Drug discovery
29
drugs
With orphan designations
Overview
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired clonal disorder caused by PIGA gene mutations, leading to deficiency of GPI-anchored complement regulatory proteins (CD55/CD59). This results in chronic complement-mediated intravascular hemolysis, thrombophilia, and bone marrow failure. Clinical features include hemolytic anemia, hemoglobinuria, fatigue, and life-threatening thrombosis. Diagnosis requires flow cytometry to detect GPI-anchored protein deficiency. Treatment focuses on complement inhibition, dramatically improving outcomes [1][6][11].
Burden
Thrombosis: Leading cause of mortality (40–67% of deaths) [6][9][15].
Clinical impact: Chronic fatigue (80%), renal impairment (50%), transfusion dependence, and impaired quality of life [4][14][16].
Economic: Mean hospitalization costs exceed $125,000; 23% require annual PNH-related hospitalizations [9][14].
Therapies
Terminal complement inhibitors: Eculizumab and ravulizumab (C5 inhibitors) reduce hemolysis and thrombosis risk [3][6][18].
Proximal inhibitors: Pegcetacoplan (C3), iptacopan (factor B), and danicopan (factor D) address residual extravascular hemolysis [3][8][13].
Supportive care: Transfusions, anticoagulation; stem cell transplant for refractory cases [6][11].
Categories: rare genetic diseases, rare hematological diseases, rare inborn errors of metabolism, rare transplant-related disorders
Drug Discovery Landscape
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
small molecule inhibitor of complement factor B | small molecules | FDA | 2024-12-11 | — | Wuhan Createrna Science and Technology Co., Ltd. |
Recombinant, Humanized, Aglycosylated, Immunoglobulin G1 kappa Anti-Factor Bb Monoclonal Antibody | antibodies | FDA | 2023-12-20 | — | NovelMed Therapeutics, Inc. |
Recombinant, Humanized, aglycosylated, IgG1 Kappa Anti-Properdin Monoclonal Antibody | antibodies | FDA | 2022-10-05 | — | NovelMed Therapeutics, Inc. |
Humanized immunoglobulin G4 monoclonal antibody directed against mannan-binding lectin-associated serine protease-3 (MASP-3) | antibodies | FDA | 2022-07-28 | — | Novo Nordisk Inc. |
Recombinant IgG-fusion protein containing a humanized anti-C5 monoclonal antibody fused with a truncated human complement FH to the heavy chain C-terminus | proteins | FDA | 2022-07-20 | — | Kira Pharmaceuticals, LLC |
cemdisiran | RNAs | FDA | 2022-02-10 | — | Regeneron Pharamecuticals, Inc. |
Vemircopan | small molecules | EMA | 2021-02-19 | — | Alexion Europe |
(1R,3S,5R)-2-(2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-N-(6-bromo-3-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide | small molecules | FDA | 2021-02-08 | — | Alexion Pharmaceuticals Inc. |
Pozelimab/Cemdisiran Combination | combination | FDA | 2020-09-08 | — | Regeneron Pharamecuticals, Inc. |
a small molecule inhibitor of human complement factor D | small molecules | FDA | 2020-08-28 | — | BioCryst Pharmaceuticals, Inc. |
iptacopan [Fabhalta] | small molecules | FDA | 2020-07-31 | 2023-12-05 | Novartis Pharmaceuticals Corporation |
(4-{(2S,4S)-4-ethoxy-1-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]piperidin-2-yl}benzoic acid-hydrogen chloride(1/1)) [FABHALTA] | small molecules | EMA | 2020-06-04 | 2024-05-21 | Novartis Europharm Limited |
pozelimab | antibodies | FDA | 2019-07-22 | — | Regeneron Pharmaceuticals Inc |
(2S,4R)-1-(2-(3-acetyl-5-(2-methylpyrimidine-5-yl)-1H-indazol-1-yl)acetyl)-N-(6-bromopyridine-2-yl)-4-fluoropyrrolidine-2-carboxamide [Voydeya] | small molecules | EMA | 2017-12-12 | 2024-04-25 | Alexion Europe SAS |
danicopan [Voydeya] | small molecules | FDA | 2017-11-02 | 2024-03-29 | Alexion Pharmaceuticals, Inc |
crovalimab-akkz [Piasky] | antibodies | FDA | 2017-09-05 | 2024-06-20 | Genentech Inc. |
Synthetic 15-amino-acid macrocyclic peptide acylated with a ethyleneglycol palmitoylated linker | peptides | FDA | 2017-07-19 | — | Ra Pharmaceuticals, Inc. |
Poly(oxy-1,2-ethanediyl), .alpha.-hydro-.omega.-hydroxy-,15,15'-diester with N-acetyl-L-isoleucyl-L-cysteinyl-L-valyl-1-methyl-L-tryptophyl-L-glutaminyl-L-.alpha.-aspartyl-L-tryptophylglycyl-L-alanyl-L-histidyl-L-arginyl-L-cysteinyl-L-threonyl-2-[2-(2-aminoethoxy)ethoxy]acetyl-N6-carboxy-L-lysinamide cyclic (2.fwdarw.12)-(disulfide); where two identical synthetic peptide domains are covalently linked at the ends of the polyethylene glycol chain [ASPAVELI] | peptides | EMA | 2017-05-22 | 2021-12-14 | Swedish Orphan Biovitrum AB (publ) |
Ravulizumab-cwvz [Ultomiris] | antibodies | FDA | 2017-01-04 | 2018-12-21 | Alexion Pharmaceuticals, Inc. |
Zilucoplan [RA101495] | peptides | EMA | 2016-10-14 | — | UCB Pharma |
nomacopan | proteins | FDA | 2016-09-08 | — | Akari Therapeutics Plc |
Recombinant protein derived from the saliva of the Ornithodoros moubata tick | proteins | EMA | 2016-08-29 | — | Akari Malta Limited |
Ravulizumab [Ultomiris] | antibodies | EMA | 2016-05-30 | — | [INACTIVE] Alexion Europe |
S3,S13-cyclo(D-tyrolsyl-L-isoleucyl-L-cysteinyl-L-valyl-1-methyl-L-tryptophyl-L-glutaminyl-L-aspartyl-L-tryptophyl-N-methyl-L-glycyl-L-alanyl-L-histidyl-L-arginyl-L-cysteinyl-N-methyl-L-isoleucinamide) | peptides | FDA | 2014-10-09 | — | Amyndas Pharmaceuticals |
S3,S13-cyclo(D-tyrolsyl-L-isoleucyl-L-cysteinyl-L-valyl-1-methyl-L-tryptophyl-L-glutaminyl-L-aspartyl-L-tryptophyl-N-methyl-L-glycyl-L-alanyl-L-histidyl-L-arginyl-L-cysteinyl-N-methyl-L-isoleucinamide) | peptides | EMA | 2014-08-22 | — | Amyndas Pharmaceuticals S.A. |
pegcetacoplan [Empaveli] | peptides | FDA | 2014-04-20 | 2021-05-14 | Apellis Pharmaceuticals, Inc. |
Bardoxolone methyl [Soliris] | small molecules | EMA | 2003-10-17 | — | Alexion Europe |
eculizumab [Soliris] | antibodies | FDA | 2003-08-20 | 2007-03-16 | Alexion Pharmaceuticals, Inc. |
Mirococept | proteins | EMA | 2002-09-11 | — | [INACTIVE] Aligen Therapeutics S.L. |