Asciminib

Usage

Asciminib is prescribed for the treatment of adult patients with:

• Newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in chronic phase (CP). This indication is approved under accelerated approval based on the major molecular response rate. Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trial(s).
• Previously treated Ph+ CML in CP.
• Ph+ CML in CP with the T315I mutation.

Pharmacological Classification: Asciminib is a kinase inhibitor, specifically a BCR-ABL tyrosine kinase inhibitor.

Mechanism of Action: Asciminib acts by binding to the ABL myristoyl pocket (also known as the STAMP), a distinct and previously untargeted allosteric site on the ABL protein. Unlike other tyrosine kinase inhibitors that bind to the ATP-binding site, asciminib’s unique binding site allows it to inhibit BCR-ABL activity, including T315I mutant forms, which are often resistant to other TKIs. This leads to the suppression of the proliferation of leukemic cells.

Alternate Names

International Nonproprietary Name (INN): Asciminib

Brand Name: Scemblix®

How It Works

Pharmacodynamics: Asciminib selectively inhibits BCR-ABL1 tyrosine kinase activity by binding to the ABL myristoyl pocket, thus preventing substrate phosphorylation and downstream signaling, ultimately leading to leukemic cell death. It exhibits activity against various BCR-ABL1 mutations, including the T315I mutation, which confers resistance to many other TKIs.

Pharmacokinetics:

• Absorption: Asciminib is administered orally and reaches peak plasma concentrations approximately 2 hours post-dose. Food significantly decreases its absorption, hence it should be taken on an empty stomach (at least 2 hours before or 1 hour after food).
• Metabolism: Asciminib is primarily metabolized in the liver, mainly via CYP3A4. It is also an inhibitor of CYP3A4, CYP2C9, and P-glycoprotein (P-gp).
• Elimination: Asciminib is predominantly eliminated via biliary/fecal excretion (approximately 80%), with a smaller fraction eliminated renally (approximately 11%).

Mode of Action: Asciminib allosterically inhibits BCR-ABL1 tyrosine kinase activity by binding to the myristoyl binding site (STAMP) on the ABL kinase domain. This unique binding mode distinguishes it from other TKIs and allows it to overcome resistance caused by mutations in the ATP-binding site, such as the T315I mutation.

Receptor Binding/Enzyme Inhibition/Neurotransmitter Modulation: Asciminib acts through enzyme inhibition (BCR-ABL1 tyrosine kinase). It is also an inhibitor of CYP3A4, CYP2C9, and P-gp. It does not directly modulate neurotransmitters or bind to classic receptors.

Elimination Pathways: Primarily biliary/fecal excretion (about 80% of the dose), with a minor contribution from renal excretion (about 11%).

Dosage

Standard Dosage

Adults:

• Ph+ CML-CP (Previously Treated): 80 mg orally once daily OR 40 mg orally twice daily (approximately 12 hours apart).
• Ph+ CML-CP (Newly Diagnosed): 80 mg orally once daily OR 40 mg orally twice daily (approximately 12 hours apart).
• Ph+ CML-CP with T315I Mutation: 200 mg orally twice daily (approximately 12 hours apart).

Children: The safety and efficacy of asciminib in pediatric patients below 18 years of age have not been established. No data are available.

Special Cases:

• Elderly Patients: No dose adjustment is required in patients aged 65 years and older.
• Patients with Renal Impairment: No dose adjustment is required.
• Patients with Hepatic Dysfunction: No dose adjustment is required.
• Patients with Comorbid Conditions: Close monitoring is advised for patients with pre-existing cardiovascular disease, hypertension, or pancreatic issues.

Clinical Use Cases

The provided sources currently only list approved indications for chronic phase Ph+ CML. Thus, there is no information on dosage recommendations for:

• Intubation
• Surgical Procedures
• Mechanical Ventilation
• Intensive Care Unit (ICU) Use
• Emergency Situations (e.g., status epilepticus, cardiac arrest)

Dosage Adjustments

Dose reductions may be necessary for managing myelosuppression (thrombocytopenia, neutropenia, anemia) or pancreatic toxicity (elevated amylase and/or lipase). Consult the full prescribing information for detailed dose adjustment recommendations.

Side Effects

Common Side Effects

Upper respiratory tract infections, musculoskeletal pain, fatigue, nausea, rash, diarrhea, headache, dizziness, peripheral edema.

Rare but Serious Side Effects

Myelosuppression (thrombocytopenia, neutropenia, anemia), pancreatitis, hypertension, QTc prolongation, cardiovascular events.

Long-Term Effects

Potential long-term effects are not fully characterized, but may include cardiovascular complications and secondary malignancies, as with other TKIs. Continued monitoring is required.

Adverse Drug Reactions (ADR)

Clinically significant ADRs include severe myelosuppression, pancreatitis, and cardiovascular events, requiring prompt medical intervention.

Contraindications

Known hypersensitivity to asciminib or any component of the formulation.

