Leniolisib

Identification

Summary

Leniolisib is a phosphoinositide 3-kinase-delta inhibitor that is used to treat activated phosphoinositide 3-kinase delta syndrome.

Brand Names

Joenja

Generic Name

Leniolisib

DrugBank Accession Number

DB16217

Background

Leniolisib is a potent and selective inhibitor of phosphoinositide 3-kinase δ (PI3Kδ). The FDA approved leniolisib on March 24, 2023, making it the first treatment for activated phosphoinositide 3-kinase delta syndrome (APDS).¹⁰ APDS is a primary immunodeficiency caused by mutations in genes encoding the PI3Kδ, thereby increasing the activity of PI3Kδ, causing immune dysfunction, and elevating susceptibility to infections.^1,2 Leniolisib works to inhibit hyperactive PI3Kδ.⁹ Investigations for using leniolisib in primary Sjögren’s syndrome are ongoing.³

Type

Small Molecule

Groups

Approved, Investigational

Structure

3D

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MOLSDF3D-SDFPDBSMILESInChI

Similar Structures

Structure for Leniolisib (DB16217)

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Weight

Average: 450.466
Monoisotopic: 450.199108558

Chemical Formula

C₂₁H₂₅F₃N₆O₂

Synonyms

• Cdz-173 free base
• Cdz173 free base
• Leniolisib

External IDs

• CDZ-173-NX
• CDZ173
• CDZ173-NX

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Pharmacology

Indication

Leniolisib is indicated for the treatment of activated phosphoinositide 3-kinase delta (PI3Kδ) syndrome (APDS) in adult and pediatric patients 12 years of age and older.⁹

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Associated Conditions

Indication Type	Indication	Combined Product Details	Approval Level	Age Group	Patient Characteristics	Dose Form
Treatment of	Activated pi3 kinase delta syndrome		••••••••••••	••••••••••• •••••

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Contraindications & Blackbox Warnings

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Pharmacodynamics

Leniolisib works to block aberrant PI3Kδ-dependent signalling pathways of immune cells, such as B and T cells, neutrophils, monocytes, basophils, plasmocytoid dendritic cells, and mast cells.³ In vitro, leniolisib dose-dependently suppresses the PI3Kδ pathway hyperactivation in cell lines overexpressing p110δ mutants and in primary immune cells from patients with APDS.² Ex vivo pharmacodynamics of leniolisib in the proportion of phosphorylated Akt (pAkt)- positive B cells were assessed intra-individually at 10, 30, and 70 mg twice daily for four weeks at each dose level in patients with APDS. Within the explored dose range, higher leniolisib plasma concentrations were generally associated with a higher reduction of pAkt-positive B cells. Higher doses were associated with a slightly higher peak and more sustained reduction. Treatment with leniolisib 70 mg twice a day at a steady state is estimated to produce a time-averaged reduction of pAkt-positive B cells by approximately 80%.⁹

Mechanism of action

Phosphoinositide-3-kinase δ (PI3Kδ) is a lipid kinase activated downstream of tyrosine kinase receptors and G-protein–coupled receptors in immune cells.^1,3,8 It mediates the PI3K/AKT pathway, which is involved in cell proliferation, growth, and survival.^6,7 A heterodimer made up of a regulatory subunit (p85α) and a catalytic subunit (p110δ), PI3Kδ is primarily expressed on hematopoietic cells such as lymphocytes and myeloid cells. It converts phosphatidylinositol-4,5-bisphosphate (PIP2) to phosphatidylinositol-3,4,5-trisphosphate (PIP3), a signalling molecule that downstream proteins like the AKT kinase, which activate mammalian target of rapamycin (mTOR) complex I and inhibit FOXO family of transcription factors.^1,2 APDS is associated with gain-of-function variants in the gene encoding p110δ or loss of function variants in the gene encoding p85α, each causing hyperactivity of PI3K-delta, reduced T cell function, lymphadenopathy, and immunodeficiency.^1,9

Leniolisib inhibits PI3Kδ by blocking the active binding site in the p110δ subunit.² In cell-free isolated enzyme assays, the selectivity was higher for PI3K-delta over PI3K-alpha (28-fold), PI3K-beta (43-fold), and PI3K-gamma (257-fold), as well as the broader kinome. In cell-based assays, leniolisib reduced pAKT pathway activity and inhibited proliferation and activation of B and T cell subsets. Leniolisib inhibits the signalling pathways that lead to increased production of PIP3, hyperactivity of the downstream mTOR/AKT pathway, and the dysregulation of B and T cells.⁹

