Paroxysmal nocturnal hemoglobinuria

Summary

Paroxysmal nocturnal hemoglobinuria (MONDO:0100244) is a disease with 1 cohort gene and 153 clinical trials. Top therapeutic interventions include eculizumab, ravulizumab, and danicopan.

At a glance

• Prevalence: 1-9 / 100 000 (Europe) [Orphanet-validated]
• Cohort genes: 1
• ClinVar variants: 10
• Phenotypes (HPO): 44
• Clinical trials: 153

Clinical features

Epidemiology

Prevalence records

3 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000	2	Europe	Validated
Annual incidence	1-9 / 1 000 000	0.35	United Kingdom	Validated
Point prevalence	1-9 / 100 000	3.81	United Kingdom	Validated

Signs & symptoms

Clinical features (HPO)

44 HPO clinical features (Orphanet curated; top 44 by frequency):

HPO ID	Term	Frequency
HP:0030272	Abnormal erythrocyte enzyme activity	Obligate (100%)
HP:0001878	Hemolytic anemia	Very frequent (80-99%)
HP:0001903	Anemia	Very frequent (80-99%)
HP:0003641	Hemoglobinuria	Very frequent (80-99%)
HP:0025406	Asthenia	Very frequent (80-99%)
HP:0001907	Thromboembolism	Frequent (30-79%)
HP:0001923	Reticulocytosis	Frequent (30-79%)
HP:0002094	Dyspnea	Frequent (30-79%)
HP:0002315	Headache	Frequent (30-79%)
HP:0002574	Episodic abdominal pain	Frequent (30-79%)
HP:0002625	Deep venous thrombosis	Frequent (30-79%)
HP:0003138	Increased blood urea nitrogen	Frequent (30-79%)
HP:0004936	Venous thrombosis	Frequent (30-79%)
HP:0008282	Unconjugated hyperbilirubinemia	Frequent (30-79%)
HP:0012543	Hemosiderinuria	Frequent (30-79%)
HP:0012622	Chronic kidney disease	Frequent (30-79%)
HP:0020181	Reduced haptoglobin level	Frequent (30-79%)
HP:0025435	Increased circulating lactate dehydrogenase concentration	Frequent (30-79%)
HP:0032106	Conjunctival icterus	Frequent (30-79%)
HP:0032147	Erythromelalgia	Frequent (30-79%)
HP:0040303	Decreased serum iron	Frequent (30-79%)
HP:0100749	Chest pain	Frequent (30-79%)
HP:0000083	Renal insufficiency	Occasional (5-29%)
HP:0000093	Proteinuria	Occasional (5-29%)
HP:0000802	Impotence	Occasional (5-29%)
HP:0000822	Hypertension	Occasional (5-29%)
HP:0000952	Jaundice	Occasional (5-29%)
HP:0001254	Lethargy	Occasional (5-29%)
HP:0001297	Stroke	Occasional (5-29%)
HP:0001658	Myocardial infarction	Occasional (5-29%)
HP:0001873	Thrombocytopenia	Occasional (5-29%)
HP:0001876	Pancytopenia	Occasional (5-29%)
HP:0001882	Leukopenia	Occasional (5-29%)
HP:0001919	Acute kidney injury	Occasional (5-29%)
HP:0002204	Pulmonary embolism	Occasional (5-29%)
HP:0002639	Budd-Chiari syndrome	Occasional (5-29%)
HP:0004420	Arterial thrombosis	Occasional (5-29%)
HP:0012132	Erythroid hyperplasia	Occasional (5-29%)
HP:0030248	Mesenteric venous thrombosis	Occasional (5-29%)
HP:0032043	Odynophagia	Occasional (5-29%)
HP:0001994	Renal Fanconi syndrome	Very rare (<1-4%)
HP:0002015	Dysphagia	Very rare (<1-4%)
HP:0003076	Glycosuria	Very rare (<1-4%)
HP:0025271	Esophageal spasms	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	paroxysmal nocturnal hemoglobinuria
Mondo ID	MONDO:0100244
OMIM	300818
Orphanet	447
DOID	DOID:0060284
ICD-10-CM	D59.5
ICD-11	859588467
NCIT	C61233
SNOMED CT	1963002
UMLS	C0024790
MedGen	7471
GARD	0007337
MedDRA	10034042
NORD	1557
Is cancer (heuristic)	no

