Details of Disease

General Information of Disease (ID: DISBHMYH)

• Disease Name: Paroxysmal nocturnal haemoglobinuria
• Synonyms: PNH; hereditary paroxysmal nocturnal hemoglobinuria; paroxysmal hemoglobinuria; Marchiafava-Micheli disease; acquired paroxysmal nocturnal hemoglobinuria; inherited paroxysmal nocturnal hemoglobinuria
• Disease Class: 3A20-3A2Z: Haemolytic anemia
• Definition: Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal hematopoietic stem cell disorder characterized by corpuscular hemolytic anemia, bone marrow failure and frequent thrombotic events.
• Disease Hierarchy:
  DIS803XQ: Hemolytic anemia
  DISB4MLC: Acquired metabolic disease
  DISLZR99: Disorder of GPI anchor biosynthesis
  DISCMKMX: Acquired aplastic anemia
  DISHX91R: Hemoglobinuria
  DISBHMYH: Paroxysmal nocturnal haemoglobinuria
• ICD Code:
  ICD-11: ICD-11: 3A21.0
  ICD-10: ICD-10: D59.5
  Expand ICD-11: '3A21.0
  Expand ICD-10: 'D59.5
• Disease Identifiers:
  MONDO ID: MONDO_0100244
  MESH ID: D006457
  UMLS CUI: C0024790
  MedGen ID: 7471
  HPO ID: HP:0004818
  Orphanet ID: 447
  SNOMED CT ID: 1963002

Drug-Interaction Atlas (DIA) of This Disease

This Disease is Treated as An Indication in 6 Approved Drug(s)

Drug Name	Drug ID	Highest Status	Drug Type	REF
Eculizumab	DMJGWZ7	Approved	Monoclonal antibody	[1]
Iptacopan	DM9EZM0	Approved	Small molecular drug	[2]
Pegcetacoplan	DM4HQ52	Approved	NA	[3]
Pozelimab	DMTE8DC	Approved	Antibody	[4]
Ravulizumab	DMSWNJF	Approved	Antibody	[5]
Zilucoplan	DM9Z4N5	Approved	NA	[6]

This Disease is Treated as An Indication in 7 Clinical Trial Drug(s)

Drug Name	Drug ID	Highest Status	Drug Type	REF
ABP959	DMDXE4I	Phase 3	Small molecular drug	[7]
ALXN2040	DMLJ18Y	Phase 3	NA	[8]
Coversin	DMMEAOL	Phase 3	Recombinant?protein	[9]
SB12	DMME6GJ	Phase 3	Antibody	[10]
BCX-9930	DMBNC1I	Phase 2	Small molecule	[11]
Cemdisiran	DM1S2FZ	Phase 2	Small interfering RNA	[12]
Vemircopan	DM3RZ9H	Phase 2	Small molecule	[13]

Molecular Interaction Atlas (MIA) of This Disease

This Disease Is Related to 16 DTT Molecule(s)

Gene Name	DTT ID	Evidence Level	Mode of Inheritance	REF
FUT4	TTNV1KZ	Limited	Biomarker	[14]
PRTN3	TT5MLC4	Limited	Altered Expression	[15]
SELL	TT2IYXF	Limited	Biomarker	[16]
FCGR3A	TTIFOC0	moderate	Biomarker	[17]
CD14	TT6I7DC	Strong	Altered Expression	[18]
CD24	TTCTYNP	Strong	Biomarker	[18]
CD34	TTZAVYN	Strong	Altered Expression	[19]
CD52	TTQT5S9	Strong	Biomarker	[20]
CD55	TT5Z9WY	Strong	Biomarker	[21]
CD59	TTBGTEJ	Strong	Biomarker	[22]
CFD	TT8D13I	Strong	Biomarker	[23]
CR1	TTEA8OW	Strong	Genetic Variation	[24]
FLNA	TTSTRZY	Strong	Genetic Variation	[25]
GEM	TTAZF9M	Strong	Genetic Variation	[26]
PMS1	TTX1ISF	Strong	Biomarker	[27]
PTPRC	TTUS45N	Strong	Genetic Variation	[28]