Target	Actions	Organism
APhosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform	inhibitor	Humans

Absorption

The systemic drug exposure (AUC and C_max) of leniolisib increases dose proportionally. During twice daily dosing approximately 12 hours apart, leniolisib accumulates approximately 1.4-fold (range of 1.0 to 2.2) in achieving steady-state. Steady-state drug concentrations can be expected to be reached after approximately two to three days. The T_max is about one hour. Food has negligible effects on the systemic exposure of leniolisib.⁹

Volume of distribution

The systemic decay in leniolisib plasma concentration over time is bi-exponential, indicating a distribution delay toward peripheral tissues. The volume of distribution of leniolisib is estimated to be 28.5 L in patients with APDS.⁹

Protein binding

Leniolisib is 94.5% bound to plasma proteins.⁹

Metabolism

About 60% of leniolisib is metabolized by the liver. Leniolisib undergoes oxidative metabolism, which is primarily mediated by CYP3A4 (94.5%), as well as CYP3A5 (3.5%), CYP1A2 (0.7%) and CYP2D6 (0.7%) to a minor extent.^4,9 Few metabolites of leniolisib have been characterized in one study; however, no metabolites were abundant in plasma relative to the parent drug. Other metabolic pathways include dealkylation, demethylation, and hydroxylation.⁵

Other suggested excretion routes include intestinal secretion by BCRP and CYP1A1-mediated extrahepatic metabolism.^4,9

Hover over products below to view reaction partners

• Leniolisib
  • Leniolisib M6 metabolite
  • Leniolisib M7 metabolite
  • Leniolisib M10 metabolite
  • Leniolisib M9 metabolite
  • Leniolisib M43 metabolite
    • Leniolisib M48 metabolite
  • Leniolisib M1 metabolite
    • Leniolisib M48 metabolite

Route of elimination

The mean recovery of total 14C-radioactivity following a single oral dose of 70 mg ¹⁴C-leniolisib was 92.5% following 168 hours post-dose. About 67% and 25.5% of the recovered dose were in feces and urine, respectively. Of the recovered dose in urine, 6.32% was in unchanged parent drug form and the predominant drug-related material.⁹

Half-life

The effective half-life is approximately seven hours. The apparent terminal elimination half-life is approximately 10 hours.⁹

Clearance

In one study, healthy volunteers received leniolisib single ascending doses up to 400 mg and multiple ascending doses up to 140 mg twice daily for 14 days. Oral drug clearance from plasma (CL/F) was 4 L/h.⁴

Adverse Effects

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Toxicity

No information on the LD₅₀ of leniolisib is available. If overdosage occurs, monitor the patient for any signs or symptoms of adverse reactions. Treatment of overdose with leniolisib consists of general supportive measures, including monitoring of vital signs as well as observation of the clinical status of the patient.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.

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

Drug	Interaction
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Abemaciclib	The excretion of Abemaciclib can be decreased when combined with Leniolisib.
Acenocoumarol	The metabolism of Acenocoumarol can be decreased when combined with Leniolisib.
Acetaminophen	The metabolism of Acetaminophen can be decreased when combined with Leniolisib.
Acyclovir	The metabolism of Acyclovir can be decreased when combined with Leniolisib.
Adenovirus type 7 vaccine live	The therapeutic efficacy of Adenovirus type 7 vaccine live can be decreased when used in combination with Leniolisib.

Food Interactions

• Take with or without food. Food has negligible effects on systemic exposure of leniolisib.

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Product Ingredients

Ingredient	UNII	CAS	InChI Key
Leniolisib phosphate	3700M1H39Q	1354691-97-6	XXEDEGOAYSGNPS-ZOWNYOTGSA-N

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Joenja	Tablet, film coated	70 mg/1	Oral	Pharming Healthcare Inc.	2023-03-29	Not applicable

Categories

Drug Categories

• BCRP/ABCG2 Inhibitors
• BCRP/ABCG2 Substrates
• Cytochrome P-450 CYP1A2 Inhibitors
• Cytochrome P-450 CYP1A2 Inhibitors (strength unknown)
• Cytochrome P-450 CYP1A2 Substrates
• Cytochrome P-450 CYP2D6 Substrates
• Cytochrome P-450 CYP3A Substrates
• Cytochrome P-450 CYP3A4 Substrates
• Cytochrome P-450 CYP3A5 Substrates
• Cytochrome P-450 Enzyme Inhibitors
• Cytochrome P-450 Substrates
• Kinase Inhibitor
• OATP1B1/SLCO1B1 Inhibitors
• OATP1B3 inhibitors
• P-glycoprotein substrates