Drug Interactions

Asciminib interacts with numerous medications, including strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, clarithromycin, ritonavir), strong CYP3A4 inducers (e.g., rifampin, St. John’s wort), CYP2C9 substrates (e.g., warfarin), and P-gp substrates (e.g., digoxin). Consult a comprehensive drug interaction resource for detailed information before co-prescribing. It is also important to consider interactions with OTC medications, supplements, and food (e.g., grapefruit juice).

Pregnancy and Breastfeeding

Pregnancy Safety Category: Asciminib may cause fetal harm. Women of childbearing potential should use effective contraception during treatment and for at least 1 week after the last dose. Pregnancy status should be verified before starting treatment.

Breastfeeding: Breastfeeding is not recommended during treatment and for at least 1 week after the last dose.

Drug Profile Summary

• Mechanism of Action: Binds to the ABL myristoyl pocket, allosterically inhibiting BCR-ABL1 tyrosine kinase.
• Side Effects: Common: Upper respiratory tract infections, musculoskeletal pain, fatigue, nausea, rash, diarrhea. Serious: Myelosuppression, pancreatitis, cardiovascular events.
• Contraindications: Hypersensitivity to asciminib.
• Drug Interactions: Multiple; consult a drug interaction resource before co-prescribing.
• Pregnancy & Breastfeeding: Avoid use during pregnancy and breastfeeding.
• Dosage: Adults (Ph+ CML-CP previously treated): 80 mg once daily or 40 mg twice daily; (Ph+ CML-CP with T315I): 200 mg twice daily.
• Monitoring Parameters: Complete blood counts (CBCs), lipase, amylase, blood pressure, ECG (for QTc interval), liver function tests.

Popular Combinations

Asciminib is generally used as a single agent. Combination therapies are being investigated in clinical trials.

Precautions

• General Precautions: Monitor for myelosuppression, pancreatitis, hypertension, and cardiovascular events.
• Specific Populations: See dosage adjustments for elderly patients and those with renal or hepatic impairment.
• Pregnant Women: Contraindicated.
• Breastfeeding Mothers: Contraindicated.
• Children & Elderly: No pediatric data available. No dose adjustments needed for elderly patients.
• Menstruating Individuals: Potential for decreased fertility. Effective contraception is essential.
• Lifestyle Considerations: Alcohol consumption in moderation is generally permissible. Smoking should be avoided. No specific dietary restrictions other than avoiding food intake around asciminib administration. Caution advised while driving or operating machinery if dizziness or fatigue occurs.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Asciminib?

A: The recommended dosage depends on the specific indication:

• Ph+ CML-CP (Previously Treated): 80 mg orally once daily or 40 mg orally twice daily.
• Ph+ CML-CP (Newly Diagnosed): 80 mg orally once daily or 40 mg orally twice daily.
• Ph+ CML-CP with the T315I Mutation: 200 mg orally twice daily.

Q2: How should Asciminib be administered?

A: Asciminib tablets should be swallowed whole with water, without food. Food should be avoided for at least 2 hours before and 1 hour after each dose.

Q3: What are the most common side effects of Asciminib?

A: The most common side effects include upper respiratory infections, musculoskeletal pain, fatigue, nausea, rash, and diarrhea.

Q4: Are there any serious side effects associated with Asciminib?

A: Yes, serious side effects can include myelosuppression (low blood cell counts), pancreatitis (inflammation of the pancreas), hypertension (high blood pressure), and cardiovascular events. Regular monitoring is essential.

Q5: What are the contraindications for Asciminib?

A: The main contraindication is hypersensitivity to asciminib or any of its components.

Q6: Can Asciminib be used during pregnancy or breastfeeding?

A: Asciminib is not recommended for use during pregnancy and breastfeeding due to the potential risk of fetal harm and infant exposure. Effective contraception is essential during treatment and for at least one week after the last dose.

Q7: How does Asciminib interact with other medications?

A: Asciminib can interact with many medications, including strong CYP3A4 inhibitors and inducers, CYP2C9 substrates, and P-gp substrates. Consult a comprehensive drug interaction checker and/or pharmacist before co-prescribing.

Q8: What should patients be advised regarding lifestyle while taking Asciminib?

A: Patients should be advised to avoid food intake around the time of asciminib administration. Moderate alcohol consumption is generally permissible. Smoking is discouraged. Caution is needed while driving or operating machinery if experiencing side effects like dizziness or fatigue.

Q9: How is resistance to other TKIs relevant to the use of Asciminib?

A: Asciminib’s unique binding mechanism allows it to be effective even in patients with CML who have developed resistance to other TKIs, especially those with the T315I mutation.

Q10: What monitoring parameters are crucial for patients on Asciminib therapy?

A: Regular monitoring of complete blood counts (CBCs), lipase, amylase, blood pressure, and ECG (for QTc interval) is essential. Liver function tests should also be conducted periodically.