This Disease Is Related to 1 DME Molecule(s)

Gene Name	DME ID	Evidence Level	Mode of Inheritance	REF
HPRT1	DEVXTP5	Limited	Genetic Variation	[29]

This Disease Is Related to 26 DOT Molecule(s)

Gene Name	DOT ID	Evidence Level	Mode of Inheritance	REF
ARFGEF2	OTM3CQZT	Limited	Genetic Variation	[25]
BST1	OTAV5SE7	Limited	Posttranslational Modification	[18]
CEACAM8	OTLL9WWO	Limited	Biomarker	[17]
FCGR3B	OTSLSPZG	Limited	Biomarker	[17]
NEDD4L	OT1B19RU	Limited	Genetic Variation	[25]
PIGT	OTWA8819	Limited	Biomarker	[30]
ATP8B1	OTALGS63	Strong	Genetic Variation	[31]
C6	OTCKR304	Strong	Altered Expression	[32]
CD48	OT83ZNPP	Strong	Genetic Variation	[33]
CELSR3	OT8P6QNJ	Strong	Genetic Variation	[34]
CLYBL	OTXZLTST	Strong	Biomarker	[35]
CRLS1	OT7XNL0K	Strong	Biomarker	[36]
CTC1	OTRJY7QD	Strong	Genetic Variation	[37]
DAB1	OTPL9MA3	Strong	Genetic Variation	[38]
ECI2	OT2TP4IX	Strong	Biomarker	[39]
EFS	OT06O7XL	Strong	Biomarker	[40]
ERGIC2	OT3MEGIU	Strong	Biomarker	[41]
GYPB	OTESHUIX	Strong	Genetic Variation	[42]
GYPE	OTBHAG6A	Strong	Genetic Variation	[42]
KIR3DL1	OTPOSXFX	Strong	Genetic Variation	[26]
PGAP1	OT1WQ55V	Strong	Altered Expression	[43]
PIGF	OTJKE6VW	Strong	Biomarker	[44]
PIGM	OTY98K40	Strong	Genetic Variation	[45]
POLR3E	OT69PWBM	Strong	Biomarker	[40]
RPL6	OTRU71O4	Strong	Altered Expression	[46]
TBCE	OTGBSTKS	Strong	Biomarker	[47]

