Drug discovery
20
drugs
With orphan designations
Overview
X-linked adrenoleukodystrophy (X-ALD) is an X-linked recessive disorder caused by ABCD1 mutations, leading to impaired peroxisomal breakdown of very-long-chain fatty acids (VLCFAs). This results in progressive neurodegeneration (demyelination, myelopathy) and adrenal insufficiency. Phenotypes include childhood cerebral ALD (rapidly fatal without intervention), adrenomyeloneuropathy (AMN), and isolated adrenal dysfunction [1][2][6]. Early diagnosis via VLCFA testing and MRI monitoring is critical for timely intervention [6][8].
Structured Overview
Burden
Mortality: Untreated cerebral ALD leads to death within 2–5 years of symptom onset [1][12].
Morbidity: Progressive paraparesis, incontinence, and neuropsychiatric decline in AMN; fractures, falls, and reduced QoL in females [4][14].
Healthcare challenges: Delayed diagnosis (>40% of females initially misdiagnosed), limited disease-modifying treatments for AMN [4][14].
Therapies
Hematopoietic stem cell transplant (HSCT): Curative for early-stage cerebral ALD (Loes score <9) [8][11].
Adrenal replacement: Lifelong glucocorticoid/mineralocorticoid therapy for adrenal insufficiency [6][8].
Emerging therapies: Gene therapy (lentiviral ABCD1 correction) and pharmacological agents (e.g., HDAC inhibitors) under investigation [3][13].
Categories: rare endocrine diseases, rare genetic diseases, rare inborn errors of metabolism, rare infertility disorders, rare neurological diseases, rare transplant-related disorders
Drug Discovery Landscape
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Potassium 2-chloro-3-(1-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)-6-oxo-5-phenyl-6,7-dihydrothieno[2,3-b]pyridin-4-olate monohydrate | gene therapies | EMA | 2022-12-09 | — | Poxel |
Pozetaldogene ormesparvovec | gene therapies | EMA | 2022-11-11 | — | Voisin Consulting Life Sciences |
(R)-deuteropioglitazone hydrochloride | small molecules | EMA | 2022-11-10 | — | Poxel |
potassium 2-chloro-3-(1-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)-6-oxo- 5-phenyl-6,7-dihydrothieno[2, 3-b]pyridin-4-olate hydrate | small molecules | FDA | 2022-05-12 | — | SCYNEXIS, Inc. |
(R)-5-({4-[2-(5-ethyl-2-pyridyl)ethoxy]phenyl}methyl)-(5-2H)-1,3-thiazolidine-2,4-dione hydrochloride | small molecules | FDA | 2022-04-11 | — | Poxel S.A. |
a non-replicating recombinant adeno-associated virus serotype 9 (AAV9) gene therapy vector containing the human adenosine triphosphate (ATP)-binding cassette (ABC) sub-family D member 1 (ABCD1) gene | gene therapies | FDA | 2022-03-14 | — | SwanBio Therapeutics, Inc. |
Fingolimod | small molecules | EMA | 2021-11-12 | — | Consorcio Centro de Investigación Biomédica en Red |
2?(3,5?dichloro?4?([4?hydroxy?3?(propan?2?yl)phenyl]methyl)phenoxy)?N?methylacetamide | gene therapies | FDA | 2021-07-22 | — | Autobahn Therapeutics, Inc. |
Dimethyl fumarate | small molecules | EMA | 2020-01-09 | — | Consorcio Centro de Investigación Biomédica en Red |
generation 4 hydroxyl-terminated polyamidoamine dendrimer containing an ethylene diamine (EDA) core, amidoamine repate units, and 64 hydroxyl end groups | other | FDA | 2017-03-22 | — | Ashvattha Therapeutics |
hydroxypioglitazone | small molecules | FDA | 2017-01-30 | — | Minoryx Therapeutics S.L. |
((4-(3-benzyl-4-hydroxybenzyl)-3,5-dimethylphenoxy)methyl)phosphonic acid | small molecules | FDA | 2016-12-05 | — | Viking Therapeutics, Inc. |
5-[4-[2-(5-(1-hydroxyethyl)-2-pyridinyl)ethoxy]benzyl]-2,4-thiazolidinedione hydrochloride | small molecules | EMA | 2016-11-18 | — | Minoryx Therapeutics S.L. |
Temsirolimus | small molecules | EMA | 2016-05-30 | — | Consorcio Centro de Investigación Biomédica en Red |
Pioglitazone | small molecules | EMA | 2014-02-19 | — | Minoryx Therapeutics S.L. |
Elivaldogene autotemcel [Skysona] | gene therapies | EMA | 2012-06-06 | — | bluebird bio (Netherlands) B.V. |
elivaldogene autotemcel [Skysona] | gene therapies | FDA | 2012-04-19 | 2022-09-16 | Genetix Biotherapeutics Inc. |
sobetirome | small molecules | FDA | 2011-04-29 | — | Naftali Kaminski, MD |
S-adenosylmethionine | — | FDA | 1998-04-30 | — | Genopia USA, Inc. |
Glyceryl trioleate and glyceryl trierucate | small molecules | FDA | 1995-02-14 | — | Moser, Hugo W. M.D. |