Asciminib - Mechanism of Action, Indications, Dosage, Precautions, Warnings and Adverse Drug Reactions

Overview

Tyrosine kinase inhibitors (TKIs) such as Asciminib treat Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in the chronic phase. It prevents the BCR-ABL1 fusion protein's ABL1 kinase activity, which promotes CML growth. In Ph+ CML with the T315I mutation, Asciminib has demonstrated advantages. This mutation results in a mutant BCR-ABL1 that is usually resistant to treatment. Because Asciminib binds to the BCR-ABL1 protein's myristoyl pocket and locks it into an inactive conformation, it is distinct from other allosteric drugs. On October 29, 2021, the FDA (Food and Drug Administration) approved Asciminib.

Drug Group

A member of the BCR-ABL class of tyrosine kinase inhibitors, Asciminib is a tyrosine kinase inhibitor. Drugs known as Tyrosine Kinase Inhibitors (TKIs) block the action of tyrosine kinases, which use signal transduction cascades to activate proteins. By inhibiting enzymes and stopping cell development, these are frequently utilized as anticancer medications, improving outcomes in chronic myelogenous leukemia (a type of white blood cell cancer characterized by the uncontrolled proliferation of myeloid cells in the bone marrow and their build-up in the blood) and treating other conditions such as idiopathic pulmonary fibrosis (a disorder where breathing becomes increasingly difficult due to lung scarring).

Indications

Asciminib is a kinase inhibitor prescribed for adult patients with

• Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in the chronic phase (CP), who had received two or more Tyrosine Kinase Inhibitors (TKIs) before symptoms developed. This indication is approved under accelerated approval because of the Major Molecular Response (MMR). Upon confirmation and description of clinical benefit in a confirmatory trial, this indication's continued approval may be subject to change.

• Ph+ CML in the chronic phase has the mutation T315I.

Dosage Forms and Available Strengths

Asciminib is available in 20 mg (milligrams) film-coated tablets and 40 mg dosages.

Warnings and Precautions

• Myelosuppression: Severe neutropenia and thrombocytopenia may occur. Throughout treatment, check Complete Blood Counts (CBCs) periodically and adjust by stopping the medication or reducing the dosage.

• Pancreatic Toxicity: Keep an eye on serum amylase and lipase levels. Depending on the severity, interrupt, restart at a lower dose, or stop taking Asciminib. When abdominal symptoms accompany a rise in lipase, check for pancreatitis (a pancreas inflammation).

• Hypertension: Monitor blood pressure and manage it as a doctor prescribes. If hypertension (high blood pressure (140/90 mmHg (millimeters of mercury) or higher)) is not under medical control, cease taking Asciminib, reduce the dosage, or interrupt it.

• Hypersensitivity: This may result in reactions that are too sensitive. When clinically necessary, start the proper treatment and be vigilant for signs and symptoms in patients.

• Cardiovascular Toxicity: There is a chance of cardiovascular toxicity. Watch for cardiovascular signs and symptoms in patients with cardiovascular risk factors. Start the right course of treatment when the doctor directs it.

• Embryo-Fetal Toxicity: Embryo-fetal toxicity may be harmful to the fetus. Advise women who are capable of becoming pregnant to use effective contraception and to be aware of the possible risks to the fetus.

For Patients

What Is Chronic Myeloid Leukemia (CML)?

The rare malignancy Chronic Myeloid Leukemia (CML), sometimes called chronic granulocytic leukemia, damages the bone marrow and causes an increase in white blood cells. Although it can happen at any age, elderly people are usually affected. The Philadelphia chromosome, a genetic mutation that produces the gene BCR-ABL and causes unchecked myeloid cell proliferation, is connected to Chronic Myeloid Leukemia (CML).

How Does Asciminib Work?

A translocation of the Philadelphia chromosome that results in the oncogenic fusion gene BCR-ABL1 is the main factor driving the progression of Chronic Myeloid Leukemia (CML). Tyrosine kinase and transforming activities of this protein, BCR-ABL1, are increased and contribute to the proliferation of CML. By locking the fusion protein into an inactive form, the allosteric inhibitor Asciminib stops the oncogenic potential of the protein.

