Progressive familial intrahepatic cholestasis type 1

Summary

Progressive familial intrahepatic cholestasis type 1 (MONDO:0008892) is a disease caused by ATP8B1 (GenCC Definitive), with 8 cohort genes and 27 clinical trials. Top therapeutic interventions include maralixibat, odevixibat, and glycerol phenylbutyrate.

At a glance

• Prevalence: 1-9 / 100 000 (Europe)
• Causal gene: ATP8B1 (GenCC Definitive)
• Cohort genes: 8
• ClinVar variants: 238
• Clinical trials: 27

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000		Europe	Not yet validated

Identifiers

Disease identifiers

Field	Value
Canonical name	progressive familial intrahepatic cholestasis type 1
Mondo ID	MONDO:0008892
OMIM	211600
Orphanet	79306
DOID	DOID:0070226
ICD-11	1414850183
UMLS	C4551898
MedGen	1645830
GARD	0009802
Is cancer (heuristic)	no

Also known as: Byler disease · Byler’s disease · cholestasis, fatal intrahepatic · cholestasis, progressive familial intrahepatic 1 · cholestasis, progressive familial intrahepatic, 1 · cholestasis, progressive familial intrahepatic, type 1 · FIC1 deficiency · PFIC1 · progressive familial intrahepatic cholestasis · severe ATP8B1 deficiency

Data availability: 238 ClinVar variants · 5 GenCC gene-disease records · 15 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › progressive familial intrahepatic cholestasis › progressive familial intrahepatic cholestasis type 1

Related subtypes (15): benign recurrent intrahepatic cholestasis type 1, progressive familial intrahepatic cholestasis type 2, progressive familial intrahepatic cholestasis type 3, hereditary North American Indian childhood cirrhosis, cholestasis, progressive familial intrahepatic, 4, cholestasis, progressive familial intrahepatic, 5, MYO5B-related progressive familial intrahepatic cholestasis, cholestasis, progressive familial intrahepatic, 6, cholestasis, progressive familial intrahepatic, 7, with or without hearing loss, cholestasis, progressive familial intrahepatic, 8, cholestasis, progressive familial intrahepatic, 9, cholestasis, progressive familial intrahepatic, 10, cholestasis, progressive familial intrahepatic, 11, cholestasis, progressive familial intrahepatic, 12, cholestasis, progressive familial intrahepatic, 13

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

238 retrieved; paginated sample, class counts are floors:

92 uncertain significance, 47 conflicting classifications of pathogenicity, 27 benign, 27 pathogenic, 15 likely pathogenic, 14 pathogenic/likely pathogenic, 11 benign/likely benign, 3 likely benign, 2 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1070887	NM_003742.4(ABCB11):c.1460G>C (p.Arg487Pro)	ABCB11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1446289	NM_003742.4(ABCB11):c.1621A>C (p.Ile541Leu)	ABCB11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2679946	NM_003742.4(ABCB11):c.779G>A (p.Gly260Asp)	ABCB11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3776863	NM_003742.4(ABCB11):c.1583_1584del (p.Ile528fs)	ABCB11	Pathogenic	criteria provided, multiple submitters, no conflicts
3776883	NM_003742.4(ABCB11):c.386G>A (p.Cys129Tyr)	ABCB11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
6589	NM_003742.4(ABCB11):c.1723C>T (p.Arg575Ter)	ABCB11	Pathogenic	criteria provided, multiple submitters, no conflicts
594504	NM_000443.4(ABCB4):c.3724dup (p.Ile1242fs)	ABCB4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
595241	NM_000443.4(ABCB4):c.1553del (p.Leu518fs)	ABCB4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
596680	NM_000443.4(ABCB4):c.475C>T (p.Arg159Ter)	ABCB4	Pathogenic	criteria provided, multiple submitters, no conflicts
802328	NM_000443.4(ABCB4):c.1714C>T (p.Gln572Ter)	ABCB4	Pathogenic	criteria provided, multiple submitters, no conflicts
4072093	Single allele	ALPK2	Pathogenic	criteria provided, single submitter
1195884	NM_001374385.1(ATP8B1):c.-25-4014_181+2209del	ATP8B1	Pathogenic	criteria provided, single submitter
1195885	NC_000018.9:g.55335906_55346620dup	ATP8B1	Pathogenic	criteria provided, single submitter
126382	NM_001374385.1(ATP8B1):c.1993G>T (p.Glu665Ter)	ATP8B1	Pathogenic	criteria provided, multiple submitters, no conflicts
1301678	NM_001374385.1(ATP8B1):c.3040C>T (p.Arg1014Ter)	ATP8B1	Pathogenic	criteria provided, multiple submitters, no conflicts
1687217	NM_001374385.1(ATP8B1):c.213dup (p.Lys72fs)	ATP8B1	Pathogenic	criteria provided, single submitter
1698723	NM_001374385.1(ATP8B1):c.2821C>T (p.Arg941Ter)	ATP8B1	Pathogenic	criteria provided, multiple submitters, no conflicts
1698811	NM_001374385.1(ATP8B1):c.1573C>T (p.Arg525Ter)	ATP8B1	Pathogenic	criteria provided, multiple submitters, no conflicts
2627551	NM_001374385.1(ATP8B1):c.2500_2588del (p.Met834fs)	ATP8B1	Pathogenic	criteria provided, single submitter
2687798	NM_001374385.1(ATP8B1):c.555-1G>C	ATP8B1	Pathogenic	criteria provided, multiple submitters, no conflicts
2687832	NM_001374385.1(ATP8B1):c.2614dup (p.Gln872fs)	ATP8B1	Pathogenic	criteria provided, single submitter
2736747	NM_001374385.1(ATP8B1):c.1336G>A (p.Gly446Arg)	ATP8B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2736748	NM_001374385.1(ATP8B1):c.886C>T (p.Arg296Cys)	ATP8B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4072081	NM_001374385.1(ATP8B1):c.958_967del (p.Met320fs)	ATP8B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4292858	NM_001374385.1(ATP8B1):c.1473+1G>C	ATP8B1	Pathogenic	criteria provided, multiple submitters, no conflicts
502324	NM_001374385.1(ATP8B1):c.1799G>A (p.Arg600Gln)	ATP8B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
595193	NM_001374385.1(ATP8B1):c.2854C>T (p.Arg952Ter)	ATP8B1	Pathogenic	criteria provided, multiple submitters, no conflicts
7262	NM_001374385.1(ATP8B1):c.923G>T (p.Gly308Val)	ATP8B1	Pathogenic	criteria provided, multiple submitters, no conflicts
7265	NM_001374385.1(ATP8B1):c.2097+2T>C	ATP8B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
7267	NM_001374385.1(ATP8B1):c.1982T>C (p.Ile661Thr)	ATP8B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 13 · Orphanet: 14 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
ATP8B1	Definitive	Autosomal recessive	progressive familial intrahepatic cholestasis type 1	7
MYO5B	Strong	Autosomal recessive	cholestasis, progressive familial intrahepatic, 10	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ATP8B1	Orphanet:69665	Intrahepatic cholestasis of pregnancy
ATP8B1	Orphanet:79306	Progressive familial intrahepatic cholestasis type 1
ATP8B1	Orphanet:99960	Benign recurrent intrahepatic cholestasis type 1
MYO5B	Orphanet:2290	Microvillus inclusion disease
MYO5B	Orphanet:480491	MYO5B-related progressive familial intrahepatic cholestasis
MYO5B	Orphanet:79306	Progressive familial intrahepatic cholestasis type 1
ABCB11	Orphanet:69665	Intrahepatic cholestasis of pregnancy
ABCB11	Orphanet:79304	Progressive familial intrahepatic cholestasis type 2
ABCB11	Orphanet:99961	Benign recurrent intrahepatic cholestasis type 2
ABCB4	Orphanet:69663	Low phospholipid-associated cholelithiasis
ABCB4	Orphanet:69665	Intrahepatic cholestasis of pregnancy
ABCB4	Orphanet:79305	Progressive familial intrahepatic cholestasis type 3
NR1H4	Orphanet:480476	Progressive familial intrahepatic cholestasis type 5
NR1H4	Orphanet:69665	Intrahepatic cholestasis of pregnancy

