Asciminib Explained

Width:200
Tradename:Scemblix
Dailymedid:Asciminib
Pregnancy Au:D
Pregnancy Au Comment:[1]
Routes Of Administration:By mouth
Class:Tyrosine kinase inhibitor
Atc Prefix:L01
Atc Suffix:EA06
Legal Au:S4
Legal Au Comment:[2]
Legal Ca:Rx-only
Legal Ca Comment:[3] [4]
Legal Us:Rx-only
Legal Us Comment:[5]
Legal Eu:Rx-only
Legal Eu Comment:[6]
Index2 Label:as HCl
Cas Number:1492952-76-7
Cas Number2:2119669-71-3
Pubchem:72165228
Pubchem2:133082086
Iuphar Ligand:8962
Drugbank:DB12597
Chemspiderid:52085218
Unii:L1F3R18W77
Unii2:C5U34S9XFV
Kegg:D11403
Kegg2:D11404
Chembl:4208229
Chembl2:4297220
Pdb Ligand:AY7
Synonyms:ABL001
Stdinchi:1S/C20H18ClF2N5O3/c21-20(22,23)31-15-3-1-13(2-4-15)26-19(30)12-9-16(17-5-7-25-27-17)18(24-10-12)28-8-6-14(29)11-28/h1-5,7,9-10,14,29H,6,8,11H2,(H,25,27)(H,26,30)/t14-/m1/s1
Stdinchikey:VOVZXURTCKPRDQ-CQSZACIVSA-N
Smiles:O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2ccn[nH]2)c1
Iupac Name:N-4-[chloro(difluoro)methoxy]phenyl]-6-[(3''R'')-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamide;hydrochloride
C:20
H:18
Cl:1
F:2
N:5
O:3

Asciminib, sold under the brand name Scemblix, is a medication used to treat Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML).[7] [8] Asciminib is a protein kinase inhibitor.

The most common adverse reactions include upper respiratory tract infections, musculoskeletal pain, fatigue, nausea, rash, and diarrhea.

Asciminib was approved for medical use in the United States in October 2021,[9] [10] [11] and in the European Union in August 2022.

Mechanism of action

Asciminib is described as a "STAMP inhibitor," which means "specifically targeting the ABL myristoyl pocket." The wild-type ABL has a myristoylated N-terminus, which binds to an allosteric site, but the ABL fusion protein does not have the myristoylated domain. In the wild-type protein, when myristoylated N-terminus binds to the allosteric site, the kinase has reduced activity. Since the mutant fusion protein does not have the myristoylated N-terminus domain, it is not subject to this form of regulation, and thus the fusion protein is constitutively active. Asciminib binds to the allosteric site, resulting in an inhibition of bcr-abl activity.[12]

Unlike other bcr-abl inhibitors, such as imatinib, asciminib does not bind to the ATP-binding site on the active site of the enzyme. Asciminib and active site bcr-abl inhibitors have non-overlapping resistance mutations. The mutations A337V and P223S overcome the inhibitory activity of asciminib,[13] but asciminib is not affected by the notorious T315I mutation that affects most ATP-competitive active site inhibitors, except ponatinib.

Adverse effects

Common side effects of Asciminib are symptoms of a cold, muscle pain, joint pain, bone pain, fatigue, nausea, diarrhea, rash as well as the patient displaying abnormal blood tests.[14] Serious side effects of the medication include high blood pressure, low blood cell count, problems with the pancreas, and heart issues. Side effects of the medication on the pancreas may be observed via changes in serum lipase and amylase levels.[15]

Pharmacodynamics

Asciminib is a substrate of the CYP3A4 enzyme. Asciminib is an inhibitor of CYP3A4, CYP2C9, and P-glycoprotein. Asciminib reaches steady state in 3 days. The volume of distribution of Asciminib is 151 L.