Also known as: acquired paroxysmal nocturnal hemoglobinuria · hereditary paroxysmal nocturnal hemoglobinuria · inherited paroxysmal nocturnal hemoglobinuria · Marchiafava-Micheli disease · paroxysmal hemoglobinuria · PNH

Data availability: 10 ClinVar variants · 1 GenCC gene-disease record · 1 HPO phenotype · 19 cell lines.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › urinary system disorder › kidney disorder › proteinuria › hemoglobinuria › paroxysmal nocturnal hemoglobinuria

Subtypes (2): paroxysmal nocturnal hemoglobinuria 1, paroxysmal nocturnal hemoglobinuria 2

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

10 retrieved; paginated sample, class counts are floors:

9 pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
9957	NM_002641.4(PIGA):c.1188+2del	PIGA	Pathogenic	no assertion criteria provided
9959	NM_002641.4(PIGA):c.459_460insA (p.His154fs)	PIGA	Pathogenic	no assertion criteria provided
9960	NM_002641.4(PIGA):c.1115del (p.Pro372fs)	PIGA	Pathogenic	no assertion criteria provided
9961	NM_002641.4(PIGA):c.163C>T (p.Gln55Ter)	PIGA	Pathogenic	no assertion criteria provided
9962	NM_002641.4(PIGA):c.249_250insGT (p.Thr84fs)	PIGA	Pathogenic	no assertion criteria provided
9963	NM_002641.4(PIGA):c.431del (p.Thr144fs)	PIGA	Pathogenic	no assertion criteria provided
9964	NM_002641.4(PIGA):c.1323_1324del (p.Leu442fs)	PIGA	Pathogenic	no assertion criteria provided
9965	NM_002641.4(PIGA):c.1188+1G>A	PIGA	Pathogenic	no assertion criteria provided
9966	NM_002641.4(PIGA):c.1355_1356insAATTGAGATGGATGACTCCAGATTCTATCATTGA (p.Asp452delinsGluIleGluMetAspAspSerArgPheTyrHisTer)	PIGA	Pathogenic	no assertion criteria provided
9958	NM_002641.4(PIGA):c.294C>A (p.Tyr98Ter)	PIGA	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 5 · 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
PIGA	Supportive	Unknown	paroxysmal nocturnal hemoglobinuria	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PIGA	Orphanet:293181	Epilepsy of infancy with migrating focal seizures
PIGA	Orphanet:300496	Multiple congenital anomalies-hypotonia-seizures syndrome type 2
PIGA	Orphanet:397922	Ferro-cerebro-cutaneous syndrome
PIGA	Orphanet:447	Paroxysmal nocturnal hemoglobinuria
PIGA	Orphanet:697160	Infantile epileptic spasms syndrome

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PIGA	HGNC:8957	ENSG00000165195	P37287	Phosphatidylinositol N-acetylglucosaminyltransferase subunit A	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PIGA	Phosphatidylinositol N-acetylglucosaminyltransferase subunit A	Catalytic subunit of the glycosylphosphatidylinositol-N-acetylglucosaminyltransferase (GPI-GnT) complex that catalyzes the transfer of N-acetylglucosamine from UDP-N-acetylglucosamine to phosphatidylinositol and participates in the first s…

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PIGA	Other/Unknown	no		Glyco_trans_1, PIGA_GPI_anchor_biosynthesis, PIG-A/GPI3

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
endometrium epithelium	1
mucosa of stomach	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PIGA	266	ubiquitous	marker	secondary oocyte, mucosa of stomach, endometrium epithelium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PIGA	2,324

Structural data

PDB: 0 · AlphaFold-only: 1 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PIGA	P37287	86.22

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 1 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Synthesis of glycosylphosphatidylinositol (GPI)	1	634.4×	0.002	PIGA

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
GPI anchor biosynthetic process	1	495.6×	0.004	PIGA
cellular response to leukemia inhibitory factor	1	159.0×	0.006	PIGA

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PIGA	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

0 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.