Cohort genes → proteins

8 cohort genes, 7 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	8

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ATP8B1	HGNC:3706	ENSG00000081923	O43520	Phospholipid-transporting ATPase IC	gencc,clinvar
MYO5B	HGNC:7603	ENSG00000167306	Q9ULV0	Unconventional myosin-Vb	gencc
ALPK2	HGNC:20565	ENSG00000198796	Q86TB3	Alpha-protein kinase 2	clinvar
LSR	HGNC:29572	ENSG00000105699	Q86X29	Lipolysis-stimulated lipoprotein receptor	clinvar
ABCB11	HGNC:42	ENSG00000073734	O95342	Bile salt export pump	clinvar
ABCB4	HGNC:45	ENSG00000005471	P21439	Phosphatidylcholine translocator ABCB4	clinvar
ATP8B1-AS1	HGNC:56042	ENSG00000267040		ATP8B1 antisense RNA 1	clinvar
NR1H4	HGNC:7967	ENSG00000012504	Q96RI1	Bile acid receptor	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ATP8B1	Phospholipid-transporting ATPase IC	Catalytic component of a P4-ATPase flippase complex which catalyzes the hydrolysis of ATP coupled to the transport of phospholipids, in particular phosphatidylcholines (PC), from the outer to the inner leaflet of the plasma membrane.
MYO5B	Unconventional myosin-Vb	May be involved in vesicular trafficking via its association with the CART complex.
ALPK2	Alpha-protein kinase 2	Protein kinase that recognizes phosphorylation sites in which the surrounding peptides have an alpha-helical conformation.
LSR	Lipolysis-stimulated lipoprotein receptor	Probable role in the clearance of triglyceride-rich lipoprotein from blood.
ABCB11	Bile salt export pump	Catalyzes the transport of the major hydrophobic bile salts, such as taurine and glycine-conjugated cholic acid across the canalicular membrane of hepatocytes in an ATP-dependent manner, therefore participates in hepatic bile acid homeosta…
ABCB4	Phosphatidylcholine translocator ABCB4	Energy-dependent phospholipid efflux translocator that acts as a positive regulator of biliary lipid secretion.
NR1H4	Bile acid receptor	Ligand-activated transcription factor.

Protein-family classification

Druggable: 5 · Difficult: 2 · Unknown: 1 · Druggable fraction: 0.62

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Transporter	2	19.4×	0.031
Nuclear receptor	1	48.2×	0.072
Antibody/Immunoglobulin	1	3.6×	0.446
Kinase	1	3.5×	0.446
Scaffold/PPI	1	2.2×	0.531
Transcription factor	1	1.0×	0.751
Other/Unknown	1	0.2×	0.999

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ATP8B1	Transcription factor	no	7.6.2.1	P_typ_ATPase, P-type_ATPase_IV, ATPase_P-typ_transduc_dom_A_sf
MYO5B	Scaffold/PPI	no		IQ_motif_EF-hand-BS, Myosin_head_motor_dom-like, Dilute_dom
ALPK2	Kinase	yes		Ig_sub2, Ig_sub, a-kinase_dom
LSR	Antibody/Immunoglobulin	yes		Ig_sub, Ig-like_dom, LISCH7
ABCB11	Transporter	yes		ABC_transporter-like_ATP-bd, AAA+_ATPase, ABC1_TM_dom
ABCB4	Transporter	yes		ABC_transporter-like_ATP-bd, AAA+_ATPase, ABC1_TM_dom
ATP8B1-AS1	Other/Unknown	no
NR1H4	Nuclear receptor	yes		Nucl_hrmn_rcpt_lig-bd, Znf_hrmn_rcpt, Nuclear_hrmn_rcpt

Expression context

Cohort genes with no expression data: 0.

