose combination product Orkambi for the management of Cystic Fibrosis (CF) in patients aged 6 years and older. Cystic Fibrosis is an autosomal recessive disorder caused by one of several different mutations in the gene for the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein, a transmembrane ion channel involved in the transport of chloride and sodium ions across cell membranes of the lungs, pancreas, and other organs. Mutations in the CFTR gene result in altered production, misfolding, or function of the CFTR protein and consequently abnormal fluid and ion transport across cell membranes.^3,4 As a result, CF patients produce thick, sticky mucus that clogs the ducts of organs where it is produced making patients more susceptible to infections, lung damage, pancreatic insufficiency, and malnutrition.⁵ Lumacaftor improves CF symptoms and underlying disease pathology by aiding the conformational stability of F508del-mutated CFTR proteins, preventing misfolding and resulting in increased processing and trafficking of mature protein to the cell surface.

Results from clinical trials indicated that treatment with Orkambi (lumacaftor/ivacaftor) results in improved lung function, reduced chance of experiencing a pulmonary exacerbation, increased weight gain, and improvements in CF symptoms.^Label This data has been heavily scrutinized, however, with clinical trials showing only modest improvements despite a hefty yearly cost of $259,000 for Orkambi.⁸ Improvements in lung function (ppFEV1) were found to be statistically significant, but minimal, with only a 2.6-3.0% change from baseline with more than 70% of patients failing to achieve an absolute improvement of at least 5%.^8,9

A wide variety of CFTR mutations correlate to the Cystic Fibrosis phenotype and are associated with differing levels of disease severity. The most common mutation, affecting approximately 70% of patients with CF worldwide, is known as F508del-CFTR, or delta-F508 (ΔF508), in which a deletion in the amino acid phenylalanine at position 508 results in impaired production of the CFTR protein, thereby causing a significant reduction in the amount of ion transporter present on cell membranes.⁶ When used in combination with Ivacaftor as the fixed dose combination product Orkambi, lumacaftor is specific for the management of CF in patients with delta-F508 mutations as it acts as a protein-folding chaperone, aiding the conformational stability of the mutated CFTR protein. Consequently, lumacaftor increases successful production of CFTR ion channels and the total number of receptors available for use at the cell membrane for fluid and ion transport.² The next most common mutation, G551D, affecting 4-5% of CF patients worldwide, is characterized as a missense mutation, whereby there is sufficient amount of protein at the cell surface, but opening and closing mechanisms of the channel are altered.⁷ Treatment of patients with G551D and other rarer missense mutations is usually managed with Ivacaftor (Kalydeco), as it aids with altered gating mechanisms by potentiating channel opening probability of CFTR protein.

Prior to the development of lumacaftor and Ivacaftor (Kalydeco), management of CF primarily involved therapies for the control of infections, nutritional support, clearance of mucus, and management of symptoms rather than improvements in the underlying disease process. Approved for use by the Food and Drug Administration in July 2015 and by Health Canada in January 2016, Orkambi was the first combination product approved for the management of Cystic Fibrosis with delta-F508 mutations.

Ivacaftor is manufactured and distributed by Vertex Pharmaceuticals.

Type

Small Molecule

Groups

Approved

Structure

3D

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MOLSDF3D-SDFPDBSMILESInChI

Similar Structures

Structure for Lumacaftor (DB09280)

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Weight

Average: 452.414
Monoisotopic: 452.118378014

Chemical Formula

C₂₄H₁₈F₂N₂O₅

Synonyms

• 3-(6-{[1-(2,2-difluoro-2H-1,3-benzodioxol-5-yl)cyclopropane-1-carbonyl]amino}-3-methylpyridin-2-yl)benzoic acid
• Lumacaftor

External IDs

• VRT 826809
• VRT-826809
• VX 809
• VX-809

Pharmacology

Indication

When used in combination with the drug lumacaftor as the product Orkambi, ivacaftor is indicated for the management of CF in patients aged one year and older who are homozygous for the F508del mutation in the CFTR gene. If the patient’s genotype is unknown, an FDA-cleared CF mutation test should be used to detect the presence of the F508del mutation on both alleles of the CFTR gene.¹¹

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Associated Conditions

• Cystic Fibrosis (CF)

Contraindications & Blackbox Warnings

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Pharmacodynamics

Results from clinical trials indicated that treatment with Orkambi (lumacaftor/ Ivacaftor) results in improved lung function, reduced chance of experiencing a pulmonary exacerbation, reduced sweat chloride, increased weight gain, and improvements in CF symptoms and quality of life.^Label

Orkambi was not found to increase the QTc interval to any clinically relevant extent.^Label

Mechanism of action

Lumacaftor improves CF symptoms and underlying disease pathology by aiding the conformational stability of F508del-mutated CFTR, resulting in increased processing and trafficking of mature protein to the cell surface.^Label More specifically, lumacaftor acts as a protein-folding chaperone, preventing misfolding of CFTR ion channels and consequent destruction during processing in the endoplasmic reticulum.