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	PIGA

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
PIGA	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 153.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	50
PHASE3	39
Not specified	36
PHASE1	18
PHASE1/PHASE2	7
PHASE4	2
PHASE2/PHASE3	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03866681	PHASE4	UNKNOWN	Sirolimus Combined With Low-dose Warfarin for the Treatment of Refractory PNH
NCT04320602	PHASE4	COMPLETED	Ravulizumab in Adult Participants With Paroxysmal Nocturnal Hemoglobinuria Currently Treated With High-Dose Eculizumab
NCT03531255	PHASE3	ACTIVE_NOT_RECRUITING	Pegcetacoplan Long Term Safety and Efficacy Extension Study
NCT04432584	PHASE3	ACTIVE_NOT_RECRUITING	A Study Evaluating the Safety, Pharmacokinetics, and Efficacy of Crovalimab Versus Eculizumab in Participants With Paroxysmal Nocturnal Hemoglobinuria (PNH) Currently Treated With Complement Inhibitors
NCT04434092	PHASE3	ACTIVE_NOT_RECRUITING	A Study Evaluating the Efficacy and Safety of Crovalimab Versus Eculizumab in Participants With Paroxysmal Nocturnal Hemoglobinuria (PNH) Not Previously Treated With Complement Inhibitors
NCT04654468	PHASE3	ACTIVE_NOT_RECRUITING	A Study Evaluating the Efficacy, Safety, Pharmacokinetics and Pharmacodynamics of Crovalimab in Participants With Paroxysmal Nocturnal Hemoglobinuria (PNH) Not Previously Treated With Complement Inhibition
NCT04747613	PHASE3	ACTIVE_NOT_RECRUITING	Long-term Safety and Tolerability of Iptacopan in Patients With Paroxysmal Nocturnal Hemoglobinuria
NCT05133531	PHASE3	ACTIVE_NOT_RECRUITING	A Study to Evaluate How Safe Pozelimab + Cemdisiran Combination Therapy is and How Well it Works in Adult Patients With Paroxysmal Nocturnal Hemoglobinuria (PNH) Who Have Not Recently Received or Have Not Received Complement Inhibitor Treatment
NCT05389449	PHASE3	ACTIVE_NOT_RECRUITING	A Long-term Safety and Efficacy Study of Danicopan as an Add-on Therapy to Complement Component 5 Inhibitor (C5i) in Participants With PNH
NCT05744921	PHASE3	RECRUITING	A Study in Adult Patients With Paroxysmal Nocturnal Hemoglobinuria (PNH) to Evaluate How Safe Long-term Treatment With Pozelimab + Cemdisiran Combination Therapy is and How Well it Works
NCT06449001	PHASE3	RECRUITING	Study of Danicopan as Add-on Treatment to Ravulizumab or Eculizumab in Pediatric Participants With PNH Who Have Clinically Significant Extravascular Hemolysis
NCT06932471	PHASE3	RECRUITING	Study of Safety and Efficacy of MY008211A in Patients With Residual Anemia Despite Anti-C5 Antibody Treatment
NCT06933914	PHASE2/PHASE3	RECRUITING	Long-term Safety and Tolerability of MY008211A Tablets in Patients With Paroxysmal Nocturnal Hemoglobinuria
NCT06934967	PHASE3	RECRUITING	Study to Assess the Pharmacokinetics, Safety, and Tolerability of Iptacopan in Pediatric PNH Patients
NCT07154745	PHASE3	RECRUITING	A Study to Evaluate How Pozelimab + Cemdisiran Combination Therapy Works in Adult Patients With Paroxysmal Nocturnal Hemoglobinuria (PNH) Whose Current Treatment is Not Working Efficiently
NCT07177859	PHASE3	NOT_YET_RECRUITING	A Phase III Study of NTQ5082 Capsules in the Treatment of Paroxysmal Nocturnal Hemoglobinuria Patients
NCT07177872	PHASE3	NOT_YET_RECRUITING	A Long-term Efficacy and Safety of NTQ5082 Capsules
NCT02946463	PHASE3	COMPLETED	ALXN1210 (Ravulizumab) Versus Eculizumab in Complement Inhibitor Treatment-Naïve Adult Participants With Paroxysmal Nocturnal Hemoglobinuria (PNH)