Classification

Not classified

Affected organisms

Not Available

Chemical Identifiers

UNII

L22772Z9CP

CAS number

1354690-24-6

InChI Key

MWKYMZXCGYXLPL-ZDUSSCGKSA-N

InChI

InChI=1S/C21H25F3N6O2/c1-3-18(31)30-6-4-13(10-30)28-19-15-11-29(7-5-17(15)26-12-27-19)14-8-16(21(22,23)24)20(32-2)25-9-14/h8-9,12-13H,3-7,10-11H2,1-2H3,(H,26,27,28)/t13-/m0/s1

IUPAC Name

1-[(3S)-3-({6-[6-methoxy-5-(trifluoromethyl)pyridin-3-yl]-5H,6H,7H,8H-pyrido[4,3-d]pyrimidin-4-yl}amino)pyrrolidin-1-yl]propan-1-one

SMILES

CCC(=O)N1CC[C@@H](C1)NC1=C2CN(CCC2=NC=N1)C1=CN=C(OC)C(=C1)C(F)(F)F

References

General References

1. Michalovich D, Nejentsev S: Activated PI3 Kinase Delta Syndrome: From Genetics to Therapy. Front Immunol. 2018 Feb 27;9:369. doi: 10.3389/fimmu.2018.00369. eCollection 2018. [Article]
2. Rao VK, Webster S, Dalm VASH, Sediva A, van Hagen PM, Holland S, Rosenzweig SD, Christ AD, Sloth B, Cabanski M, Joshi AD, de Buck S, Doucet J, Guerini D, Kalis C, Pylvaenaeinen I, Soldermann N, Kashyap A, Uzel G, Lenardo MJ, Patel DD, Lucas CL, Burkhart C: Effective "activated PI3Kdelta syndrome"-targeted therapy with the PI3Kdelta inhibitor leniolisib. Blood. 2017 Nov 23;130(21):2307-2316. doi: 10.1182/blood-2017-08-801191. Epub 2017 Sep 29. [Article]
3. Hoegenauer K, Soldermann N, Zecri F, Strang RS, Graveleau N, Wolf RM, Cooke NG, Smith AB, Hollingworth GJ, Blanz J, Gutmann S, Rummel G, Littlewood-Evans A, Burkhart C: Discovery of CDZ173 (Leniolisib), Representing a Structurally Novel Class of PI3K Delta-Selective Inhibitors. ACS Med Chem Lett. 2017 Aug 25;8(9):975-980. doi: 10.1021/acsmedchemlett.7b00293. eCollection 2017 Sep 14. [Article]
4. De Buck S, Kucher K, Hara H, Gray C, Woessner R: CYP3A but not P-gp plays a relevant role in the in vivo intestinal and hepatic clearance of the delta-specific phosphoinositide-3 kinase inhibitor leniolisib. Biopharm Drug Dispos. 2018 Sep;39(8):394-402. doi: 10.1002/bdd.2157. [Article]
5. Pearson D, Garnier M, Luneau A, James AD, Walles M: (19)F-NMR-based determination of the absorption, metabolism and excretion of the oral phosphatidylinositol-3-kinase (PI3K) delta inhibitor leniolisib (CDZ173) in healthy volunteers. Xenobiotica. 2019 Aug;49(8):953-960. doi: 10.1080/00498254.2018.1523488. Epub 2018 Nov 29. [Article]
6. Fresno Vara JA, Casado E, de Castro J, Cejas P, Belda-Iniesta C, Gonzalez-Baron M: PI3K/Akt signalling pathway and cancer. Cancer Treat Rev. 2004 Apr;30(2):193-204. doi: 10.1016/j.ctrv.2003.07.007. [Article]
7. Osaki M, Oshimura M, Ito H: PI3K-Akt pathway: its functions and alterations in human cancer. Apoptosis. 2004 Nov;9(6):667-76. doi: 10.1023/B:APPT.0000045801.15585.dd. [Article]
8. Martini M, De Santis MC, Braccini L, Gulluni F, Hirsch E: PI3K/AKT signaling pathway and cancer: an updated review. Ann Med. 2014 Sep;46(6):372-83. doi: 10.3109/07853890.2014.912836. Epub 2014 Jun 5. [Article]
9. FDA Approved Drug Products: JOENJA (leniolisib) tablets, for oral use [Link]
10. FDA News: FDA approves first treatment for activated phosphoinositide 3-kinase delta syndrome [Link]

