Asciminib

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Asciminib
Asciminib.svg
Clinical data
Trade names Scemblix
Other namesABL001
License data
Pregnancy
category
Routes of
administration 		By mouth
Drug class Tyrosine kinase inhibitor
ATC code
Legal status
Legal status
Identifiers
  • N-4-[chloro(difluoro)methoxy]phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamide;hydrochloride
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
PDB ligand
Chemical and physical data
Formula C20H18ClF2N5O3
Molar mass 449.84 g·mol−1
3D model (JSmol)
  • O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2ccn[nH]2)c1
  • InChI=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
  • Key:VOVZXURTCKPRDQ-CQSZACIVSA-N

Asciminib, sold under the brand name Scemblix, is a medication used to treat Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML). [4] [6] [7] Asciminib is a protein kinase inhibitor. [4]

Contents

The most common adverse reactions include upper respiratory tract infections, musculoskeletal pain, fatigue, nausea, rash, and diarrhea. [6]

Asciminib was approved for medical use in the United States in October 2021, [4] [8] [9] [10] and in the European Union in August 2022. [5]

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. [11]

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, [12] 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. [13] Serious side effects of the medication include high blood pressure, low blood cell count, problems with the pancreas, and heart issues. [13] Side effects of the medication on the pancreas may be observed via changes in serum lipase and amylase levels. [14]

Pharmacodynamics

Asciminib is a substrate of the CYP3A4 enzyme. [14] Asciminib is an inhibitor of CYP3A4, CYP2C9, and P-glycoprotein. [14] Asciminib reaches steady state in 3 days. The volume of distribution of Asciminib is 151 L. [14]

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). [8] 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). [8] Participants received asciminib twice daily until disease worsened or unacceptable toxicity occurred. [8] 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. [8]

Society and culture

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. [15] The applicant for this medicinal product is Novartis Europharm Limited. [15] Asciminib was approved for medical use in the European Union in August 2022. [5] [16]

The US Food and Drug Administration (FDA) granted the application for asciminib priority review, fast track, orphan drug, and breakthrough therapy designations. [6] [17] [18] [19]

Related Research Articles

<span class="mw-page-title-main">Tyrosine kinase</span> Class hi residues

A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to the tyrosine residues of specific proteins inside a cell. It functions as an "on" or "off" switch in many cellular functions.

<span class="mw-page-title-main">Philadelphia chromosome</span> Genetic abnormality in leukemia cancer cells

The Philadelphia chromosome or Philadelphia translocation (Ph) is a specific genetic abnormality in chromosome 22 of leukemia cancer cells. This chromosome is defective and unusually short because of reciprocal translocation, t(9;22)(q34;q11), of genetic material between chromosome 9 and chromosome 22, and contains a fusion gene called BCR-ABL1. This gene is the ABL1 gene of chromosome 9 juxtaposed onto the breakpoint cluster region BCR gene of chromosome 22, coding for a hybrid protein: a tyrosine kinase signaling protein that is "always on", causing the cell to divide uncontrollably by interrupting the stability of the genome and impairing various signaling pathways governing the cell cycle.

<span class="mw-page-title-main">Chronic myelogenous leukemia</span> Medical condition

Chronic myelogenous leukemia (CML), also known as chronic myeloid leukemia, is a cancer of the white blood cells. It is a form of leukemia characterized by the increased and unregulated growth of myeloid cells in the bone marrow and the accumulation of these cells in the blood. CML is a clonal bone marrow stem cell disorder in which a proliferation of mature granulocytes and their precursors is found; characteristic increase in basophils is clinically relevant. It is a type of myeloproliferative neoplasm associated with a characteristic chromosomal translocation called the Philadelphia chromosome.

<span class="mw-page-title-main">Imatinib</span> Chemical compound

Imatinib, sold under the brand names Gleevec and Glivec (both marketed worldwide by Novartis) among others, is an oral targeted therapy medication used to treat cancer. Imatinib is a small molecule inhibitor targeting multiple tyrosine kinases such as CSF1R, ABL, c-KIT, FLT3, and PDGFR-β. Specifically, it is used for chronic myelogenous leukemia (CML) and acute lymphocytic leukemia (ALL) that are Philadelphia chromosome–positive (Ph+), certain types of gastrointestinal stromal tumors (GIST), hypereosinophilic syndrome (HES), chronic eosinophilic leukemia (CEL), systemic mastocytosis, and myelodysplastic syndrome.

<span class="mw-page-title-main">Nilotinib</span> Chemical compound

Nilotinib, sold under the brand name Tasigna marketed worldwide by Novartis, is a medication used to treat chronic myelogenous leukemia (CML) which has the Philadelphia chromosome. It may be used both in initial cases of chronic phase CML as well as in accelerated and chronic phase CML that has not responded to imatinib. It is taken by mouth.

