LENIOLISIB

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C21H25F3N6O2
Molecular Weight	450.4574
Optical Activity	UNSPECIFIED
Defined Stereocenters	1 / 1
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CCC(=O)N1CC[C@@H](C1)NC2=NC=NC3=C2CN(CC3)C4=CN=C(OC)C(=C4)C(F)(F)F

InChI

InChIKey=MWKYMZXCGYXLPL-ZDUSSCGKSA-N

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

HIDE SMILES / InChI

Description
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/217759s000lbl.pdf|https://pubmed.ncbi.nlm.nih.gov/37256490

Leniolisib (JOENJA®) is an oral selective phosphoinositide 3-kinase-delta (PI3Kdelta) inhibitor being developed by Pharming Group NV in-licensed from Novartis for the treatment of immunodeficiency disorders. Leniolisib inhibits PI3K-delta by blocking the active binding site of PI3K-delta. In cell-free isolated enzyme assays, leniolisib was selective 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. Gain-of-function variants in the gene encoding the p110-delta catalytic subunit or loss of function variants in the gene encoding the p85-alpha regulatory subunit each cause hyperactivity of PI3K-delta. Leniolisib inhibits the signalling pathways that lead to increased production of PIP3, hyperactivity of the downstream mTOR/AKT pathway, and to the dysregulation of B and T cells. In March 2023, leniolisib received its first approval for the treatment of activated PI3Kdelta syndrome (APDS) in adult and paediatric patients 12 years of age and older. Leniolisib is also under regulatory review in European Union for the treatment of APDS. Development of leniolisib for the treatment of Sjögren's syndrome has been discontinued.

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
PI3-kinase p110-delta subunit 43 Target ID: CHEMBL3130 Sources: https://pubmed.ncbi.nlm.nih.gov/28947947\|https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/217759s000lbl.pdf	Inhibitor 8504		0.011 µM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Activated phosphoinositide 3-kinase delta syndrome (APDS) 2 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/217759s000lbl.pdf	Primary		Approved 8583	JOENJA Approved Use JOENJA is a kinase inhibitor indicated for the treatment of activated phosphoinositide 3-kinase delta (PI3Kdelta) syndrome (APDS) in adult and pediatric patients 12 years of age and older. Launch Date 2023

C_max

Value	Dose	Co-administered	Analyte	Population
3153 ng/mL CLINICAL TRIAL https://www.toetsingonline.nl/to/ccmo_search.nsf/02E1E3F67E28A71FC12588400015A953/$file/M3.%20Synopsis%20Clinical%20study%20report%2014Mar22.pdf	70 mg single, oral dose: 70 mg route of administration: Oral experiment type: SINGLE co-administered:		LENIOLISIB plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED

AUC

Value	Dose	Co-administered	Analyte	Population
16008 ng × h/mL CLINICAL TRIAL https://www.toetsingonline.nl/to/ccmo_search.nsf/02E1E3F67E28A71FC12588400015A953/$file/M3.%20Synopsis%20Clinical%20study%20report%2014Mar22.pdf	70 mg single, oral dose: 70 mg route of administration: Oral experiment type: SINGLE co-administered:		LENIOLISIB plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED

T_1/2

Value	Dose	Co-administered	Analyte	Population
6.39 h CLINICAL TRIAL https://www.toetsingonline.nl/to/ccmo_search.nsf/02E1E3F67E28A71FC12588400015A953/$file/M3.%20Synopsis%20Clinical%20study%20report%2014Mar22.pdf	70 mg single, oral dose: 70 mg route of administration: Oral experiment type: SINGLE co-administered:		LENIOLISIB plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED

F_unbound

Value	Dose	Co-administered	Analyte	Population
5.5% DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/217759s000lbl.pdf	unknown, unknown		LENIOLISIB plasma	Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1946 inducer 1087	inducer 440 substrate 1193 inhibitor 2438	substrate 1388 inhibitor 2507	inhibitor 2217

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
OCT2 779 MATE1 415 OATP1B1 1079 OAT1 725 CYP1A2 2153 UGT1A1 246 MATE2-K 77 P-gp 1741 OAT3 747 BCRP 910 OATP1B3 961 OCT1 620 CYP2C19 2057 CYP2A6 879 CYP2C8 1057 CYP3A4/5 296 SULT1E1 5 CYP2B6 926 CYP2E1 1060 BSEP 550	CYP1A1 389 BCRP 697 CYP3A5 446 CYP1A2 1197 CYP2C8 810 CYP1B1 104 FMO1 25 CYP2E1 729 OCT1 393 FMO5 5 MRP2 252 OATP1B1 503 CYP2A6 626 CYP4F2 11 CYP4F12 10 CYP2J2 71 OCT2 434 OAT3 391 OATP1B3 435 FMO3 77 CYP2B6 776 CYP2C19 1119 OAT1 395 P-gp 2052 CYP4F3B 7 CYP4A11 137	CYP1A2 832 CYP2B6 669

