Inventory of research progress on the new mechanism drug Asciminib for chronic myeloid leukemia

ATP-competitive tyrosine kinase inhibitor (TKI) targeting BCR-ABL1 is the main drug for the treatment of chronic myeloid leukemia (CML)
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Although TKI greatly reduces the mortality of CML patients and improves the long-term survival outcome, there are still some patients with treatment failure, and the more treatment lines, the worse the prognosis
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Therefore, CML patients who are resistant/intolerant to two or more TKIs still have great unmet needs, and there is an urgent need to optimize treatment drugs to break the situation
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The emergence of a new BCR-ABL allosteric inhibitor (Asciminib) has ignited hope for TKI-resistant/intolerant CML patients
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Background Although the use of ATP-competitive TKI targeting BCR-ABL1 has greatly improved the long-term survival outcomes of CML patients, there are still some patients who develop drug resistance and/or intolerance and require dressing changes (Table 1)
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According to the European Treatment and Outcome Study (EUTOS), 28% of patients treated with imatinib and 20%-22% of patients treated with second-generation TKIs require dressing change
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Asciminib is a new type of BCR-ABL allosteric inhibitor, which not only has TKI-level curative effect, but also reduces off-target effects
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This article describes the mechanism of action of Asciminib (in vitro study data) and completed/in progress/future clinical trials
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Table 1.
TKI remarks that can be used for second-line treatment and above: ALT, glutamate aminotransferase; AST, aspartate aminotransferase; CCyR, complete cytogenetic remission; CHR, complete hematological remission; CML, chronic myelogenous leukemia; MCyR , The main cytogenetic response; MR4.
5, 4.
5-Log molecular response (BCR-ABL1IS ≤0.
0032%); OS, overall survival rate; PFS, progression-free survival rate; TKI, tyrosine kinase inhibitor
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The mechanism of action and pharmacokinetics of Asciminib The myristoyl pocket in ABL kinase is its own negative regulatory site.
It initiates allosteric regulation by binding to the myristoylated N-terminus of ABL itself, so that ABL kinase maintains an inhibitory conformation.

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In CML, the BCR protein replaces the original N-terminus of ABL1, making the pocket lose its regulatory function
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Asciminib strongly binds to the BCR-ABL1 myristoyl pocket (Kd[dissociation constant]=0.
5 nM-0.
8 nM) to restore the inhibition of ABL kinase
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Asciminib has high specificity (IC50=1-20 nM) and high selectivity
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In vitro research data show that Asciminib is active against mutations in common resistance sites of TKIs (including T315I), and the combination of Asciminib and traditional TKIs (such as nilotinib) is an effective strategy to combat mutation resistance
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Human pharmacokinetic results show that after a single administration of Asciminib, as the exposure dose ratio increases, the drug is rapidly absorbed (median Tmax [peak time] 2-3 hours); after repeated administration, Asciminib drug There is a small amount (<2 times) to moderate (about 2 times) accumulation in the body; the half-life of Asciminib is 5-6 hours
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Asciminib clinical data summary table 2.
Asciminib single agent or combined TKI treatment efficacy and safety data Remarks: ALT, glutamate aminotransferase; AST, aspartate aminotransferase; CCyR, complete cytogenetic remission; CHR, complete hematological remission ; CML, chronic myeloid leukemia; DMR, deep molecular response; MCyR, major cytogenetic response; MMR, major molecular response; MR4, 4.
0-Log molecular response (BCR-ABL1IS ≤0.
01%); MR4.
5 , 4.
5-Log molecular response (BCR-ABL1IS ≤0.
0032%); OS, overall survival rate; PFS, progression-free survival rate; TKI, tyrosine kinase inhibitor
.

Asciminib ongoing trials Various trials evaluating Asciminib are ongoing, including Asciminib as a single agent or Asciminib combined with TKIs for the treatment of newly diagnosed patients (NCT04666259 and NCT03906292)/previously treated patients (NCT04216563, NCT03578367 or ASK4MORE) (Table 3 )
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The NCT03605277 and NCT02857868 trials are designed to explore the pharmacokinetics and safety of Asciminib in patients with renal impairment and liver impairment, respectively
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Spain reported a patient who used Asciminib for sympathetic medication outside of clinical trials.
At a median time of 8.
8 months, the cumulative incidence of complete cytogenetic remission and the cumulative incidence of MMR were 48% and 33%, respectively.
And its safety results are consistent with those reported in the Phase 1 clinical study
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Table 3.
Remarks on ongoing clinical trials of Asciminib: ALL, acute lymphoblastic leukemia; CML, chronic myelogenous leukemia
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Conclusions and expert opinions Asciminib is a very promising CML treatment drug, and may be an effective choice for third-line CML and T315I positive patients
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In the future, further research is needed to clarify which patients can benefit from Asciminib treatment
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Due to the different mechanism of action of Asciminib, the resistance mutation spectrum of Asciminib and ATP-competitive TKI drugs does not overlap
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Asciminib-related rare mutations are still sensitive to second-generation TKI drugs
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Due to the high selectivity of BCR-ABL, Asciminib has very few off-target effects, is well tolerated and has fewer adverse events (such as fatigue and headache)
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As Asciminib is associated with elevated amylase/lipase levels, monitoring of pancreatic enzymes is required during treatment
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After a brief discontinuation of the drug, the increased amylase/lipase is reversible, and the increase in amylase/lipase levels is usually not associated with clinical pancreatitis
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The use of Asciminib in patients with specific mutations is affected by concurrent diseases, which may hinder the use of multi-target drugs, and possible cardiovascular and/or pulmonary off-target effects should be avoided
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Ongoing and future trials will evaluate Asciminib for first-line treatment or for treatment in patients who do not respond well
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These results will help us understand the patients receiving Asciminib treatment to optimize and predict the deep molecular response, thereby increasing the success rate of drug withdrawal
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Reference: Breccia M, et al.
Asciminib: an investigational agent for the treatment of chronic myeloid leukemia.
Expert Opin Investig Drugs.
2021 Aug;30(8):803-811.
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