8 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	8
unknown	0

Top tissues across cohort

Tissue	Cohort genes
right lobe of liver	4
ileal mucosa	2
liver	2
cardia of stomach	1
nipple	1
renal medulla	1
jejunal mucosa	1
lower esophagus mucosa	1
cardiac muscle of right atrium	1
left ventricle myocardium	1
myocardium	1
body of pancreas	1
mucosa of transverse colon	1
thymus	1
oocyte	1
secondary oocyte	1
buccal mucosa cell	1
pancreatic ductal cell	1
primordial germ cell in gonad	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ATP8B1	289	ubiquitous	marker	cardia of stomach, nipple, renal medulla
MYO5B	228	broad	marker	ileal mucosa, lower esophagus mucosa, jejunal mucosa
ALPK2	147	ubiquitous	marker	left ventricle myocardium, cardiac muscle of right atrium, myocardium
LSR	234	ubiquitous	marker	mucosa of transverse colon, right lobe of liver, body of pancreas
ABCB11	125	tissue_specific	marker	right lobe of liver, liver, thymus
ABCB4	188	broad	marker	right lobe of liver, secondary oocyte, oocyte
ATP8B1-AS1	199		marker	buccal mucosa cell, primordial germ cell in gonad, pancreatic ductal cell
NR1H4	136	tissue_specific	marker	right lobe of liver, liver, ileal mucosa

Protein interactions among cohort

Intra-cohort edges: 7.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MYO5B	3,604
NR1H4	3,094
ABCB11	2,407
ABCB4	2,333
LSR	1,346
ATP8B1	1,296
ALPK2	371
ATP8B1-AS1	0

Intra-cohort edges

A	B	Sources
ABCB11	ABCB4	biogrid_interaction
ABCB11	ATP8B1	string_interaction
ABCB11	NR1H4	string_interaction
ABCB4	ATP8B1	string_interaction
ABCB4	NR1H4	string_interaction
ATP8B1	MYO5B	string_interaction
ATP8B1	NR1H4	string_interaction

Structural data

PDB: 5 · AlphaFold-only: 2 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NR1H4	Q96RI1	89
ATP8B1	O43520	13
ABCB11	O95342	8
MYO5B	Q9ULV0	4
ABCB4	P21439	4

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
LSR	Q86X29	57.52
ALPK2	Q86TB3	40.99

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 28. Enrichment computed across 8 evidence-associated genes (6 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Recycling of bile acids and salts	2	200.3×	5e-04	ABCB11, NR1H4
Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol	2	152.3×	5e-04	ABCB11, NR1H4
ABC transporter disorders	2	146.4×	5e-04	ABCB11, ABCB4
Synthesis of bile acids and bile salts	2	135.9×	5e-04	ABCB11, NR1H4
Transport of small molecules	4	16.8×	5e-04	ATP8B1, LSR, ABCB4, MYO5B
Defective ABCB11 causes PFIC2 and BRIC2	1	1903.3×	0.002	ABCB11
Defective ABCB4 causes PFIC3, ICP3 and GBD1	1	1903.3×	0.002	ABCB4
Disorders of transmembrane transporters	2	46.4×	0.003	ABCB11, ABCB4
PPARA activates gene expression	2	31.5×	0.005	ABCB4, NR1H4
VLDL clearance	1	317.2×	0.009	LSR
Synthesis of bile acids and bile salts via 27-hydroxycholesterol	1	126.9×	0.020	NR1H4
LDL clearance	1	90.6×	0.025	LSR
Bile acid and bile salt metabolism	1	82.8×	0.025	ABCB11
Plasma lipoprotein clearance	1	79.3×	0.025	LSR
Metabolism of lipids	2	10.5×	0.026	ABCB11, ABCB4
Endogenous sterols	1	65.6×	0.027	NR1H4
Aquaporin-mediated transport	1	61.4×	0.027	MYO5B
SUMOylation of intracellular receptors	1	56.0×	0.028	NR1H4
Vasopressin regulates renal water homeostasis via Aquaporins	1	44.3×	0.033	MYO5B
Plasma lipoprotein assembly, remodeling, and clearance	1	38.1×	0.036	LSR
Ion transport by P-type ATPases	1	34.6×	0.038	ATP8B1
Nuclear Receptor transcription pathway	1	33.4×	0.038	NR1H4
Regulation of lipid metabolism by PPARalpha	1	23.5×	0.050	ABCB4
Metabolism of steroids	1	22.9×	0.050	ABCB11
ABC-family protein mediated transport	1	20.2×	0.054	ABCB4
Ion channel transport	1	16.0×	0.066	ATP8B1
Disease	2	4.4×	0.074	ABCB11, ABCB4
Metabolism	2	3.9×	0.088	ABCB11, ABCB4