Target	Actions	Organism
ACystic fibrosis transmembrane conductance regulator	modulator	Humans

Absorption

Following administration of Orkambi (lumacaftor/Ivacaftor) with fat containing foods, peak plasma concentrations were reached at 4 hours (Tmax). It's recommended that Orkambi should be taken with fat-containing foods as they increase absorption of lumacaftor by approximately 2-fold, and[DB08820 by 3-fold.^Label

Volume of distribution

Following oral administration of 200 mg of lumacaftor every 24 hours to cystic fibrosis patients in a fed state for 28 days, the mean (+/-SD) for apparent volumes of distribution was 86.0 (69.8) L.^Label

Protein binding

Lumacaftor is extensively protein bound in the plasma (99%), and binds primarily to albumin.^Label

Metabolism

Lumacaftor is mostly excreted unchanged in the feces and is not extensively metabolized. When metabolism does occur, oxidation and glucuronidation are the main processes involved.^Label

Route of elimination

Lumacaftor is primarily excreted unchanged in the feces (51%). A minimal amount of the parent compound and its metabolites are excreted in the urine.^Label

Half-life

The half-life of lumacaftor is approximately 26 hours.^Label

Clearance

The typical apparent clearance, CL/F (CV), of lumacaftor was estimated to be 2.38 L/hr.^Label

Adverse Effects

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Toxicity

The most common side effects (occuring in >5% of patients during clinical trials) associated with the use of Orkambi include dyspnea, nasopharyngitis, nausea, diarrhea, upper respiratory tract infection, fatigue, respiration abnormal, blood creatine phosphokinase increased, rash, flatulence, rhinorrhea, and influenza.^Label

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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1,2-Benzodiazepine	The metabolism of 1,2-Benzodiazepine can be increased when combined with Lumacaftor.
Abemaciclib	The serum concentration of Abemaciclib can be decreased when it is combined with Lumacaftor.
Abiraterone	The metabolism of Abiraterone can be increased when combined with Lumacaftor.
Abrocitinib	The serum concentration of Abrocitinib can be decreased when it is combined with Lumacaftor.
Acalabrutinib	The metabolism of Acalabrutinib can be increased when combined with Lumacaftor.
Acenocoumarol	The serum concentration of Acenocoumarol can be decreased when it is combined with Lumacaftor.
Acetaminophen	The metabolism of Acetaminophen can be increased when combined with Lumacaftor.
Acetohexamide	The metabolism of Acetohexamide can be decreased when combined with Lumacaftor.
Acetylsalicylic acid	The metabolism of Acetylsalicylic acid can be decreased when combined with Lumacaftor.
Afatinib	The serum concentration of Afatinib can be increased when it is combined with Lumacaftor.

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Food Interactions

No interactions found.

