acoramidis

{{Infobox drug

| image = Acoramidis.svg

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| pronounce = ə-corAM-i-dis

| tradename = Attruby, others

| Drugs.com = {{drugs.com|monograph|acoramidis-hydrochloride}}

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| DailyMedID = Acoramidis

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| routes_of_administration = By mouth

| class = Amyloidogenesis suppressant

| ATC_prefix = C01

| ATC_suffix = EB25

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| legal_US = Rx-only

| legal_US_comment = {{cite web | title=Attruby- acoramidis hydrochloride tablet, film coated | website=DailyMed | date=26 November 2024 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=913552ef-875d-4cb7-bf05-a7d20a394c38 | access-date=28 November 2024}}

| legal_EU = Rx-only

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| CAS_number = 1446711-81-4

| CAS_number2 = 2242751-53-5

| PubChem = 71464713

| PubChem2 = 71464713

| IUPHAR_ligand = 135307127

| DrugBank = DB17999

| ChemSpiderID = 35033544

| UNII = T12B44A1OE

| UNII2 = VY9C88C2NV

| KEGG = D11972

| KEGG2 = D11973

| ChEBI =

| ChEMBL = 3940890

| ChEMBL2 = 4650226

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| PDB_ligand = 16V

| synonyms = AG10

| IUPAC_name = 3-[3-(3,5-Dimethyl-1H-pyrazol-4-yl)propoxy]-4-fluorobenzoic acid

| C = 15 | H = 17 | F = 1 | N = 2 | O = 3

| SMILES = CC1=C(C(=NN1)C)CCCOC2=C(C=CC(=C2)C(=O)O)F

| StdInChI = 1S/C15H17FN2O3/c1-9-12(10(2)18-17-9)4-3-7-21-14-8-11(15(19)20)5-6-13(14)16/h5-6,8H,3-4,7H2,1-2H3,(H,17,18)(H,19,20)

| StdInChI2 = 1S/C15H17FN2O3.ClH/c1-9-12(10(2)18-17-9)4-3-7-21-14-8-11(15(19)20)5-6-13(14)16;/h5-6,8H,3-4,7H2,1-2H3,(H,17,18)(H,19,20);1H

| StdInChI_comment =

| StdInChIKey = WBFUHHBPNXWNCC-UHFFFAOYSA-N

| StdInChIKey2 = MGFZEARHINUOMX-UHFFFAOYSA-N

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Acoramidis, sold under the brand name Attruby, is a medication used for the treatment of cardiomyopathy. It is a near-complete (>90%) transthyretin stabilizer, developed to mimic the protective properties of the naturally-occurring T119M mutation,{{cite journal | vauthors = Penchala SC, Connelly S, Wang Y, Park MS, Zhao L, Baranczak A, Rappley I, Vogel H, Liedtke M, Witteles RM, Powers ET, Reixach N, Chan WK, Wilson IA, Kelly JW, Graef IA, Alhamadsheh MM | title = AG10 inhibits amyloidogenesis and cellular toxicity of the familial amyloid cardiomyopathy-associated V122I transthyretin | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 110 | issue = 24 | pages = 9992–9997 | date = June 2013 | pmid = 23716704 | pmc = 3683741 | doi = 10.1073/pnas.1300761110 | doi-access = free | bibcode = 2013PNAS..110.9992P }}{{cite journal | vauthors = Miller M, Pal A, Albusairi W, Joo H, Pappas B, Haque Tuhin MT, Liang D, Jampala R, Liu F, Khan J, Faaij M, Park M, Chan W, Graef I, Zamboni R, Kumar N, Fox J, Sinha U, Alhamadsheh M | title = Enthalpy-Driven Stabilization of Transthyretin by AG10 Mimics a Naturally Occurring Genetic Variant That Protects from Transthyretin Amyloidosis | journal = Journal of Medicinal Chemistry | volume = 61 | issue = 17 | pages = 7862–7876 | date = September 2018 | pmid = 30133284 | pmc = 6276790 | doi = 10.1021/acs.jmedchem.8b00817 }} to treat transthyretin amyloid cardiomyopathy. It is taken by mouth.

The most common adverse reactions include diarrhea and upper abdominal pain.

Acoramidis was approved for medical use in the United States in November 2024,{{cite web | title=FDA approves drug for heart disorder caused by transthyretin-mediated | website=U.S. Food and Drug Administration | date=1 October 2024 | url=https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-drug-heart-disorder-caused-transthyretin-mediated-amyloidosis | access-date=27 November 2024}} {{PD-notice}}{{cite web | title=Novel Drug Approvals for 2024 | website=U.S. Food and Drug Administration (FDA) | date=1 October 2024 | url=https://www.fda.gov/drugs/novel-drug-approvals-fda/novel-drug-approvals-2024 | access-date=20 December 2024}}{{Cite web |date=25 November 2024 |title=FDA approves BridgeBio Pharma's Attruby to treat rare heart disease ATTR-CM |url=https://pmlive.com/pharma_news/fda-approves-bridgebios-attruby-to-treat-rare-heart-disease-attr-cm/ |access-date=25 November 2024 |website=PMLiVE }}{{cite report | title=New Drug Therapy Approvals 2024 | website=U.S. Food and Drug Administration (FDA) | date=January 2025 | url=https://www.fda.gov/media/184967/download | format=PDF | access-date=21 January 2025 | archive-url=https://web.archive.org/web/20250121045744/https://www.fda.gov/media/184967/download | archive-date=21 January 2025 | url-status=live }} and in the European Union in February 2025.