References

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• [2] FDA Approved Drug Products from FDA Official Website. 2023. Application Number: 218276
• [3] FDA Approved Drug Products from FDA Official Website. 2023. Application Number: 215014.
• [4] ClinicalTrials.gov (NCT04888507) Pozelimab and Cemdisiran Combination Therapy in Adult Participants With Paroxysmal Nocturnal Hemoglobinuria Who Switch From Eculizumab Therapy. U.S. National Institutes of Health.
• [5] 2018 FDA drug approvals.Nat Rev Drug Discov. 2019 Feb;18(2):85-89.
• [6] Anti-ageing pipeline starts to mature.Nat Rev Drug Discov. 2018 Sep;17(9):609-612.
• [7] ClinicalTrials.gov (NCT03818607) A Study Evaluating the Efficacy and Safety of ABP 959 Compared With Eculizumab in Adult Participants With PNH (DAHLIA). U.S. National Institutes of Health.
• [8] ClinicalTrials.gov (NCT04469465) A Phase 3 Study of Danicopan (ALXN2040) as Add-on Therapy to a C5 Inhibitor (Eculizumab or Ravulizumab) in Patients With Paroxysmal Nocturnal Hemoglobinuria Who Have Clinically Evident Extravascular Hemolysis (EVH). U.S.National Institutes of Health.
• [9] ClinicalTrials.gov (NCT03427060) Coversin in PNH in Patients With Resistance to Eculizumab Due to Complement C5 Polymorphisms (CONSENTII). U.S. National Institutes of Health.
• [10] ClinicalTrials.gov (NCT04058158) A Study to Compare SB12 (Proposed Eculizumab Biosimilar) to Soliris in Subjects With Paroxysmal Nocturnal Haemoglobinuria. U.S. National Institutes of Health.
• [11] ClinicalTrials.gov (NCT05116774) A Randomized, Open-Label, Multicenter, Parallel-Group Study to Evaluate the Efficacy, Safety, and Tolerability of Oral BCX9930 Monotherapy for the Treatment of PNH in Subjects With Inadequate Response to C5 Inhibitor Therapy. U.S.National Institutes of Health.
• [12] ClinicalTrials.gov (NCT02352493) A Phase 1/2 Study of an Investigational Drug, ALN-CC5, in Healthy Adult Volunteers and Patients With PNH. U.S. National Institutes of Health.
• [13] ClinicalTrials.gov (NCT04170023) A Phase 2 Open-Label Proof of Concept Study to Assess the Efficacy, Safety, and Pharmacokinetics of the Oral Factor D (FD) Inhibitor ALXN2050 (ACH-0145228) in Paroxysmal Nocturnal Hemoglobinuria (PNH) Patients as Monotherapy. U.S.National Institutes of Health.
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• [18] Diagnosis of paroxysmal nocturnal hemoglobinuria with flowcytometry panels including CD157: Data from the real world.Cytometry B Clin Cytom. 2020 Mar;98(2):193-202. doi: 10.1002/cyto.b.21847. Epub 2019 Sep 30.
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• [20] The PNH phenotype cells that emerge in most patients after CAMPATH-1H therapy are present prior to treatment.Br J Haematol. 1999 Oct;107(1):148-53. doi: 10.1046/j.1365-2141.1999.01676.x.
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• [22] CD71 improves delineation of PNH type III, PNH type II, and normal immature RBCS in patients with paroxysmal nocturnal hemoglobinuria.Cytometry B Clin Cytom. 2020 Mar;98(2):179-192. doi: 10.1002/cyto.b.21853. Epub 2019 Nov 8.
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• [25] Multiple genomic copy number variants associated with periventricular nodular heterotopia indicate extreme genetic heterogeneity.Eur J Hum Genet. 2019 Jun;27(6):909-918. doi: 10.1038/s41431-019-0335-3. Epub 2019 Jan 25.
• [26] Killer immunoglobulin-like receptors (KIR) and their HLA-ligands in Italian paroxysmal nocturnal haemoglobinuria (PNH) patients.Tissue Antigens. 2012 Oct;80(4):322-7. doi: 10.1111/j.1399-0039.2012.01932.x. Epub 2012 Jul 17.
• [27] Clinical impact of HLA-DR15, a minor population of paroxysmal nocturnal haemoglobinuria-type cells, and an aplastic anaemia-associated autoantibody in children with acquired aplastic anaemia.Br J Haematol. 2008 Jul;142(3):427-35. doi: 10.1111/j.1365-2141.2008.07182.x. Epub 2008 Jun 3.