Products

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Mixture Products

Name	Ingredients	Dosage	Route	Labeller	Marketing Start	Marketing End	Region	Image
Orkambi	Lumacaftor (100 mg/1) + Ivacaftor (125 mg/1)	Granule	Oral	Vertex Pharmaceuticals Incorporated	2018-08-07	Not applicable
Orkambi	Lumacaftor (150 mg) + Ivacaftor (188 mg)	Granule	Oral	Vertex Pharmaceuticals (Ireland) Limited	2020-12-22	Not applicable
Orkambi	Lumacaftor (75 mg/1) + Ivacaftor (94 mg/1)	Granule	Oral	Vertex Pharmaceuticals Incorporated	2022-09-02	Not applicable
Orkambi	Lumacaftor (100 mg) + Ivacaftor (125 mg)	Tablet	Oral	Vertex Pharmaceuticals Incorporated	2017-05-03	Not applicable
Orkambi	Lumacaftor (200 mg) + Ivacaftor (125 mg)	Tablet, film coated	Oral	Vertex Pharmaceuticals (Ireland) Limited	2016-09-08	2020-12-14
Orkambi	Lumacaftor (150 mg / sachet) + Ivacaftor (188 mg / sachet)	Granule	Oral	Vertex Pharmaceuticals Incorporated	2018-12-14	Not applicable
Orkambi	Lumacaftor (100 mg/1) + Ivacaftor (125 mg/1)	Tablet, film coated	Oral	Vertex Pharmaceuticals Incorporated	2016-09-28	Not applicable
Orkambi	Lumacaftor (100 mg) + Ivacaftor (125 mg)	Granule	Oral	Vertex Pharmaceuticals (Ireland) Limited	2020-12-22	Not applicable
Orkambi	Lumacaftor (200 mg) + Ivacaftor (125 mg)	Tablet	Oral	Vertex Pharmaceuticals Incorporated	2016-01-27	Not applicable
Orkambi	Lumacaftor (150 mg/1) + Ivacaftor (188 mg/1)	Granule	Oral	Vertex Pharmaceuticals Incorporated	2018-08-07	Not applicable

Categories

ATC Codes

R07AX30 — Ivacaftor and lumacaftor

• R07AX — Other respiratory system products
• R07A — OTHER RESPIRATORY SYSTEM PRODUCTS
• R07 — OTHER RESPIRATORY SYSTEM PRODUCTS
• R — RESPIRATORY SYSTEM

Drug Categories

• Amines
• Cytochrome P-450 CYP2B6 Inducers
• Cytochrome P-450 CYP2B6 Inducers (strength unknown)
• Cytochrome P-450 CYP2C19 Inducers
• Cytochrome P-450 CYP2C19 Inducers (strength unknown)
• Cytochrome P-450 CYP2C8 Inducers
• Cytochrome P-450 CYP2C8 Inducers (strength unknown)
• Cytochrome P-450 CYP2C8 Inhibitors
• Cytochrome P-450 CYP2C8 Inhibitors (strength unknown)
• Cytochrome P-450 CYP2C9 Inducers
• Cytochrome P-450 CYP2C9 Inducers (strength unknown)
• Cytochrome P-450 CYP2C9 Inhibitors
• Cytochrome P-450 CYP2C9 Inhibitors (strength unknown)
• Cytochrome P-450 CYP3A Inducers
• Cytochrome P-450 CYP3A Inducers (strong)
• Cytochrome P-450 CYP3A4 Inducers
• Cytochrome P-450 CYP3A4 Inducers (strong)
• Cytochrome P-450 Enzyme Inducers
• Cytochrome P-450 Enzyme Inhibitors
• Dioxoles
• Heterocyclic Compounds, Fused-Ring
• P-glycoprotein inducers
• P-glycoprotein inhibitors
• Pyridines

Chemical TaxonomyProvided by Classyfire

Description

This compound belongs to the class of organic compounds known as phenylpyridines. These are polycyclic aromatic compounds containing a benzene ring linked to a pyridine ring through a CC or CN bond.

Kingdom

Organic compounds

Super Class

Organoheterocyclic compounds

Class

Pyridines and derivatives

Sub Class

Phenylpyridines

Direct Parent

Phenylpyridines

Alternative Parents

Benzodioxoles / Benzoic acids / Benzoyl derivatives / N-arylamides / Methylpyridines / Imidolactams / Cyclopropanecarboxylic acids and derivatives / Heteroaromatic compounds / Secondary carboxylic acid amides / Azacyclic compounds / Monocarboxylic acids and derivatives / Carboxylic acids / Oxacyclic compounds / Organic oxides / Hydrocarbon derivatives / Carbonyl compounds / Alkyl fluorides / Organofluorides / Organopnictogen compounds

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Substituents

2-phenylpyridine / Alkyl fluoride / Alkyl halide / Aromatic heteropolycyclic compound / Azacycle / Benzenoid / Benzodioxole / Benzoic acid / Benzoic acid or derivatives / Benzoyl / Carbonyl group / Carboxamide group / Carboxylic acid / Carboxylic acid derivative / Cyclopropanecarboxylic acid or derivatives / Heteroaromatic compound / Hydrocarbon derivative / Imidolactam / Methylpyridine / Monocarboxylic acid or derivatives / Monocyclic benzene moiety / N-arylamide / Organic nitrogen compound / Organic oxide / Organic oxygen compound / Organofluoride / Organohalogen compound / Organonitrogen compound / Organooxygen compound / Organopnictogen compound / Oxacycle / Secondary carboxylic acid amide