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 7 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
bile acid metabolic process	3	424.8×	3e-06	ATP8B1, ABCB11, NR1H4
bile acid and bile salt transport	3	277.8×	6e-06	ATP8B1, ABCB11, NR1H4
cellular response to bile acid	2	1203.7×	3e-05	ABCB4, NR1H4
xenobiotic transmembrane transport	2	267.5×	5e-04	ATP8B1, ABCB11
phospholipid translocation	2	178.3×	0.001	ATP8B1, ABCB4
negative regulation of Wnt signaling pathway involved in heart development	1	2407.4×	0.003	ALPK2
canalicular bile acid transport	1	2407.4×	0.003	ABCB11
obsolete regulation of urea metabolic process	1	2407.4×	0.003	NR1H4
positive regulation of bile acid secretion	1	2407.4×	0.003	ABCB11
regulation of plasma membrane organization	1	2407.4×	0.003	ATP8B1
positive regulation of phosphatidic acid biosynthetic process	1	2407.4×	0.003	NR1H4
obsolete positive regulation of glutamate metabolic process	1	2407.4×	0.003	NR1H4
positive regulation of ammonia assimilation cycle	1	2407.4×	0.003	NR1H4
lipid homeostasis	2	96.3×	0.003	ABCB11, ABCB4
nuclear receptor-mediated bile acid signaling pathway	1	1203.7×	0.004	NR1H4
response to fenofibrate	1	1203.7×	0.004	ABCB4
tricellular tight junction assembly	1	1203.7×	0.004	LSR
epicardium morphogenesis	1	1203.7×	0.004	ALPK2
transmembrane transport	2	48.1×	0.004	ABCB11, ABCB4
cholesterol homeostasis	2	44.6×	0.004	ABCB11, NR1H4
regulation of low-density lipoprotein particle clearance	1	802.5×	0.005	NR1H4
xenobiotic export from cell	1	802.5×	0.005	ABCB11
protein localization to tricellular tight junction	1	802.5×	0.005	LSR
obsolete regulation of bile acid metabolic process	1	802.5×	0.005	ABCB11
positive regulation of phospholipid translocation	1	601.9×	0.006	ABCB4
regulation of chloride transport	1	601.9×	0.006	ATP8B1
vestibulocochlear nerve formation	1	481.5×	0.007	ATP8B1
bile acid secretion	1	481.5×	0.007	ABCB4
negative regulation of very-low-density lipoprotein particle remodeling	1	401.2×	0.007	NR1H4
regulation of fatty acid beta-oxidation	1	401.2×	0.007	ABCB11

