Asciminib

Asciminib is indicated for the treatment of adults with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase, previously treated with two or more tyrosine kinase inhibitors; or Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase with the T315I mutation.

In October 2024, the US Food and Drug Administration (FDA) expanded the indicated to include people with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase.{{cite web | title=Cancer Accelerated Approvals | website=U.S. Food and Drug Administration (FDA) | date=1 October 2024 | url=https://www.fda.gov/drugs/resources-information-approved-drugs/ongoing-cancer-accelerated-approvals | access-date=6 December 2024}}

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.{{Cite web |title=Asciminib Uses, Side Effects & Warnings |url=https://www.drugs.com/mtm/asciminib.html |access-date=21 June 2022 |website=Drugs.com |archive-date=21 June 2022 |archive-url=https://web.archive.org/web/20220621181047/https://www.drugs.com/mtm/asciminib.html |url-status=live }} 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.{{Cite web |title=Scemblix (asciminib) dosing, indications, interactions, adverse effects, and more |url=https://reference.medscape.com/drug/scemblix-asciminib-4000255#5 |access-date=27 June 2022 |website=reference.medscape.com |archive-date=2 August 2022 |archive-url=https://web.archive.org/web/20220802062703/https://reference.medscape.com/drug/scemblix-asciminib-4000255#5 |url-status=live }}

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.{{cite journal | vauthors = 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 | display-authors = 6 | title = Discovery of Asciminib (ABL001), an Allosteric Inhibitor of the Tyrosine Kinase Activity of BCR-ABL1 | journal = Journal of Medicinal Chemistry | volume = 61 | issue = 18 | pages = 8120–8135 | date = September 2018 | pmid = 30137981 | doi = 10.1021/acs.jmedchem.8b01040 | s2cid = 52073282 | doi-access = free }}

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,{{cite journal | vauthors = Jones JK, Thompson EM | title = Allosteric Inhibition of ABL Kinases: Therapeutic Potential in Cancer | journal = Molecular Cancer Therapeutics | volume = 19 | issue = 9 | pages = 1763–1769 | date = September 2020 | pmid = 32606014 | pmc = 7484003 | doi = 10.1158/1535-7163.MCT-20-0069 }} but asciminib is not affected by the notorious T315I mutation that affects most ATP-competitive active site inhibitors, except ponatinib.

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

The efficacy of asciminib in the treatment of participants with Ph+ CML-CP with the T315I mutation was evaluated in a multi-center open-label study CABL001X2101 (NCT02081378). Testing for T315I mutation utilized a qualitative p210 BCR-ABL mutation test using Sanger Sequencing.

The US Food and Drug Administration (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.

The efficacy of asciminib in the treatment of participants with Ph+ CML in chronic phase (Ph+ CML-CP), previously treated with two or more tyrosine kinase inhibitors was evaluated in the multi-center, randomized, active-controlled, and open-label study ASCEMBL (NCT 03106779).

The efficacy of asciminib in the treatment of participants with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase was evaluated in the multi-center, randomized, active-controlled, and open-label study ASC4FIRST (NCT04971226). A total of 405 participants were randomized (1:1) to receive either asciminib or investigator-selected tyrosine kinase inhibitors (IS-TKIs) (imatinib, nilotinib, dasatinib, or bosutinib). The main efficacy outcome measure was major molecular response rate at 48 weeks. The major molecular response rate at 48 weeks was 68% (95% CI: 61, 74) in the asciminib arm and 49% (95% CI: 42, 56) in the IS-TKIs arm (difference 19% [95% CI: 10, 28], p-value <0.001). Within the imatinib stratum, the major molecular response rate was 69% (95% CI: 59, 78) in the asciminib arm and 40% (95% CI: 31, 50) in the IS-TKIs arm (difference 30% [95% CI: 17, 42], p-value <0.001).

In June 2022, 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 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.{{cite web | title=Scemblix: Pending EC decision | website=European Medicines Agency | date=23 June 2022 | url=https://www.ema.europa.eu/en/medicines/human/summaries-opinion/scemblix | access-date=26 June 2022 | archive-date=26 June 2022 | archive-url=https://web.archive.org/web/20220626031706/https://www.ema.europa.eu/en/medicines/human/summaries-opinion/scemblix | url-status=live }} Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged. Asciminib was approved for medical use in the European Union in August 2022.{{cite web | title=Scemblix Product information | website=Union Register of medicinal products | url=https://ec.europa.eu/health/documents/community-register/html/h1670.htm | access-date=3 March 2023 | archive-date=3 March 2023 | archive-url=https://web.archive.org/web/20230303202247/https://ec.europa.eu/health/documents/community-register/html/h1670.htm | url-status=live }}

The US Food and Drug Administration (FDA) granted the application for asciminib priority review, fast track, orphan drug, and breakthrough therapy designations.{{cite web | title=Asciminib Orphan Drug Designations and Approvals | website=U.S. Food and Drug Administration (FDA) | date=27 February 2017 | url=https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=556416 | access-date=29 October 2021 | archive-date=29 October 2021 | archive-url=https://web.archive.org/web/20211029225012/https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=556416 | url-status=live }}{{cite press release | title=Novartis receives FDA Breakthrough Therapy designations for investigational STAMP inhibitor asciminib (ABL001) in chronic myeloid leukemia | website=Novartis | date=8 February 2020 | url=https://www.novartis.com/news/media-releases/novartis-receives-fda-breakthrough-therapy-designations-investigational-stamp-inhibitor-asciminib-abl001-chronic-myeloid-leukemia | access-date=29 October 2021 | archive-date=29 October 2021 | archive-url=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 | url-status=live }}{{cite report | title=Advancing Health Through Innovation: New Drug Therapy Approvals 2021 | website=U.S. Food and Drug Administration (FDA) | date=13 May 2022 | url=https://www.fda.gov/media/155227/download | format=PDF | access-date=22 January 2023 | archive-date=6 December 2022 | archive-url=https://web.archive.org/web/20221206210020/https://www.fda.gov/media/155227/download | url-status=live }} {{PD-notice}}

In July 2024, the US Food and Drug Administration (FDA) granted priority review designation to asciminib for the treatment of newly diagnosed adults with Philadelphia chromosome-positive CML in chronic phase.{{Cite web |last=Priyan |first=Vishnu |date=2024-07-30 |title=FDA grants priority review for Novartis' leukaemia treatment |url=https://www.pharmaceutical-technology.com/news/fda-novartis-leukaemia-treatment/ |access-date=2024-07-30 |website=Pharmaceutical Technology }} The FDA granted accelerated approval to asciminib for adults with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in chronic phase (CP). The applicant was Novartis AG.{{cite web | title=FDA grants accelerated approval to asciminib for newly diagnosed chronic myeloid leukemia | website=U.S. Food and Drug Administration (FDA) | date=29 October 2024 | url=https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-asciminib-newly-diagnosed-chronic-myeloid-leukemia | access-date=30 October 2024 }} {{PD-notice}}

{{reflist}}

• {{ClinicalTrialsGov|NCT02081378|A Phase I Study of Oral ABL001 in Patients With CML or Ph+ ALL}}
• {{ClinicalTrialsGov|NCT03106779|Study of Efficacy of CML-CP Patients Treated With ABL001 Versus Bosutinib, Previously Treated With 2 or More TKIs}}
• {{ClinicalTrialsGov|NCT04971226|A Study of Oral Asciminib Versus Other TKIs in Adults With Newly Diagnosed Ph+ CML-CP}}

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Category:Non-receptor tyrosine kinase inhibitors

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