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Molecular Framework

Aromatic heteropolycyclic compounds

External Descriptors

Not Available

Affected organisms

Not Available

Chemical Identifiers

UNII

EGP8L81APK

CAS number

936727-05-8

InChI Key

UFSKUSARDNFIRC-UHFFFAOYSA-N

InChI

InChI=1S/C24H18F2N2O5/c1-13-5-8-19(27-20(13)14-3-2-4-15(11-14)21(29)30)28-22(31)23(9-10-23)16-6-7-17-18(12-16)33-24(25,26)32-17/h2-8,11-12H,9-10H2,1H3,(H,29,30)(H,27,28,31)

IUPAC Name

3-{6-[1-(2,2-difluoro-2H-1,3-benzodioxol-5-yl)cyclopropaneamido]-3-methylpyridin-2-yl}benzoic acid

SMILES

CC1=CC=C(NC(=O)C2(CC2)C2=CC=C3OC(F)(F)OC3=C2)N=C1C1=CC(=CC=C1)C(O)=O

References

General References

1. Boyle MP, Bell SC, Konstan MW, McColley SA, Rowe SM, Rietschel E, Huang X, Waltz D, Patel NR, Rodman D: A CFTR corrector (lumacaftor) and a CFTR potentiator (ivacaftor) for treatment of patients with cystic fibrosis who have a phe508del CFTR mutation: a phase 2 randomised controlled trial. Lancet Respir Med. 2014 Jul;2(7):527-38. doi: 10.1016/S2213-2600(14)70132-8. Epub 2014 Jun 24. [Article]
2. Kuk K, Taylor-Cousar JL: Lumacaftor and ivacaftor in the management of patients with cystic fibrosis: current evidence and future prospects. Ther Adv Respir Dis. 2015 Dec;9(6):313-26. doi: 10.1177/1753465815601934. Epub 2015 Sep 28. [Article]
3. Saint-Criq V, Gray MA: Role of CFTR in epithelial physiology. Cell Mol Life Sci. 2017 Jan;74(1):93-115. doi: 10.1007/s00018-016-2391-y. Epub 2016 Oct 6. [Article]
4. Kunzelmann K, Mall M: Pharmacotherapy of the ion transport defect in cystic fibrosis: role of purinergic receptor agonists and other potential therapeutics. Am J Respir Med. 2003;2(4):299-309. [Article]
5. Fraser-Pitt D, O'Neil D: Cystic fibrosis - a multiorgan protein misfolding disease. Future Sci OA. 2015 Sep 1;1(2):FSO57. doi: 10.4155/fso.15.57. eCollection 2015 Sep. [Article]
6. MacDonald KD, McKenzie KR, Zeitlin PL: Cystic fibrosis transmembrane regulator protein mutations: 'class' opportunity for novel drug innovation. Paediatr Drugs. 2007;9(1):1-10. [Article]
7. Yu H, Burton B, Huang CJ, Worley J, Cao D, Johnson JP Jr, Urrutia A, Joubran J, Seepersaud S, Sussky K, Hoffman BJ, Van Goor F: Ivacaftor potentiation of multiple CFTR channels with gating mutations. J Cyst Fibros. 2012 May;11(3):237-45. doi: 10.1016/j.jcf.2011.12.005. Epub 2012 Jan 30. [Article]
8. Mayer M: Lumacaftor-ivacaftor (Orkambi) for cystic fibrosis: behind the 'breakthrough'. Evid Based Med. 2016 Jun;21(3):83-6. doi: 10.1136/ebmed-2015-110325. Epub 2015 Dec 30. [Article]
9. The Canadian Drug Expert Committee (CDEC): Lumacaftor/Ivacaftor Recommendation [Link]
10. FDA Approved Drug Products: ORKAMBI (lumacaftor/ivacaftor) granules or tablets, for oral use [Link]
11. FDA Approved Drug Products: ORKAMBI (lumacaftor and ivacaftor) tablets or granules, for oral use (September 2022) [Link]

