Action and Spectrum

Actions and Spectrum: 

asciminib is a small-molecule drug that belongs to class of drugs known as kinase inhibitors. It is specifically designed to target and inhibit a protein called ABL1, a tyrosine kinase involved in developing and progressing certain types of leukemia, mainly chronic myeloid leukemia (CML). asciminib works by binding to a specific region of the ABL1 protein, known as the myristoyl pocket, thereby preventing its activity. 

The action of asciminib is unique compared to other available tyrosine kinase inhibitors used in treating CML. While other drugs, such as imatinib, dasatinib, and nilotinib, target the active site of the ABL1 protein, asciminib targets a different region, the myristoyl pocket. This alternative binding site allows asciminib to overcome specific resistance mutations that can develop in the ABL1 protein, making it effective against CML resistant to other tyrosine kinase inhibitors. 

By inhibiting the ABL1 protein, asciminib helps reduce leukemia cells’ growth and survival, ultimately leading to the suppression of the disease. It is primarily used to treat chronic phase chronic myeloid leukemia (CP-CML) in patients who have previously received one or more tyrosine kinase inhibitors and have developed resistance or intolerance to them. 

The spectrum of activity of asciminib is limited to the inhibition of ABL1 kinase and its activity against specific mutations that confer resistance to other tyrosine kinase inhibitors. It is not effective against other tyrosine kinases or different types of cancers unrelated to CML. Therefore, asciminib’s therapeutic use is limited to treating CP-CML patients with specific resistance mutations and has exhausted other treatment options. 

Drug Interaction

Adverse Reaction

Frequency defined 

>10% 

Prior treated Ph+ CP-CML 

Neutrophil count decreased (39%) 

Hemoglobin decreased (35%) 

Hypertension (13%) 

Amylase increased (12%) 

Platelet count decreased (46%) 

Cholesterol increased (11%) 

Lymphocyte count decreased (18%) 

Musculoskeletal pain (22%) 

Bilirubin increased (12%) 

Fatigue (17%) 

Uric acid increased (19%) 

Diarrhea (12%) 

ALT increased (23%) 

Calcium corrected decreased (14%) 

Rash (17%) 

Creatine kinase increased (27%) 

Headache (19%) 

AST increased (19%) 

Nausea (12%) 

Creatinine increased (14%) 

Upper respiratory tract infection (26%) 

Lipase increased (14%) 

Arthralgia (12%) 

Phosphate decreased (17%) 

Ph+ CP-CML with the T3151 mutation 

Hemoglobin decreased (44%) 

Bilirubin increased (23%) 

Cough (15%) 

Nausea (27%) 

Lipase increased (46%) 

Creatinine increased (31%) 

AST increased (35%) 

Phosphate decreased (40%) 

Musculoskeletal pain (42%) 

Potassium increased (48%) 

Alkaline phosphate increased (13%) 

Neutrophil count decreased (44%) 

Pruritus (13%) 

Rash (27%) 

Platelet count decreased (25%) 

Cholesterol increased (15%) 

Vomiting (19%) 

Calcium corrected decreased (33%) 

Amylase increased (29%) 

Headache (19%) 

Hypertension (13%) 

Lymphocyte count decreased (42%) 

Diarrhea (21%) 

Arthralgia (17%) 

Hemorrhage (15%) 

Fatigue (31%) 

Upper respiratory tract infection (13%) 

Creatine kinase increased (27%) 

1-10% 

Prior treated Ph+ CP-CML 

Urticaria (<10%) 

Dizziness (<10%) 

Pruritus (<10%) 

Pneumonia (<10%) 

Hemorrhage (<10%) 

Arrhythmia (including electrocardiogram QT prolonged) (<10%) 

Constipation (<10%) 

Vision blurred (<10%) 

Edema (<10%) 

Lower respiratory tract infection (<10%) 

Abdominal pain (10%) 

Vomiting (<10%) 

Hypothyroidism (<10%) 

Palpitations (<10%) 

Dry eye (<10%) 

Dyspnea (<10%) 

Peripheral neuropathy (<10%) 

Influenza (<10%) 

Pyrexia (<10%) 

Cardiac failure congestive (<10%) 

Potassium decreased (10%) 

Cough (<10%) 

Decreased appetite (<10%) 

Pleural effusion (<10%) 

Urinary tract infection (<10%) 

Constipation (<10%) 

Febrile neutropenia (<10%) 

Ph+ CP-CML with the T3151 mutation 

Lower respiratory tract infection (<10%) 

Dyspnea (<10%) 

Dizziness (<10%) 

Dry eye (<10%) 

Constipation (<10%) 

Dyslipidemia (<10%) 

Cardiac failure congestive (<10%) 

Vision blurred (<10%) 

Urticaria (<10%) 

Pyrexia (<10%) 