Therapeutics

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 3 · Undrugged: 5

Druggability breadth: 3 of 8 evidence-associated genes (38%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
ABCB11	TELMISARTAN
NR1H4	CLOTRIMAZOLE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ABCB11	327	4
NR1H4	41	4
ABCB4	1	2
ATP8B1	0	0
MYO5B	0	0
ALPK2	0	0
LSR	0	0
ATP8B1-AS1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
TELMISARTAN	4	ABCB11
BEXAROTENE	4	ABCB11
PROGESTERONE	4	ABCB11
CLOTRIMAZOLE	4	ABCB11, NR1H4
LATANOPROST	4	ABCB11
SIMVASTATIN	4	ABCB11, NR1H4
METHYSERGIDE	4	ABCB11
VALSARTAN	4	ABCB11
BROMFENAC	4	ABCB11
CLOPIDOGREL BISULFATE	4	ABCB11
DIBUCAINE	4	ABCB11
VALRUBICIN	4	ABCB11
RIMONABANT	4	ABCB11, NR1H4
ARIPIPRAZOLE	4	ABCB11
DICYCLOMINE	4	ABCB11
ACITRETIN	4	ABCB11
TELITHROMYCIN	4	ABCB11
EZETIMIBE	4	ABCB11
SAQUINAVIR	4	ABCB11
CLOBETASOL PROPIONATE	4	ABCB11
AMPRENAVIR	4	ABCB11
MOMETASONE FUROATE	4	ABCB11
NORETHINDRONE	4	ABCB11
ATAZANAVIR	4	ABCB11
FEBUXOSTAT	4	ABCB11
PONATINIB	4	ABCB11
TETRABENAZINE	4	ABCB11
CELECOXIB	4	ABCB11
VILANTEROL	4	ABCB11
EXEMESTANE	4	ABCB11

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
NR1H4	1,034	Binding:873, Functional:154, ADMET:6, Unclassified:1
ABCB11	85	Binding:37, ADMET:31, Functional:13, Toxicity:4
ABCB4	4	ADMET:3, Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ATP8B1	7.6.2.1	P-type phospholipid transporter

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
NR1H4	1,034

Pharmacogenomics

Cohort genes with a PharmGKB record: 7; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

30 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
TELMISARTAN	4	ABCB11
BEXAROTENE	4	ABCB11
PROGESTERONE	4	ABCB11
CLOTRIMAZOLE	4	ABCB11, NR1H4
LATANOPROST	4	ABCB11
SIMVASTATIN	4	ABCB11, NR1H4
METHYSERGIDE	4	ABCB11
VALSARTAN	4	ABCB11
BROMFENAC	4	ABCB11
CLOPIDOGREL BISULFATE	4	ABCB11
DIBUCAINE	4	ABCB11
VALRUBICIN	4	ABCB11
RIMONABANT	4	ABCB11, NR1H4
ARIPIPRAZOLE	4	ABCB11
DICYCLOMINE	4	ABCB11
ACITRETIN	4	ABCB11
TELITHROMYCIN	4	ABCB11
EZETIMIBE	4	ABCB11
SAQUINAVIR	4	ABCB11
CLOBETASOL PROPIONATE	4	ABCB11
AMPRENAVIR	4	ABCB11
MOMETASONE FUROATE	4	ABCB11
NORETHINDRONE	4	ABCB11
ATAZANAVIR	4	ABCB11
FEBUXOSTAT	4	ABCB11
PONATINIB	4	ABCB11
TETRABENAZINE	4	ABCB11
CELECOXIB	4	ABCB11
VILANTEROL	4	ABCB11
EXEMESTANE	4	ABCB11

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	ABCB11, NR1H4
B	Phased (≥1) drug, not yet approved	1	ABCB4
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	2	ALPK2, LSR
E	Difficult family or no structure, no drug	3	ATP8B1, MYO5B, ATP8B1-AS1

