Drug discovery
29
drugs
With orphan designations
Overview
Hereditary ATTR (hATTR) amyloidosis is a progressive, multisystem disorder caused by autosomal dominant mutations in the TTR gene, leading to misfolded transthyretin protein aggregates that form amyloid deposits in nerves, heart, and other organs. Symptoms include sensorimotor neuropathy, cardiomyopathy, and autonomic dysfunction. Diagnosis relies on genetic testing, tissue biopsy (Congo red staining), and cardiac scintigraphy. Early intervention with disease-modifying therapies is critical to slow progression [1][4][12].
Population
Global prevalence ≈50,000, with >150 pathogenic TTR variants [1][7][19].
Higher incidence in endemic regions (e.g., 1:538 in northern Portugal); V122I mutation prevalent in 1:25 Black individuals [2][6][16].
Median age of onset varies: 30–50s for neuropathic forms, later for cardiac phenotypes [4][6].
Burden
Diagnostic delay: ~6 years due to nonspecific symptoms mimicking common conditions (e.g., diabetic neuropathy) [7][15].
High morbidity: Progressive disability (wheelchair dependence in 5–15 years), heart failure, and mortality within 3–12 years post-symptom onset [4][7][12].
Economic impact: Annual US healthcare costs ≥$60,000/patient, driven by hospitalizations and advanced therapies [5][14].
Categories: rare cardiac diseases, rare genetic diseases, rare systemic and rheumatological diseases, rare transplant-related disorders
Drug Discovery Landscape
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
diflunisal | small molecules | FDA | 2025-07-03 | — | Purpose Pharma International AB |
small interfering ribonucleic acid -GalNAc conjugate targeting the transthyretin messenger RNA | RNAs | FDA | 2025-06-05 | — | Chengdu Brilliant Pharmaceutical Co., Ltd. |
Florbetaben (18F) | small molecules | EMA | 2025-05-22 | — | Life Molecular Imaging GmbH |
CRISPR-associated protein 9-based TTR gene editing therapy | gene editing enzymes | FDA | 2025-03-14 | — | Accuredit Therapeutics US Ltd. |
Coramitug | antibodies | EMA | 2024-11-11 | — | Novo Nordisk A/S |
a fusion protein of humanized immunoglobulin G1 (IgG1) with a pan amyloid-reactive peptide (p5R) genetically incorporated into the C-terminus of the light chain | proteins | FDA | 2024-10-30 | — | Attralus, Inc. |
coramitug | antibodies | FDA | 2024-09-23 | — | Novo Nordisk Inc. |
Humanised IgG1 monoclonal antibody against misfolded immunoglobulin G, fused with pan-amyloid-reactive peptide p5R | antibodies | EMA | 2024-08-21 | — | Raremoon Consulting Esp S.L. |
Human IgG1 monoclonal antibody targeting amyloid transthyretin | antibodies | EMA | 2024-02-19 | — | Alexion Europe |
Eplontersen [Wainzua] | oligonucleotides | EMA | 2023-10-13 | — | AstraZeneca AB |
recombinant human anti-ATTR-immunoglobulin G1 monoclonal antibody | antibodies | FDA | 2023-10-02 | — | Alexion Pharmaceuticals, Inc. |
Iodine (124I) evuzamitide | small molecules | EMA | 2022-12-09 | — | Raremoon Consulting Esp S.L. |
Iodine (I-124) evuzamitide | small molecules | FDA | 2022-07-26 | — | Attralus, Inc. |
Diflunisal [Attrogy] | small molecules | EMA | 2022-06-21 | — | Purpose Pharma International AB |
eplontersen [Wainua] | RNAs | FDA | 2022-01-06 | 2023-12-21 | Ionis Pharmaceuticals, Inc. |
clustered regularly interspaced short palindromic repeats CRISPR/ Cas9-based gene therapy consisting of a single guide RNA targeting the human TTR gene and a messenger RNA encoding Cas9 | gene editing enzymes | FDA | 2021-10-19 | — | Intellia Therapeutics, Inc. |
Messenger RNA encoding Cas9, single guide RNA targeting the human TTR gene | combination | EMA | 2021-03-26 | — | Pharma Gateway AB |
Acoramidis [Beyonttra] | small molecules | EMA | 2018-11-20 | — | BridgeBio Europe B.V. |
acoramidis [Attruby] | small molecules | FDA | 2018-10-02 | 2024-11-22 | BridgeBio Pharma, Inc. |
vutrisiran [Amvuttra] | RNAs | FDA | 2018-05-25 | 2022-06-13 | Alnylam Pharmaceuticals, Inc. |
Synthetic double-stranded siRNA oligonucleotide targeted against transthyretin mRNA, with six phosphorothioate linkages in the backbone, and nine 2'-fluoro and thirty-five 2'-O-methyl nucleoside residues in the sequence, which is covalently linked via a phosphodiester group to a ligand containing three N-acetylgalactosamine residues [Amvuttra] | RNAs | EMA | 2018-05-25 | 2022-09-16 | Alnylam Netherlands B.V. |
revusiran | RNAs | FDA | 2015-05-18 | — | Alnylam Pharmaceuticals, Inc. |
Phosphorothioate oligonucleotide targeted to transthyretin [Tegsedi] | oligonucleotides | EMA | 2014-03-26 | 2018-07-10 | Akcea Therapeutics Ireland Limited |
Tolcapone | small molecules | FDA | 2013-12-24 | — | Corino Therapeutics, Inc. |
Inotersen [TEGSEDI™] | oligonucleotides | FDA | 2012-07-24 | 2018-10-05 | Akcea Therapeutics, Inc. |
patisiran [ONPATTRO] | RNAs | FDA | 2012-06-14 | 2018-08-10 | Alnylam Pharmaceuticals, Inc. |
Doxycycline hyclate | small molecules | EMA | 2012-04-02 | — | Giampaolo Merlini |
Synthetic double-stranded siRNA oligonucleotide directed against transthyretin mRNA [Onpattro] | RNAs | EMA | 2011-04-15 | 2018-08-29 | Alnylam Netherlands B.V. |
tafamidis | small molecules | FDA | 2006-05-23 | — | Pfizer, Inc. |