NCT03056040	PHASE3	COMPLETED	ALXN1210 Versus Eculizumab in Adult Participants With Paroxysmal Nocturnal Hemoglobinuria (PNH) Currently Treated With Eculizumab
NCT03406507	PHASE3	COMPLETED	A Study of Ravulizumab (ALXN1210) in Children and Adolescents With Paroxysmal Nocturnal Hemoglobinuria
NCT03500549	PHASE3	COMPLETED	Study to Evaluate the Efficacy and Safety of APL-2 in Patients With Paroxysmal Nocturnal Hemoglobinuria (PNH)
NCT03588026	PHASE3	COMPLETED	Treating Paroxysmal Nocturnal Haemoglobinuria Patients With rVA576
NCT03748823	PHASE3	COMPLETED	Ravulizumab Subcutaneous (SC) Versus Ravulizumab Intravenous (IV) in Adults With Paroxysmal Nocturnal Hemoglobinuria (PNH) Currently Treated With Eculizumab
NCT03818607	PHASE3	COMPLETED	A Study Evaluating the Efficacy and Safety of ABP 959 Compared With Eculizumab in Adult Participants With PNH
NCT03829449	PHASE3	TERMINATED	rVA576 (Coversin) Long Term Safety and Efficacy Surveillance Study
NCT04058158	PHASE3	COMPLETED	A Study to Compare SB12 (Proposed Eculizumab Biosimilar) to Soliris in Subjects With Paroxysmal Nocturnal Haemoglobinuria
NCT04060264	PHASE3	COMPLETED	Clinical Trial of BCD-148 and Soliris® for the Treatment of Patients With Paroxysmal Nocturnal Hemoglobinuria
NCT04085601	PHASE3	COMPLETED	A Study to Evaluate the Efficacy and Safety of Pegcetacoplan in Patients With PNH
NCT04162470	PHASE3	TERMINATED	REGN3918 in Patients With Paroxysmal Nocturnal Hemoglobinuria (PNH) to Evaluate Its Long Term Safety, Efficacy and Tolerability.
NCT04463056	PHASE3	COMPLETED	Efficacy and Safety of Elizaria® vs. Soliris® in Patients With PNH
NCT04469465	PHASE3	COMPLETED	Danicopan as Add-on Therapy to a C5 Inhibitor in Paroxysmal Nocturnal Hemoglobinuria (PNH) Participants Who Have Clinically Evident Extravascular Hemolysis (EVH)(ALPHA)
NCT04558918	PHASE3	COMPLETED	Study of Efficacy and Safety of Twice Daily Oral LNP023 in Adult PNH Patients With Residual Anemia Despite Anti-C5 Antibody Treatment
NCT04679103	PHASE3	COMPLETED	A Safety and Immunogenicity Study in Long-term Treatment of Eculizumab (JSC GENERIUM, Russian Federation)
NCT04820530	PHASE3	COMPLETED	Study of Efficacy and Safety of Twice Daily Oral Iptacopan (LNP023) in Adult PNH Patients Who Are Naive to Complement Inhibitor Therapy
NCT05131204	PHASE3	TERMINATED	Efficacy and Safety of the Combination of Pozelimab and Cemdisiran Versus Continued Eculizumab or Ravulizumab Treatment in Adult Patients With Paroxysmal Nocturnal Hemoglobinuria
NCT05630001	PHASE3	COMPLETED	Single Arm, Open Label Trial With Iptacopan Treatment for 24 Weeks, in Patients on Stable Regimen of Anti-C5 Who Switch to Iptacopan.
NCT05886244	PHASE3	COMPLETED	Eculizumab in Adult Participants With Paroxysmal Nocturnal Hemoglobinuria (PNH) in China
NCT06578949	PHASE3	COMPLETED	Efficacy, Safety, Pharmacokinetics, Pharmacodynamics, and Immunogenicity of Ravulizumab in Chinese Adults Participants With Paroxysmal Nocturnal Hemoglobinuria (PNH)
NCT06593938	PHASE3	COMPLETED	A Study to Evaluate the Efficacy and Safety of Oral HRS-5965 in Adult Paroxysmal Nocturnal Hemoglobinuria (PNH) Patients Who Are Naive to Complement Inhibitor Therapy
NCT06715943	PHASE3	COMPLETED	Efficacy and Safety of HRS-5965 in Patients With PNH Who Are Still Anemia After Anti-C5 Antibody Treatment

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
ECULIZUMAB	4	24
RAVULIZUMAB	4	16
DANICOPAN	4	9
IPTACOPAN	4	9
POZELIMAB	4	9
PEGCETACOPLAN	4	8
CROVALIMAB	4	3
LEVAMISOLE	4	2
SIROLIMUS	4	1
TREOSULFAN	4	1
CEMDISIRAN	3	7
ZILUCOPLAN	3	3
NOMACOPAN	3	1
DEXAMISOLE	2	2
OMOPRUBART	2	2
RUXOPRUBART	2	2
BRYOSTATIN 1	2	1
TESIDOLUMAB	2	1
VEMIRCOPAN	2	1