Undrugged target profiles

5 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
ATP8B1	0	ABCB11, ABCB4, NR1H4
MYO5B	0	—
ALPK2	0	—
LSR	0	—
ATP8B1-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 27.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	17
PHASE3	6
PHASE2	2
PHASE1	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03353454	PHASE3	WITHDRAWN	A Placebo-controlled Study of Maralixibat (SHP625) in Pediatric Subjects With Progressive Familial Intrahepatic Cholestasis (PFIC)
NCT03566238	PHASE3	COMPLETED	This Study Will Investigate the Efficacy and Safety of A4250 in Children With PFIC Types 1 or 2
NCT03659916	PHASE3	COMPLETED	Long Term Safety & Efficacy Study Evaluating The Effect of A4250 in Children With PFIC
NCT03905330	PHASE3	COMPLETED	A Study to Evaluate the Efficacy and Safety of Maralixibat in Subjects With Progressive Familial Intrahepatic Cholestasis (MARCH-PFIC)
NCT04185363	PHASE3	COMPLETED	An Extension Study of Maralixibat in Patients With Progressive Familial Intrahepatic Cholestasis (PFIC)
NCT05543187	PHASE3	COMPLETED	A Study of TAK-625 for the Treatment of Progressive Familial Intrahepatic Cholestasis (PFIC)
NCT02057718	PHASE2	COMPLETED	Open Label Study to Evaluate Efficacy and Long Term Safety of LUM001 (Maralixibat) in the Treatment of Cholestatic Liver Disease in Patients With Progressive Familial Intrahepatic Cholestasis
NCT04729751	PHASE2	COMPLETED	A Study to Evaluate the Safety and Tolerability of Maralixibat in Infant Participants With Cholestatic Liver Diseases Including Progressive Familial Intrahepatic Cholestasis (PFIC) and Alagille Syndrome (ALGS).
NCT02963077	PHASE1	COMPLETED	A Safety and Pharmakokinetic Study of A4250 Alone or in Combination With A3384
NCT03082937	PHASE1	COMPLETED	An Open Label, Single-dose, Single Period ADME Study of A4250 in Healthy Subjects
NCT03930810	Not specified	ENROLLING_BY_INVITATION	NAtural Course and Prognosis of PFIC and Effect of Biliary Diversion
NCT06193928	Not specified	RECRUITING	Long-Term SafEty and Clinical Outcomes of LivmArli in Patients in the United States (LEAP-US)
NCT06777914	Not specified	RECRUITING	Familial Intrahepatic Cholestasis-related Genes Associated with Disease Susceptibility in Hepato-biliary Cancers
NCT06778174	Not specified	RECRUITING	Prospective Analysis of the Treatment of Progressive Familial Intrahepatic Cholestasis (TreatFIC)
NCT06781242	Not specified	RECRUITING	Genotype-phenotype Relationship Between Cryptogenic Cholestasis and Familial Intrahepatic Cholestasis
NCT07185919	Not specified	RECRUITING	A Study of the Effectiveness, Safety and the Long-term Outcomes of Participants With Progressive Familial Intrahepatic Cholestasis (PFIC) Who Take Odevixibat (Bylvay) in South Korea
NCT07293897	Not specified	RECRUITING	A Database Study of Maralixibat (TAK-625) in Participants With Alagille Syndrome (ALGS) and Progressive Familial Intrahepatic Cholestasis (PFIC)
NCT07317193	Not specified	RECRUITING	DEFINING THE GENETIC DRIVERS OF ADULT-ONSET CHOLESTATIC LIVER DISEASE
NCT07588880	Not specified	RECRUITING	A Study of the Effectiveness, Safety and the Long-term Outcomes of Participants With Progressive Familial Intrahepatic Cholestasis (PFIC) Who Take Odevixibat (Bylvay) in China
NCT01784718	Not specified	NO_LONGER_AVAILABLE	Buphenyl Therapy for Byler’s Disease
NCT01949766	Not specified	NO_LONGER_AVAILABLE	Transition From Buphenyl to RAVICTI for the Therapy of Byler Disease
NCT02094222	Not specified	NO_LONGER_AVAILABLE	Expanded Access Protocol for an Intermediate Size Population - RAVICTI for Byler Disease
NCT02131623	Not specified	COMPLETED	Validation of the Itch Reported Outcome (ItchRO) Diaries in Pediatric Cholestatic Liver Disease
NCT04071197	Not specified	UNKNOWN	Gastrostomy-Biliary Diversion: Innovative Management for Bile Canalicular Transport Disorders
NCT04483531	Not specified	APPROVED_FOR_MARKETING	Odevixibat for the Treatment of Progressive Familial Intrahepatic Cholestasis
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening
NCT05704517	Not specified	UNKNOWN	Progressive Familial Intrahepatic Cholestasis in Indian Children - Establishing an Indian PFIC Registry

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
MARALIXIBAT	4	8
ODEVIXIBAT	4	4
GLYCEROL PHENYLBUTYRATE	4	2
CHOLESTYRAMINE	4	1
SODIUM PHENYLBUTYRATE	4	1