History

The FDA approved asciminib based on evidence from a clinical trial of 48 participants with chronic myeloid leukemia with a certain type of mutation (T315I mutation). The trial was conducted at 18 sites in ten countries (Australia, France, Germany, Italy, Japan, Netherlands, the Republic of Korea, Singapore, Spain, and the United States). Participants received asciminib twice daily until disease worsened or unacceptable toxicity occurred. The benefit of asciminib was evaluated in Philadelphia chromosome-positive chronic myeloid leukemia participants with the T315 mutation by measuring the reduction of abnormal cells in participants' blood to a very low level after 96 weeks of treatment.

Society and culture

Legal status

On 23 June 2022, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Scemblix, intended for the treatment of adults with Philadelphia chromosome‑positive chronic myeloid leukemia in chronic phase who have previously been treated with two or more tyrosine kinase inhibitors. The applicant for this medicinal product is Novartis Europharm Limited.[16] Asciminib was approved for medical use in the European Union in August 2022.[17]

The US Food and Drug Administration (FDA) granted the application for asciminib priority review, fast track, orphan drug, and breakthrough therapy designations.[18] [19] [20]

In July 2024, the US Food and Drug Administration (FDA) granted Priority Review status to asciminib for the treatment of newly diagnosed adult patients with Philadelphia chromosome-positive CML in chronic phase.[21]