Medical uses

Acoramidis is indicated for the treatment of the cardiomyopathy of wild-type or variant transthyretin-mediated amyloidosis (ATTR-CM) in adults to reduce cardiovascular death and cardiovascular-related hospitalization.{{Cite web | vauthors = LeMieux J |date=25 November 2024 |title=Bridgebio's Attruby, to Treat Heart Condition ATTR-CM, Receives FDA Approval |url=https://www.genengnews.com/topics/drug-discovery/bridgebios-attruby-to-treat-heart-condition-attr-cm-receives-fda-approval/ |access-date=25 November 2024 |website=Genetic Engineering and Biotechnology News }}

ATTR-CM is a rare and serious disease that affects the heart muscle. In people with ATTR-CM, there is a build-up of protein deposits in the heart, causing the walls of the heart to become stiff, and making the left ventricle unable to properly relax and fill with blood (called cardiomyopathy). As the condition progresses, the heart can become unable to pump blood out adequately, causing heart failure. There are two types of ATTR-CM, hereditary ATTR-CM (hATTR-CM) and wild-type ATTR-CM (wATTR-CM). In hATTR-CM, which can run in families, there's a variant in the transthyretin gene, which results in protein deposits in the heart. In wATTR-CM, there is no variant in the transthyretin gene.

Side effects

The most common side effects are diarrhea and abdominal pain.{{Cite web |date=25 November 2024 |title=FDA approves BridgeBio's Attruby for ATTR-CM treatment |url=https://www.pharmaceutical-technology.com/news/fda-bridgebios-attruby-attr-cm/ |access-date=25 November 2024 |website=Pharmaceutical Technology }}

History

The efficacy and safety of acoramidis were evaluated in a multicenter, international, randomized, double-blind, placebo-controlled study in 611 adult participants with wild-type or hereditary (variant) ATTR-CM (NCT03860935).

= Clinical trials =

Phase I data indicated acoramidis achieved near-complete (>90%) TTR stabilization across the entire dosing interval at steady state.{{cite journal | vauthors = Fox JC, Hellawell JL, Rao S, O'Reilly T, Lumpkin R, Jernelius J, Gretler D, Sinha U | display-authors = 6 | title = First-in-Human Study of AG10, a Novel, Oral, Specific, Selective, and Potent Transthyretin Stabilizer for the Treatment of Transthyretin Amyloidosis: A Phase 1 Safety, Tolerability, Pharmacokinetic, and Pharmacodynamic Study in Healthy Adult Volunteers | journal = Clinical Pharmacology in Drug Development | volume = 9 | issue = 1 | pages = 115–129 | date = January 2020 | pmid = 31172685 | pmc = 7003869 | doi = 10.1002/cpdd.700 }}

Phase II and the Open-Label Extension (OLE) data indicated after a median of 38 months, long-term treatment with acoramidis was generally well tolerated and resulted in a median decline in NT-proBNP levels, normalization of serum TTR, and sustained stabilization of TTR in individuals with ATTR-CM. {{Cite journal | vauthors = Masri A, Aras M, Falk RH, Grogan M, Jacoby D, Judge DP, Shah SJ, Witteles R, Ji AX, Wong PW, Cao X, Vanlandingham R, Katz L, Sinha U, Fox JC |date=March 2022 |title=Long-Term Safety and Tolerability of Acoramidis (Ag10) in Symptomatic Transthyretin Amyloid Cardiomyopathy: Updated Analysis from an Ongoing Phase 2 Open-Label Extension Study |journal=Journal of the American College of Cardiology |volume=79 |issue=9 |pages=227 |doi=10.1016/S0735-1097(22)01218-9}}

Phase III data from [https://clinicaltrials.gov/study/NCT03860935 ATTRibute-CM] indicated acoramidis resulted in a significantly better four-step primary hierarchical outcome containing components of mortality, morbidity, and function than placebo at 30 months in participants with ATTR-CM. Adverse events were similar in the two groups.{{cite journal | vauthors = Gillmore JD, Judge DP, Cappelli F, Fontana M, Garcia-Pavia P, Gibbs S, Grogan M, Hanna M, Hoffman J, Masri A, Maurer MS, Nativi-Nicolau J, Obici L, Poulsen SH, Rockhold F, Shah KB, Soman P, Garg J, Chiswell K, Xu H, Cao X, Lystig T, Sinha U, Fox JC | display-authors = 6 | title = Efficacy and Safety of Acoramidis in Transthyretin Amyloid Cardiomyopathy | journal = The New England Journal of Medicine | volume = 390 | issue = 2 | pages = 132–142 | date = January 2024 | pmid = 38197816 | doi = 10.1056/NEJMoa2305434 | url = https://discovery.ucl.ac.uk/id/eprint/10185423/ }}