Drug as perpetrator

Target	Modality	Activity	Clinical evidence
CYP1A2 2333	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217759Orig1s000MultidisciplineR.pdf Page: 181.0	no
CYP2A6 911	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217759Orig1s000MultidisciplineR.pdf Page: 180.0	no
CYP2B6 1160	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217759Orig1s000MultidisciplineR.pdf Page: 180.0	no
CYP2E1 1146	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217759Orig1s000MultidisciplineR.pdf Page: 180.0	no
CYP3A4/5 357	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217759Orig1s000MultidisciplineR.pdf Page: 180.0	no
P-gp 1932	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217759Orig1s000MultidisciplineR.pdf Page: 38.0	no
SULT1E1 5	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217759Orig1s000MultidisciplineR.pdf Page: 55 \| 181	no
MATE2-K 77	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217759Orig1s000MultidisciplineR.pdf Page: 38 \| 53 \| 76 \| 181	yes [IC50 0.85 uM]
OATP1B3 970	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217759Orig1s000MultidisciplineR.pdf Page: 38 \| 53 \| 76 \| 181	yes [IC50 13.4 uM]
OAT3 749	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217759Orig1s000MultidisciplineR.pdf Page: 38 \| 76 \| 181	yes [IC50 15.2 uM]
BCRP 985	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217759Orig1s000MultidisciplineR.pdf Page: 38 \| 53 \| 76 \| 181	yes [IC50 18.9 uM]
OATP1B1 1095	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217759Orig1s000MultidisciplineR.pdf Page: 38 \| 53 \| 76 \| 181	yes [IC50 3 uM]
OCT2 782	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217759Orig1s000MultidisciplineR.pdf Page: 38 \| 53 \| 76 \| 181	yes [IC50 3.4 uM]
BSEP 554	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217759Orig1s000MultidisciplineR.pdf Page: 182.0	yes [IC50 38.03 uM]
OCT1 656	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217759Orig1s000MultidisciplineR.pdf Page: 38 \| 76 \| 181	yes [IC50 39.9 uM]
MATE1 416	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217759Orig1s000MultidisciplineR.pdf Page: 38 \| 76 \| 181	yes [IC50 6.7 uM]
OAT1 730	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217759Orig1s000MultidisciplineR.pdf Page: 38 \| 76 \| 181	yes [IC50 73.8 uM]
CYP1A2 2333	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217759Orig1s000MultidisciplineR.pdf Page: 53 \| 76 \| 180	yes
CYP2B6 1160	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217759Orig1s000MultidisciplineR.pdf Page: 76 \| 181	yes
CYP2C19 2141	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217759Orig1s000MultidisciplineR.pdf Page: 76 \| 180	yes
CYP2C8 1117	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217759Orig1s000MultidisciplineR.pdf Page: 76 \| 180	yes
CYP2C9 2497	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217759Orig1s000MultidisciplineR.pdf Page: 76 \| 181	yes
CYP2C9 2497	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217759Orig1s000MultidisciplineR.pdf Page: 76 \| 180	yes
CYP2D6 2546	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217759Orig1s000MultidisciplineR.pdf Page: 76 \| 180	yes
CYP3A4 2633	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217759Orig1s000MultidisciplineR.pdf Page: 76 \| 181	yes
UGT1A1 303	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217759Orig1s000MultidisciplineR.pdf Page: 53 \| 76 \| 77 \| 181	yes	yes (co-administration study) Comment: Leniolisb increased ethinylestradiol exposure by approximately 30% and had no effect on levonorgestrel exposure. Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217759Orig1s000MultidisciplineR.pdf Page: 53 \| 76 \| 77 \| 181