<span class="mw-page-title-main">Dasatinib</span> Chemical compound

Dasatinib, sold under the brand name Sprycel among others, is a targeted therapy medication used to treat certain cases of chronic myelogenous leukemia (CML) and acute lymphoblastic leukemia (ALL). Specifically it is used to treat cases that are Philadelphia chromosome-positive (Ph+). It is taken by mouth.

<span class="mw-page-title-main">Acute myeloblastic leukemia with maturation</span> Medical condition

Acute myeloblastic leukemia with maturation (M2) is a subtype of acute myeloid leukemia (AML).

<span class="mw-page-title-main">Axitinib</span> Chemical compound

Axitinib, sold under the brand name Inlyta, is a small molecule tyrosine kinase inhibitor developed by Pfizer. It has been shown to significantly inhibit growth of breast cancer in animal (xenograft) models and has shown partial responses in clinical trials with renal cell carcinoma (RCC) and several other tumour types.

<span class="mw-page-title-main">Bosutinib</span> Chemical compound

Bosutinib, sold under the brand name Bosulif, is a small molecule BCR-ABL and src tyrosine kinase inhibitor used for the treatment of chronic myelogenous leukemia.

<span class="mw-page-title-main">ARIAD Pharmaceuticals</span> Defunct oncology company

ARIAD Pharmaceuticals, Inc. was an American oncology company, now part of Takeda Oncology, which was founded in 1991 by Harvey J. Berger, M.D. and headquartered in Cambridge, Massachusetts. ARIAD engaged in the discovery, development, and commercialization of medicines for cancer patients.

<span class="mw-page-title-main">Nicholas Lydon</span> British biochemist

Nicholas B. Lydon FRS is a British scientist and entrepreneur. In 2009, he was awarded the Lasker Clinical Award and in 2012 the Japan Prize for the development of Gleevec, also known as Imatinib, a selective BCR-ABL inhibitor for the treatment of chronic myeloid leukaemia (CML), which converted a fatal cancer into a manageable chronic condition.

<span class="mw-page-title-main">Tyrosine kinase inhibitor</span> Drug typically used in cancer treatment

A tyrosine kinase inhibitor (TKI) is a pharmaceutical drug that inhibits tyrosine kinases. Tyrosine kinases are enzymes responsible for the activation of many proteins by signal transduction cascades. The proteins are activated by adding a phosphate group to the protein (phosphorylation), a step that TKIs inhibit. TKIs are typically used as anticancer drugs. For example, they have substantially improved outcomes in chronic myelogenous leukemia. They have also been used to treat other diseases, such as idiopathic pulmonary fibrosis.

Bcr-Abl tyrosine-kinase inhibitors (TKI) are the first-line therapy for most patients with chronic myelogenous leukemia (CML). More than 90% of CML cases are caused by a chromosomal abnormality that results in the formation of a so-called Philadelphia chromosome. This abnormality was discovered by Peter Nowell in 1960 and is a consequence of fusion between the Abelson (Abl) tyrosine kinase gene at chromosome 9 and the break point cluster (Bcr) gene at chromosome 22, resulting in a chimeric oncogene (Bcr-Abl) and a constitutively active Bcr-Abl tyrosine kinase that has been implicated in the pathogenesis of CML. Compounds have been developed to selectively inhibit the tyrosine kinase.

Quizartinib, sold under the brand name Vanflyta, is an anti-cancer medication used for the treatment of acute myeloid leukemia.

<span class="mw-page-title-main">Midostaurin</span> Chemical compound

Midostaurin, sold under the brand name Rydapt & Tauritmo both by Novartis, is a multi-targeted protein kinase inhibitor that has been investigated for the treatment of acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) and advanced systemic mastocytosis. It is a semi-synthetic derivative of staurosporine, an alkaloid from the bacterium Streptomyces staurosporeus.

<span class="mw-page-title-main">Ponatinib</span> Oral drug

Ponatinib, sold under the brand name Iclusig, is a medication developed by ARIAD Pharmaceuticals for the treatment of chronic myeloid leukemia (CML) and Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL). It is a multi-targeted tyrosine-kinase inhibitor. Some forms of CML, those that have the T315I mutation, are resistant to current therapies such as imatinib. Ponatinib has been designed to be effective against these types of tumors.

<span class="mw-page-title-main">Radotinib</span> Chemical compound

Radotinib (INN; trade name Supect), and sometimes referred to by its investigational name IY5511, is a drug for the treatment of different types of cancer, most notably Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) with resistance or intolerance of other Bcr-Abl tyrosine-kinase inhibitors, such as patients resistant or intolerant to imatinib.

<span class="mw-page-title-main">Venetoclax</span> Medication

Venetoclax, sold under the brand names Venclexta and Venclyxto, is a medication used to treat adults with chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), or acute myeloid leukemia (AML).

<span class="mw-page-title-main">Bafetinib</span> Chemical compound

Bafetinib (NS-187) is an experimental cancer drug developed by Nippon Shinyaku and licensed to CytRx. It is an inhibitor of Lyn and Bcr-Abl. It reached phase II clinical trials in 2010.