Other analyses from ATTRibute-CM indicated a 50% reduction in cumulative cardiovascular hospitalizations (CVH), a 42% reduction in all-cause mortality (ACM) and recurrent CVH, and a 3-month time-to-separation of the Kaplan Meier curves for ACM or CVH. No other treatment has demonstrated this degree of treatment effect this quickly in participants with ATTR-CM.{{Cite web |title=Program Planner |url=https://www.abstractsonline.com/pp8/#!/10871/presentation/16681 |access-date=19 October 2024 |website=www.abstractsonline.com |archive-date=6 February 2021 |archive-url=https://web.archive.org/web/20210206015933/https://www.abstractsonline.com/pp8/#!/10871/presentation/16681 |url-status=live }}{{Cite report | vauthors = Alexander K, Judge D, Cappelli F, Fontana M, Garcia-Pavia P, Grogan M, Hanna M, Masri A, Maurer M |date=6 May 2024 |title=Acoramidis Achieves Early Reduction in Cardiovascular Death or Hospitalization in Transthyretin Amyloid Cardiomyopathy (ATTR-CM): Results from the ATTRibute-CM Clinical Trial OC7 (#281) |doi=10.26226/m.65f9bf8ae6f73964e1d4f069 }}{{Cite web |title=BridgeBio Shares Recurrent Event Analysis of ATTRibute-CM, Demonstrating a 42% Reduction by Acoramidis on the Composite Endpoint of All-Cause Mortality and Recurrent Cardiovascular-related Hospitalization Events |url=https://hfsa.org/bridgebio-shares-recurrent-event-analysis-attribute-cm-demonstrating-42-reduction-acoramidis |access-date=19 October 2024 |website=HFSA}}

In vitro data indicated acoramidis exhibits near-complete (>90%) TTR stabilization at therapeutic trough concentrations, and its TTR stabilization exceeds that of tafamidis' across a range of destabilizing TTR mutations.{{Cite journal | vauthors = Ji A, Wong P, Judge DP, Graef IA, Fox J, Sinha U |date=November 2023 |title=Acoramidis produces near-complete TTR stabilization in blood samples from patients with variant transthyretin amyloidosis that is greater than that achieved with tafamidis |journal=European Heart Journal |volume=44 |issue=Supplement_2 |doi=10.1093/eurheartj/ehad655.989 |issn=0195-668X }}

Society and culture

= Legal status =

Acoramidis was approved for medical use in the United States in November 2024.{{cite press release | title=Attruby (acoramidis), a Near Complete TTR Stabilizer (≥90%), approved by FDA to Reduce Cardiovascular Death and Cardiovascular-related Hospitalization in ATTR-CM Patients | publisher=BridgeBio Pharma | via=GlobeNewswire | date=23 November 2024 | url=https://www.globenewswire.com/news-release/2024/11/23/2986250/0/en/Attruby-acoramidis-a-Near-Complete-TTR-Stabilizer-90-approved-by-FDA-to-Reduce-Cardiovascular-Death-and-Cardiovascular-related-Hospitalization-in-ATTR-CM-Patients.html | access-date=28 November 2024 | archive-date=25 November 2024 | archive-url=https://web.archive.org/web/20241125210929/https://www.globenewswire.com/news-release/2024/11/23/2986250/0/en/Attruby-acoramidis-a-Near-Complete-TTR-Stabilizer-90-approved-by-FDA-to-Reduce-Cardiovascular-Death-and-Cardiovascular-related-Hospitalization-in-ATTR-CM-Patients.html | url-status=live }} The approval was granted to BridgeBio Pharma.

In December 2024, the Committee for Medicinal Products for Human Use of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Beyonttra, intended for the treatment of transthyretin amyloidosis in adults with cardiomyopathy. The applicant for this medicinal product is BridgeBio Europe B.V.{{cite web | title=Beyonttra EPAR | website=European Medicines Agency (EMA) | date=12 December 2024 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/beyonttra | access-date=15 December 2024}} Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged. Acoramidis was designated an orphan medicine by the EMA. Acoramidis was authorized for medical use in the European Union in February 2025.{{cite web | title=Beyonttra PI | website=Union Register of medicinal products | date=11 February 2025 | url=https://ec.europa.eu/health/documents/community-register/html/h1906.htm | access-date=16 February 2025}}

= Names =

During development, acoramidis was known as AG10 (the Alhamadsheh-Graef molecule 10).{{cite web | title=FDA approves Stanford Medicine-developed drug that treats rare heart disease | website=Stanford | date=27 November 2024 | url=https://med.stanford.edu/news/all-news/2024/11/spark-acoramidis.html | access-date=29 November 2024}}

Acoramidis is the international nonproprietary name.{{cite journal | vauthors = ((World Health Organization)) | year = 2024 | title = International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 83 | journal = WHO Drug Information | volume = 38 | issue = 1 | hdl = 10665/378096 | hdl-access = free | author-link = World Health Organization }}

Acoramidis is sold under the brand names Attruby and Beyonttra.