• [28] Multicenter validation of a simplified method for paroxysmal nocturnal hemoglobinuria screening.Eur J Haematol. 2017 Jul;99(1):27-35. doi: 10.1111/ejh.12885. Epub 2017 Apr 17.
• [29] Frequent HPRT mutations in paroxysmal nocturnal haemoglobinuria reflect T cell clonal expansion, not genomic instability.Br J Haematol. 2004 May;125(3):383-91. doi: 10.1111/j.1365-2141.2004.04912.x.
• [30] Complement and inflammasome overactivation mediates paroxysmal nocturnal hemoglobinuria with autoinflammation.J Clin Invest. 2019 Dec 2;129(12):5123-5136. doi: 10.1172/JCI123501.
• [31] Persisting hyperbilirubinemia in patients with paroxysmal nocturnal hemoglobinuria (PNH) chronically treated with eculizumab: The role of hepatocanalicular transporter variants.Eur J Haematol. 2017 Oct;99(4):350-356. doi: 10.1111/ejh.12927. Epub 2017 Aug 23.
• [32] Hereditary deficiency of the sixth component of complement in man. I. Immunochemical, biologic, and family studies.J Clin Invest. 1974 Feb;53(2):544-53. doi: 10.1172/JCI107588.
• [33] High frequency of several PIG-A mutations in patients with aplastic anemia and myelodysplastic syndrome.Leukemia. 2006 Apr;20(4):627-34. doi: 10.1038/sj.leu.2404135.
• [34] Paroxysmal nocturnal hemoglobinuria.Blood. 2014 Oct 30;124(18):2804-11. doi: 10.1182/blood-2014-02-522128. Epub 2014 Sep 18.
• [35] Maternal genomic neutrophil FcRIII deficiency leading to neonatal isoimmune neutropenia.Blood. 1990 Nov 15;76(10):1927-32.
• [36] The use of monoclonal antibodies and flow cytometry in the diagnosis of paroxysmal nocturnal hemoglobinuria.Blood. 1996 Jun 15;87(12):5332-40.
• [37] Impact of germline CTC1 alterations on telomere length in acquired bone marrow failure.Br J Haematol. 2019 Jun;185(5):935-939. doi: 10.1111/bjh.15862. Epub 2019 Mar 19.
• [38] Mutations in the HECT domain of NEDD4L lead to AKT-mTOR pathway deregulation and cause periventricular nodular heterotopia. Nat Genet. 2016 Nov;48(11):1349-1358. doi: 10.1038/ng.3676. Epub 2016 Oct 3.
• [39] Diazepam-binding inhibitor-related protein 1: a candidate autoantigen in acquired aplastic anemia patients harboring a minor population of paroxysmal nocturnal hemoglobinuria-type cells.Blood. 2004 Oct 15;104(8):2425-31. doi: 10.1182/blood-2004-05-1839. Epub 2004 Jun 24.
• [40] A SIN lentiviral vector containing PIGA cDNA allows long-term phenotypic correction of CD34+-derived cells from patients with paroxysmal nocturnal hemoglobinuria.Mol Ther. 2003 Mar;7(3):304-16. doi: 10.1016/s1525-0016(03)00011-x.
• [41] Monocyte antigen CD14 is a phospholipid anchored membrane protein.Blood. 1989 Jan;73(1):284-9.
• [42] Increased frequency of somatic mutations at glycophorin A loci in patients with aplastic anaemia, myelodysplastic syndrome and paroxysmal nocturnal haemoglobinuria.Br J Haematol. 1997 Aug;98(2):384-91. doi: 10.1046/j.1365-2141.1997.2233037.x.
• [43] The Monoclonal Anti-CD157 Antibody Clone SY11B5, Used for High Sensitivity Detection of PNH Clones on WBCs, Fails to Detect a Common Polymorphic Variant Encoded by BST-1.Cytometry B Clin Cytom. 2018 Jul;94(4):652-659. doi: 10.1002/cyto.b.21625. Epub 2018 Feb 9.
• [44] Structure and chromosomal localization of the GPI-anchor synthesis gene PIGF and its pseudogene psi PIGF.Genomics. 1995 Oct 10;29(3):804-7. doi: 10.1006/geno.1995.9929.
• [45] Heterogeneity in the molecular pathogenesis of paroxysmal nocturnal hemoglobinuria (PNH) syndromes and expansion mechanism of a PNH clone.Int J Hematol. 2006 Aug;84(2):97-103. doi: 10.1532/IJH97.06083.
• [46] Paroxysmal nocturnal hemoglobinuria: Differential gene expression of EGR-1 and TAXREB107.Exp Hematol. 2002 Jan;30(1):18-25. doi: 10.1016/s0301-472x(01)00763-9.
• [47] Haploidentical hematopoietic stem cell transplant in paroxysmal nocturnal hemoglobinuria.Leuk Lymphoma. 2016;57(4):835-41. doi: 10.3109/10428194.2015.1068309. Epub 2016 Feb 24.