Notes and References

  1. Web site: Updates to the Prescribing Medicines in Pregnancy database . Therapeutic Goods Administration (TGA) . 21 December 2022 . 2 January 2023 . 3 April 2022 . https://web.archive.org/web/20220403064059/https://www.tga.gov.au/updates-prescribing-medicines-pregnancy-database . live .
  2. Web site: Scemblix APMDS . Therapeutic Goods Administration (TGA) . 26 July 2022 . 2 August 2022 . 2 August 2022 . https://web.archive.org/web/20220802062710/https://www.tga.gov.au/apm-summary/scemblix . live .
  3. Web site: Scemblix Product information . . 25 April 2012 . 30 September 2022 . 1 October 2022 . https://web.archive.org/web/20221001060757/https://health-products.canada.ca/dpd-bdpp/info.do?lang=en&code=101756 . live .
  4. Web site: Details for: Scemblix . . 1 September 2022 . 3 March 2024 . 3 March 2024 . https://web.archive.org/web/20240303064243/https://dhpp.hpfb-dgpsa.ca/dhpp/resource/101756 . live .
  5. Web site: Scemblix- asciminib tablet, film coated . DailyMed . 4 November 2021 . 5 November 2021 . https://web.archive.org/web/20211105020750/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=e33001e7-3650-42b1-ae56-cddb5c43aa2b . live .
  6. Web site: Scemblix EPAR . European Medicines Agency (EMA) . 20 June 2022 . 8 September 2022 . 9 September 2022 . https://web.archive.org/web/20220909053136/https://www.ema.europa.eu/en/medicines/human/EPAR/scemblix . live . Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  7. FDA approves asciminib for Philadelphia chromosome-positive chronic myeloid leukemia . U.S. Food and Drug Administration (FDA) . 29 October 2021 . 4 November 2021 . 4 November 2021 . https://web.archive.org/web/20211104192914/https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-asciminib-philadelphia-chromosome-positive-chronic-myeloid-leukemia . live .
  8. Breccia M, Colafigli G, Scalzulli E, Martelli M . Asciminib: an investigational agent for the treatment of chronic myeloid leukemia . Expert Opinion on Investigational Drugs . 30 . 8 . 803–811 . August 2021 . 34130563 . 10.1080/13543784.2021.1941863 . 235450899 .
  9. Web site: Drug Trials Snapshots: Scemblix . U.S. Food and Drug Administration (FDA) . 17 May 2023 . 2 June 2023.
  10. Web site: Drug Approval Package: Scemblix . U.S. Food and Drug Administration (FDA) . 24 November 2021 . 2 June 2023.
  11. FDA approves Novartis Scemblix (asciminib), with novel mechanism of action for the treatment of chronic myeloid leukemia . Novartis . 29 October 2021 . 29 October 2021 . https://web.archive.org/web/20211029223728/https://www.novartis.com/news/media-releases/fda-approves-novartis-scemblix-asciminib-novel-mechanism-action-treatment-chronic-myeloid-leukemia . live .
  12. Schoepfer J, Jahnke W, Berellini G, Buonamici S, Cotesta S, Cowan-Jacob SW, Dodd S, Drueckes P, Fabbro D, Gabriel T, Groell JM, Grotzfeld RM, Hassan AQ, Henry C, Iyer V, Jones D, Lombardo F, Loo A, Manley PW, Pellé X, Rummel G, Salem B, Warmuth M, Wylie AA, Zoller T, Marzinzik AL, Furet P . 6 . Discovery of Asciminib (ABL001), an Allosteric Inhibitor of the Tyrosine Kinase Activity of BCR-ABL1 . Journal of Medicinal Chemistry . 61 . 18 . 8120–8135 . September 2018 . 30137981 . 10.1021/acs.jmedchem.8b01040 . 52073282 . free .
  13. Jones JK, Thompson EM . Allosteric Inhibition of ABL Kinases: Therapeutic Potential in Cancer . Molecular Cancer Therapeutics . 19 . 9 . 1763–1769 . September 2020 . 32606014 . 7484003 . 10.1158/1535-7163.MCT-20-0069 .
  14. Web site: Asciminib Uses, Side Effects & Warnings . 21 June 2022 . Drugs.com . en . 21 June 2022 . https://web.archive.org/web/20220621181047/https://www.drugs.com/mtm/asciminib.html . live .
  15. Web site: Scemblix (asciminib) dosing, indications, interactions, adverse effects, and more . 27 June 2022 . reference.medscape.com . 2 August 2022 . https://web.archive.org/web/20220802062703/https://reference.medscape.com/drug/scemblix-asciminib-4000255#5 . live .
  16. Web site: Scemblix: Pending EC decision . European Medicines Agency . 23 June 2022 . 26 June 2022 . 26 June 2022 . https://web.archive.org/web/20220626031706/https://www.ema.europa.eu/en/medicines/human/summaries-opinion/scemblix . live . Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  17. Web site: Scemblix Product information . Union Register of medicinal products . 3 March 2023 . 3 March 2023 . https://web.archive.org/web/20230303202247/https://ec.europa.eu/health/documents/community-register/html/h1670.htm . live .
  18. Web site: Asciminib Orphan Drug Designations and Approvals . U.S. Food and Drug Administration (FDA) . 27 February 2017 . 29 October 2021 . 29 October 2021 . https://web.archive.org/web/20211029225012/https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=556416 . live .
  19. Novartis receives FDA Breakthrough Therapy designations for investigational STAMP inhibitor asciminib (ABL001) in chronic myeloid leukemia . Novartis . 8 February 2020 . 29 October 2021 . 29 October 2021 . https://web.archive.org/web/20211029224844/https://www.novartis.com/news/media-releases/novartis-receives-fda-breakthrough-therapy-designations-investigational-stamp-inhibitor-asciminib-abl001-chronic-myeloid-leukemia . live .
  20. Advancing Health Through Innovation: New Drug Therapy Approvals 2021 . U.S. Food and Drug Administration (FDA) . 13 May 2022 . PDF . 22 January 2023 . 6 December 2022 . https://web.archive.org/web/20221206210020/https://www.fda.gov/media/155227/download . live .
  21. Web site: Priyan . Vishnu . 2024-07-30 . FDA grants priority review for Novartis’ leukaemia treatment . 2024-07-30 . Pharmaceutical Technology . en-US.

This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Asciminib".

Except where otherwise indicated, Everything.Explained.Today is © Copyright 2009-2024, A B Cryer, All Rights Reserved. Cookie policy.