Palpitations (<10%) 

Arrhythmia (<10%) 

Pleural effusion (<10%) 

Pancreatitis (<10%) 

Pneumonia (<10%) 

Decreased appetite (<10%) 

Black Box Warning

Black Box Warning: 

None 

Contraindication / Caution

Contraindication/Caution: 

Contraindication 

None 

Caution 

While specific cautions associated with asciminib may vary based on regulatory approvals and country-specific guidelines, here are some general cautions to consider: 

• Hepatic Impairment: asciminib may potentially cause liver toxicity. Caution should be exercised when prescribing asciminib to patients with pre-existing liver disease or impaired liver function. Regular monitoring of LFT (liver function tests) is recommended during treatment. 
• QT Interval Prolongation: asciminib may prolong the QT interval, which could increase the risk of serious cardiac arrhythmias. It should be generally used cautiously in patients with a history of or predisposition to QT interval prolongation or those taking medications known to prolong the QT interval. Electrocardiogram (ECG) monitoring may be necessary. 
• Hemorrhage: asciminib may increase the risk of bleeding. Caution should be exercised in individuals with a history of bleeding disorders or those receiving anticoagulant therapy. Close monitoring for signs of bleeding, such as easy bruising, petechiae, or gastrointestinal bleeding, is essential. 
• Fluid Retention: asciminib may cause fluid retention, including peripheral edema and pleural effusion. Patients should be generally monitored for signs and symptoms of fluid retention, and appropriate management should be initiated. 
• Myelosuppression: asciminib can suppress the bone marrow, decreasing blood cell counts. Regular monitoring of blood counts, including complete blood cell count (CBC), is necessary. Dose modifications or interruptions may be required based on hematological toxicity. 
• Pregnancy and Breastfeeding: The use of asciminib during pregnancy or breastfeeding has not been adequately studied.

Pregnancy / Lactation

Pregnancy consideration:  

AU TGA pregnancy category: D
US FDA pregnancy category: Not assigned 

Lactation:   

Excreted into human milk is Not known. 

Pregnancy category: 

• Category A: well-controlled and Satisfactory studies show no risk to the fetus in the first or later trimester. 
• Category B: there was no evidence of risk to the fetus in animal studies, and there were not enough studies on pregnant women. 
• Category C: there was evidence of risk of adverse effects in animal reproduction studies, and no adequate evidence in human studies must take care of potential risks in pregnant women.    
• Category D: adequate data with sufficient evidence of human fetal risk from various platforms, but despite the potential risk, and used only in emergency cases for potential benefits.    
• Category X: Drugs listed in this category outweigh the risks over benefits. Hence these categories of drugs need to be avoided by pregnant women.    
• Category N: There is no data available for the drug under this category 

Pharmacology

Pharmacology: 

asciminib is a small-molecule drug that belongs to the class of tyrosine kinase inhibitors (TKIs). It specifically targets the ABL1 protein kinase, which is involved in developing and progressing chronic myeloid leukemia (CML). 

Here are some critical aspects of the pharmacology of asciminib: 

• Mechanism of Action: asciminib inhibits the activity of ABL1 kinase by binding to a specific protein region called the myristoyl pocket. This binding prevents the activation and signaling of ABL1, ultimately suppressing leukemia cell growth and survival. 
• Selectivity: asciminib exhibits high selectivity for ABL1 kinase and has limited activity against other kinases. It is designed to target ABL1 specifically and has a unique binding site compared to other TKIs, allowing it to overcome specific resistance mutations that can develop in ABL1. 
• Resistance Mutations: asciminib is effective against specific resistance mutations in the BCR-ABL1 fusion gene, such as the T315I mutation. This mutation confers resistance to other TKIs, but asciminib can still inhibit the activity of ABL1 in the presence of this mutation. 
• Pharmacokinetics: asciminib is administered orally as tablets. It is well absorbed, and food does not significantly affect its absorption. The drug is generally metabolized in the liver primarily through cytochrome P450 (CYP) 3A4 metabolism. The exact pharmacokinetic parameters, such as absorption, distribution, metabolism, and elimination, may vary based on individual patient factors and specific formulations. 
• Drug Interactions: asciminib may interact with drugs that are strong inducers or inhibitors of CYP3A4, which can affect its metabolism and concentration in the body. Caution should be exercised when co-administering asciminib with medications that can potentially interact with and alter its pharmacokinetics. 

Pharmacodynamics: 

Mechanism of action: asciminib is a small-molecule drug-selective inhibitor of the ABL1 protein kinase. The ABL1 kinase is a crucial component of the BCR-ABL1 fusion protein associated with chronic myeloid leukemia (CML) development and progression. 

The mechanism of action of asciminib involves its specific binding to a unique region of the ABL1 protein known as the myristoyl pocket. This binding inhibits the activity of ABL1 kinase and disrupts the signaling pathways that contribute to the growth and survival of leukemia cells. 