External Links

ChemSpider

52083264

BindingDB

118299

RxNav

2633005

ChEMBL

CHEMBL3643413

PDBe Ligand

9NQ

Wikipedia

Leniolisib

PDB Entries

5o83

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
3	Active Not Recruiting	Treatment	APD	1
3	Recruiting	Treatment	APD	1
3	Recruiting	Treatment	APDS Gene Mutation	1
2	Completed	Treatment	Primary Sjögren's Syndrome (pSS)	1
2, 3	Active Not Recruiting	Treatment	Activated PI3Kdelta Syndrome (APDS); PASLI Disease	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Tablet, film coated	Oral	70 mg/1

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)	Region
US8653092	No	2014-02-18	2032-02-19

Properties

State

Solid

Experimental Properties

Property	Value	Source
water solubility	<1 mg/mL	https://www.selleckchem.com/msds/MSDS_S8752.pdf

Predicted Properties

Property	Value	Source
logP	2.01	Chemaxon
pKa (Strongest Acidic)	18.21	Chemaxon
pKa (Strongest Basic)	5.43	Chemaxon
Physiological Charge	0	Chemaxon
Hydrogen Acceptor Count	7	Chemaxon
Hydrogen Donor Count	1	Chemaxon
Polar Surface Area	83.48 Å2	Chemaxon
Rotatable Bond Count	6	Chemaxon
Refractivity	115.08 m3·mol-1	Chemaxon
Polarizability	43.46 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, Negative (Annotated)	Predicted LC-MS/MS	splash10-006t-0000900000-a2bcc1cab0dd31e6e136
Predicted MS/MS Spectrum - 10V, Positive (Annotated)	Predicted LC-MS/MS	splash10-0udi-0004900000-37e9b0f773ad7325777e
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	splash10-0udj-0007900000-0912d4197d70801ce729
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	splash10-03di-0019200000-31c01db42cf066b2187a
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	splash10-004j-0009100000-788f8eaee2206e82ebac
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	splash10-014l-1239200000-5a63f6ccab314f41063a
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. Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform

Kind

Protein

Organism

Humans

Pharmacological action

Yes

Actions

Inhibitor

General Function

Phosphatidylinositol-4,5-bisphosphate 3-kinase activity

Specific Function

Phosphoinositide-3-kinase (PI3K) that phosphorylates PftdIns(4,5)P2 (Phosphatidylinositol 4,5-bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 plays a key role by rec...

Gene Name

PIK3CD

Uniprot ID

O00329

Uniprot Name

Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform

Molecular Weight

119478.065 Da

References

1. Rao VK, Webster S, Dalm VASH, Sediva A, van Hagen PM, Holland S, Rosenzweig SD, Christ AD, Sloth B, Cabanski M, Joshi AD, de Buck S, Doucet J, Guerini D, Kalis C, Pylvaenaeinen I, Soldermann N, Kashyap A, Uzel G, Lenardo MJ, Patel DD, Lucas CL, Burkhart C: Effective "activated PI3Kdelta syndrome"-targeted therapy with the PI3Kdelta inhibitor leniolisib. Blood. 2017 Nov 23;130(21):2307-2316. doi: 10.1182/blood-2017-08-801191. Epub 2017 Sep 29. [Article]
2. Hoegenauer K, Soldermann N, Zecri F, Strang RS, Graveleau N, Wolf RM, Cooke NG, Smith AB, Hollingworth GJ, Blanz J, Gutmann S, Rummel G, Littlewood-Evans A, Burkhart C: Discovery of CDZ173 (Leniolisib), Representing a Structurally Novel Class of PI3K Delta-Selective Inhibitors. ACS Med Chem Lett. 2017 Aug 25;8(9):975-980. doi: 10.1021/acsmedchemlett.7b00293. eCollection 2017 Sep 14. [Article]
3. FDA Approved Drug Products: JOENJA (leniolisib) tablets, for oral use [Link]

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Drug created at December 15, 2020 18:15 / Updated at April 11, 2023 23:56