External Links

Human Metabolome Database

HMDB0247669

KEGG Drug

D10134

PubChem Compound

16678941

PubChem Substance

310265173

ChemSpider

17611836

BindingDB

50289703

RxNav

1655922

ChEBI

90951

ChEMBL

CHEMBL2103870

ZINC

ZINC000064033452

PharmGKB

PA166114483

PDBe Ligand

VX8

RxList

RxList Drug Page

Drugs.com

Drugs.com Drug Page

Wikipedia

Lumacaftor

PDB Entries

7svd / 7svr / 8eio

FDA label

Download (335 KB)

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
4	Completed	Other	Cystic Fibrosis (CF)	1
4	Terminated	Treatment	Cystic Fibrosis (CF)	2
3	Active Not Recruiting	Treatment	Cystic Fibrosis (CF)	1
3	Completed	Treatment	Advanced Lung Disease / Cystic Fibrosis (CF)	1
3	Completed	Treatment	Cystic Fibrosis (CF)	6
3	Completed	Treatment	Cystic Fibrosis, Homozygous for the F508del CFTR Mutation	2
3	Completed	Treatment	Cystic Fibrosis, Homozygous or Heterozygous for the F508del-CFTR Mutation	1
2	Completed	Treatment	Cystic Fibrosis (CF)	5
2	Recruiting	Treatment	Long QT Syndrome (LQTS)	1
1	Completed	Not Available	Cystic Fibrosis (CF)	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Granule	Oral
Tablet	Oral
Tablet, film coated	Oral

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)	Region
US8324242	No	2012-12-04	2027-04-18
US8754224	No	2014-06-17	2026-12-28
US8410274	No	2013-04-02	2026-12-28
US7495103	No	2009-02-24	2027-05-20
US8741933	No	2014-06-03	2026-11-08
US8716338	No	2014-05-06	2026-11-08
US8846718	No	2014-09-30	2028-12-04
US8653103	No	2014-02-18	2028-12-04
US9216969	No	2015-12-22	2026-11-08
US8507534	No	2013-08-13	2030-09-20
US8993600	No	2015-03-31	2030-12-11
US9670163	No	2017-06-06	2026-12-28
US9192606	No	2015-11-24	2029-09-29
US7973038	No	2011-07-05	2026-11-08
US9150552	No	2015-10-06	2028-12-04
US9931334	No	2018-04-03	2026-12-28
US10076513	No	2018-09-18	2028-12-04
US10597384	No	2020-03-24	2028-12-04
US10646481	No	2020-05-12	2029-08-13
US11052075	No	2021-07-06	2028-12-04

Properties

State

Solid

Experimental Properties

Not Available

Predicted Properties

Property	Value	Source
Water Solubility	0.00376 mg/mL	ALOGPS
logP	4.37	ALOGPS
logP	5.77	Chemaxon
logS	-5.1	ALOGPS
pKa (Strongest Acidic)	4.17	Chemaxon
pKa (Strongest Basic)	3.5	Chemaxon
Physiological Charge	-1	Chemaxon
Hydrogen Acceptor Count	6	Chemaxon
Hydrogen Donor Count	2	Chemaxon
Polar Surface Area	97.75 Å2	Chemaxon
Rotatable Bond Count	5	Chemaxon
Refractivity	111.97 m3·mol-1	Chemaxon
Polarizability	44.12 Å3	Chemaxon
Number of Rings	5	Chemaxon
Bioavailability	1	Chemaxon
Rule of Five	No	Chemaxon
Ghose Filter	No	Chemaxon
Veber's Rule	No	Chemaxon
MDDR-like Rule	No	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	Not Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	Not Available

Targets

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Details1. Cystic fibrosis transmembrane conductance regulator

Kind

Protein

Organism

Humans

Pharmacological action

Yes

Actions

Modulator

General Function

Pdz domain binding

Specific Function

Involved in the transport of chloride ions. May regulate bicarbonate secretion and salvage in epithelial cells by regulating the SLC4A7 transporter. Can inhibit the chloride channel activity of ANO...

Gene Name

CFTR

Uniprot ID

P13569

Uniprot Name

Cystic fibrosis transmembrane conductance regulator

Molecular Weight

168139.895 Da

References

1. Kuk K, Taylor-Cousar JL: Lumacaftor and ivacaftor in the management of patients with cystic fibrosis: current evidence and future prospects. Ther Adv Respir Dis. 2015 Dec;9(6):313-26. doi: 10.1177/1753465815601934. Epub 2015 Sep 28. [Article]

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Drug created at October 29, 2015 15:12 / Updated at September 07, 2022 02:10