Here are the critical steps involved in the mechanism of action of asciminib: 

• Binding to the Myristoyl Pocket: asciminib is designed to bind to the Myristoyl pocket of the ABL1 protein selectively. This binding site is distinct from the ATP-binding site targeted by other tyrosine kinase inhibitors (TKIs). asciminib’s interaction with the myristoyl pocket allows it to overcome specific resistance mutations that can develop in the ATP-binding site of ABL1, such as the T315I mutation. 
• Inhibition of ABL1 Kinase Activity: By binding to the myristoyl pocket, asciminib prevents the activation and signaling of ABL1 kinase. This inhibition disrupts the downstream signaling pathways promoting cell growth and survival, reducing leukemia cells’ proliferation. 
• Suppression of Leukemia Cell Growth: The inhibition of ABL1 kinase activity by asciminib results in the suppression of leukemia cell growth. asciminib specifically targets the BCR-ABL1 fusion protein, a CML hallmark. By interfering with this protein’s activity, asciminib helps control the growth and spread of leukemia cells. 

Pharmacokinetics: 

Absorption 

asciminib is administered orally as tablets. asciminib is expected to undergo absorption in the gastrointestinal tract after oral ingestion. Factors such as food intake and the formulation of the drug may influence the rate and extent of its absorption. 

Distribution 

Once asciminib is absorbed into the bloodstream, it will likely be distributed to various tissues and organs. The specific distribution pattern of asciminib, including its volume of distribution, tissue penetration, and protein binding, would require specific pharmacokinetic studies to be determined accurately. 

Metabolism 

asciminib is expected to undergo metabolism primarily in the liver, likely through the action of enzymes such as cytochrome P450 (CYP) enzymes. The specific metabolic pathways and the formation of active or inactive metabolites of asciminib would require detailed pharmacokinetic studies for definitive information. 

Elimination and Excretion 

The excretion pathways and the extent to which asciminib and its metabolites are eliminated through urine or bile need to be well-established. 

Adminstartion

Administration: 

Oral administration 

asciminib is an orally administered medication. Here are some general guidelines for the administration of asciminib: 

• Dosage: The recommended dosage of asciminib can vary depending on the specific treatment protocol and patient characteristics. It is key to follow the prescribed dosage instructions the healthcare professional provides. 
• Timing: asciminib is usually taken once daily, with or without food. It is generally recommended to take asciminib at the same time every day for the maintenance of consistent blood levels of the medication. 
• Swallowing: asciminib tablets should be swallowed whole with a glass of water. It should not crush, chew, or break the tablets unless specifically instructed by a healthcare professional. 
• Compliance: It is essential to adhere to the prescribed treatment regimen and not miss any doses. If a dose is missed, taking it as soon as possible is generally recommended. However, if the next scheduled dose is missed, it should be skipped and the following dose should be taken at the appropriate time. It is important to avoid taking a double dose of the medication to compensate for the missed dose.
• Interactions: asciminib may interact with certain medications, including strong CYP3A4 inducers or inhibitors. To assess potential drug interactions, it is crucial to inform the healthcare professional about taking all medications, including prescription, over-the-counter, and herbal supplements. 
• Special Instructions: Certain factors, like liver impairment, may require dose adjustments or special monitoring. It is key to follow the specific instructions the healthcare professional provides regarding dose modifications, monitoring, or additional precautions. 

Patient Information Leaflet

Patient information leaflet 

Generic Name: asciminib 

Pronounced: [ as-KIM-i-nib ] 

Why do we use asciminib? 

asciminib is primarily used to treat chronic phase chronic myeloid leukemia (CP-CML) in adult patients who have previously received one or more tyrosine kinase inhibitors (TKIs) and have developed resistance or intolerance to them. It explicitly targets ABL1, a protein kinase involved in the development and progression of CML. 

Here are some critical uses of asciminib: 

• CP-CML with T315I Mutation: asciminib is indicated for treating adult patients with CP-CML with the T315I mutation in the BCR-ABL1 fusion gene. This mutation is associated with resistance to other TKIs, including imatinib, dasatinib, and nilotinib. 
• CP-CML with Other Resistance Mutations: asciminib may also be used in adult patients with CP-CML who have developed resistance or intolerance to other TKIs due to specific mutations in the BCR-ABL1 fusion gene, excluding the T315I mutation. asciminib’s unique mechanism of action allows it to overcome specific resistance mutations and inhibit the activity of ABL1 kinase. 

It is key to note that the use of asciminib may be limited to specific patient populations with certain resistance mutations and prior treatment history. A healthcare professional should determine the decision to use asciminib and the specific treatment plan based on individual patient factors, including the genetic profile of the leukemia cells and the patient’s overall health.