Drug as victim

Target	Modality	Activity	Clinical evidence
CYP1A2 1197	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217759Orig1s000MultidisciplineR.pdf Page: 52 \| 180	likely
CYP1B1 104	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217759Orig1s000MultidisciplineR.pdf Page: 180.0	likely
CYP2A6 626	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217759Orig1s000MultidisciplineR.pdf Page: 180.0	likely
CYP2B6 776	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217759Orig1s000MultidisciplineR.pdf Page: 180.0	likely
CYP2C19 1119	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217759Orig1s000MultidisciplineR.pdf Page: 180.0	likely
CYP2C8 810	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217759Orig1s000MultidisciplineR.pdf Page: 180.0	likely
CYP2C9 1193	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217759Orig1s000MultidisciplineR.pdf Page: 180.0	likely
CYP2E1 729	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217759Orig1s000MultidisciplineR.pdf Page: 180.0	likely
CYP2J2 71	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217759Orig1s000MultidisciplineR.pdf Page: 180.0	likely
CYP4A11 137	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217759Orig1s000MultidisciplineR.pdf Page: 180.0	likely
CYP4F12 10	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217759Orig1s000MultidisciplineR.pdf Page: 180.0	likely
CYP4F2 11	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217759Orig1s000MultidisciplineR.pdf Page: 180.0	likely
CYP4F3B 7	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217759Orig1s000MultidisciplineR.pdf Page: 180.0	likely
FMO1 25	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217759Orig1s000MultidisciplineR.pdf Page: 180.0	likely
FMO3 77	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217759Orig1s000MultidisciplineR.pdf Page: 180.0	likely
FMO5 5	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217759Orig1s000MultidisciplineR.pdf Page: 180.0	likely
CYP3A4 1946	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217759Orig1s000MultidisciplineR.pdf Page: 52 \| 53 \| 72 \| 180	major	yes (co-administration study) Comment: co-administration with itraconazole (a strong dual inhibitor of CYP3A4 and P-gp) increased leniolisib AUCinf by approximately 2-fold and Cmax by 25%. Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217759Orig1s000MultidisciplineR.pdf Page: 52 \| 53 \| 72 \| 180
CYP2D6 1388	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217759Orig1s000MultidisciplineR.pdf Page: 52 \| 180	minor
CYP3A5 446	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217759Orig1s000MultidisciplineR.pdf Page: 52 \| 180	minor
MRP2 252	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217759Orig1s000MultidisciplineR.pdf Page: 181.0	no
OATP1B1 503	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217759Orig1s000MultidisciplineR.pdf Page: 181.0	no
OATP1B3 435	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217759Orig1s000MultidisciplineR.pdf Page: 181.0	no
OCT1 393	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217759Orig1s000MultidisciplineR.pdf Page: 181.0	no
OCT2 434	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217759Orig1s000MultidisciplineR.pdf Page: 181.0	no
BCRP 697	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217759Orig1s000MultidisciplineR.pdf Page: 52 \| 181	yes
CYP1A1 389	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217759Orig1s000MultidisciplineR.pdf Page: 52 \| 180	yes
OAT1 395	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217759Orig1s000MultidisciplineR.pdf Page: 181.0	yes
OAT3 391	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217759Orig1s000MultidisciplineR.pdf Page: 181.0	yes
P-gp 2052	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217759Orig1s000MultidisciplineR.pdf Page: 181.0	yes

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 2263	inhibitor 2237 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217759Orig1s000MultidisciplineR.pdf Page: 38.0

PubMed

Title	Date	PubMed
Leniolisib.	2006	37094051
Effective "activated PI3Kδ syndrome"-targeted therapy with the PI3Kδ inhibitor leniolisib.	2017 Nov 23	28972011
Leniolisib: First Approval.	2023 Jul	37256490
A randomized, placebo-controlled phase 3 trial of the PI3Kδ inhibitor leniolisib for activated PI3Kδ syndrome.	2023 Mar 2	36399712

Patents

Sample Use Guides

In Vivo Use Guide

Recommended dosage: 70 mg administered orally twice daily approximately 12 hours apart, with or without food, in adult and pediatric patients 12 years of age and older and weighing ≥45kg.

Route of Administration: Oral

In Vitro Use Guide

Leniolisib (CDZ 173) is a potent PI3Kdelta selective inhibitor with biochemical IC50 values of 0.244, 0.424, 2.23 and 0.011 uM for PI3Kalpha, PI3Kbeta, PI3Kgamma and PI3Kdelta, respectively.

Name

Type

Language

LENIOLISIB

Official Name

English

leniolisib [INN]

Preferred Name

English

LENIOLISIB [USAN]

Common Name

English

CDZ173 FREE BASE

Common Name

English

CDZ-173-NX

Code

English

CDZ173-NX

Code

English

Leniolisib [WHO-DD]

Common Name

English

1-((3S)-3-((6-(6-METHOXY-5-(TRIFLUOROMETHYL)PYRIMIDIN-3-YL)-5,6,7,8-TETRAHYDROPYRIDO(4,3-D)PYRIMIDIN-4-YL)AMINO)PYRROLIDIN-1-YL)PROPAN-1-ONE

Common Name

English

1-PROPANONE, 1-((3S)-3-((5,6,7,8-TETRAHYDRO-6-(6-METHOXY-5-(TRIFLUOROMETHYL)-3-PYRIDINYL)PYRIDO(4,3-D)PYRIMIDIN-4-YL)AMINO)-1-PYRROLIDINYL)-

Systematic Name

English

CDZ-173 FREE BASE

Common Name

English

Classification Tree Code System Code

FDA ORPHAN DRUG

504315