<span class="mw-page-title-main">Ivosidenib</span> Anti-cancer medication

Ivosidenib, sold under the brand name Tibsovo, is an anti-cancer medication for the treatment of acute myeloid leukemia (AML) and cholangiocarcinoma. It is a small molecule inhibitor of isocitrate dehydrogenase-1 (IDH1), which is mutated in several forms of cancer. Ivosidenib is an isocitrate dehydrogenase-1 inhibitor that works by decreasing abnormal production of the oncometabolite 2-hydroxyglutarate (2-HG), leading to differentiation of malignant cells.

References

  1. 1 2 "Scemblix APMDS". Therapeutic Goods Administration (TGA). 26 July 2022. Archived from the original on 2 August 2022. Retrieved 2 August 2022.
  2. ↑ "Updates to the Prescribing Medicines in Pregnancy database". Therapeutic Goods Administration (TGA). 21 December 2022. Archived from the original on 3 April 2022. Retrieved 2 January 2023.
  3. ↑ "Scemblix Product information". Health Canada. 25 April 2012. Archived from the original on 1 October 2022. Retrieved 30 September 2022.
  4. 1 2 3 4 "Scemblix- asciminib tablet, film coated". DailyMed. Archived from the original on 5 November 2021. Retrieved 4 November 2021.
  5. 1 2 3 "Scemblix EPAR". European Medicines Agency (EMA). 20 June 2022. Archived from the original on 9 September 2022. Retrieved 8 September 2022. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  6. 1 2 3 "FDA approves asciminib for Philadelphia chromosome-positive chronic myeloid leukemia". U.S. Food and Drug Administration (FDA) (Press release). 29 October 2021. Archived from the original on 4 November 2021. Retrieved 4 November 2021.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  7. ↑ Breccia M, Colafigli G, Scalzulli E, Martelli M (August 2021). "Asciminib: an investigational agent for the treatment of chronic myeloid leukemia". Expert Opinion on Investigational Drugs. 30 (8): 803–811. doi:10.1080/13543784.2021.1941863. PMID   34130563. S2CID   235450899.
  8. 1 2 3 4 5 "Drug Trials Snapshots: Scemblix". U.S. Food and Drug Administration (FDA). 17 May 2023. Retrieved 2 June 2023.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  9. ↑ "Drug Approval Package: Scemblix". U.S. Food and Drug Administration (FDA). 24 November 2021. Retrieved 2 June 2023.
  10. ↑ "FDA approves Novartis Scemblix (asciminib), with novel mechanism of action for the treatment of chronic myeloid leukemia". Novartis (Press release). Archived from the original on 29 October 2021. Retrieved 29 October 2021.
  11. ↑ Schoepfer J, Jahnke W, Berellini G, Buonamici S, Cotesta S, Cowan-Jacob SW, et al. (September 2018). "Discovery of Asciminib (ABL001), an Allosteric Inhibitor of the Tyrosine Kinase Activity of BCR-ABL1". Journal of Medicinal Chemistry. 61 (18): 8120–8135. doi: 10.1021/acs.jmedchem.8b01040 . PMID   30137981. S2CID   52073282.
  12. ↑ Jones JK, Thompson EM (September 2020). "Allosteric Inhibition of ABL Kinases: Therapeutic Potential in Cancer". Molecular Cancer Therapeutics. 19 (9): 1763–1769. doi:10.1158/1535-7163.MCT-20-0069. PMC   7484003 . PMID   32606014.
  13. 1 2 "Asciminib Uses, Side Effects & Warnings". Drugs.com. Archived from the original on 21 June 2022. Retrieved 21 June 2022.
  14. 1 2 3 4 "Scemblix (asciminib) dosing, indications, interactions, adverse effects, and more". reference.medscape.com. Archived from the original on 2 August 2022. Retrieved 27 June 2022.
  15. 1 2 "Scemblix: Pending EC decision". European Medicines Agency. 23 June 2022. Archived from the original on 26 June 2022. Retrieved 26 June 2022. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  16. ↑ "Scemblix Product information". Union Register of medicinal products. Archived from the original on 3 March 2023. Retrieved 3 March 2023.
  17. ↑ "Asciminib Orphan Drug Designations and Approvals". U.S. Food and Drug Administration (FDA). 27 February 2017. Archived from the original on 29 October 2021. Retrieved 29 October 2021.
  18. ↑ "Novartis receives FDA Breakthrough Therapy designations for investigational STAMP inhibitor asciminib (ABL001) in chronic myeloid leukemia". Novartis (Press release). 8 February 2020. Archived from the original on 29 October 2021. Retrieved 29 October 2021.
  19. ↑ Advancing Health Through Innovation: New Drug Therapy Approvals 2021 (PDF). U.S. Food and Drug Administration (FDA) (Report). 13 May 2022. Archived from the original on 6 December 2022. Retrieved 22 January 2023.PD-icon.svg This article incorporates text from this source, which is in the public domain .
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