What Are the Benefits of Asciminib?

Adult patients with Philadelphia chromosome-positive Chronic Myeloid Leukemia (CML) are treated with Asciminib. This BCR-ABL tyrosine kinase inhibitor works by allosterically binding to the ABL myristoyl pocket (STAMP) to block the abnormal kinase activity of the BCR-ABL1 oncoprotein. This focused strategy hinders the growth and division of cancer cells, which aids in the management of CML. Asciminib has demonstrated strong efficacy in clinical practice in patients with CML who have had extensive pretreatment and a suitable safety profile. It has been utilized in real-world situations and is typically recommended at a mean dose of 40 mg twice daily, although there is presently little data from these uses. Additionally, Asciminib may be utilized in patients whose CML carries the T315I mutation or who have received at least two tyrosine kinase inhibitors. It is also being investigated for its potential to treat other kinds of cancer.

How Is Asciminib Administered?

Asciminib is a tablet that is taken orally, ideally once or twice a day, right before or after a meal, on an empty stomach. It is crucial to adhere to the instructions on the prescription label and ask the doctor or pharmacist any questions patients may have. Take only what is recommended. Chew, break, or crush the tablets; instead, swallow the tablet whole. The doctor may change the dosage or cease therapy based on the reaction and any adverse effects. During treatment, discuss any concerns with the doctor, and even if patients feel better, keep taking Asciminib. Always get the doctor's approval before quitting. For the patient, request a copy of the manufacturer's information.

What Are the Side Effects of Asciminib?

Asciminib’s adverse effects are possible. Inform the physician if any of these symptoms worsen or persist:

• Pain in the muscles, bones, or joints.

• Fatigue.

• Nausea.

• Diarrhea.

Certain adverse effects may be dangerous. Call the doctor right away if patients exhibit any of these symptoms or seek emergency care:

• Unexpected bleeding or easily bruised blood in the stools or urine.

• Fever or infection symptoms.

• Stomach pain or discomfort, nausea, or vomiting.

• Confusion, headaches, dizziness, chest pain, or shortness of breath.

• Rash, difficulty breathing or swallowing, swelling of the face, lips, or tongue, rash or skin flushing, dizziness or feeling faint, fever, or fast heartbeat.

• Breathing difficulties, chest pain or pressure, a feeling of an erratic or fast heartbeat, swelling in the ankles or feet, weight gain, numbness or weakness on either side of the body, eyesight problems or loss of vision, trouble speaking, and jaw, back, neck, or arm pain.

There could be more adverse effects from Asciminib. Contact the doctor if patients experience any odd side effects while taking this medicine.

What Are the Things to Inform the Doctor Before Taking Asciminib?

• If patients are susceptible to an allergy to ingredients in Asciminib, other medications, or Asciminib itself, inform the doctor and pharmacist before taking the medication. Get an ingredient list from the pharmacist.

• Inform the physician and pharmacist about all other medications—prescription and Over-the-counter (OTC)—vitamins, dietary supplements, and herbal items patients currently use or intend to take while taking Ascinimib. The doctor might need to carefully monitor for any adverse effects or adjust the dosages of the medications.

• Inform the physician if patients intend to get pregnant or are already pregnant. Pregnancy should be avoided during Asciminib use and for one week following the last dosage. Consult the physician about birth control options that are suitable for patients.

• Contact the physician if patients become pregnant while taking Asciminib. The fetus may suffer from Asciminib.

• Avoid breastfeeding while taking Asciminib and for one week following the last dosage.

• Patients should be aware that Asciminib may cause women to become less fertile. Consult the physician about the possible side effects of Asciminib.

Missed Dose

If patients take the prescription twice a day for more than six hours or daily for more than twelve hours, skip the dose and go back to the regular schedule the following day. If patients take it twice daily for longer than six hours, skip the dose and start the next dose according to the regular schedule. Do not take two doses to make up for the missed ones.

Overdose

Get in touch with the poison control helpline right away if an overdose happens. Contact emergency authorities if a patient passes out, experiences a seizure, has trouble breathing, or cannot be made to wake up.

Overdosage symptoms can include:

• Unexplained bleeding or bruises.

• Fever, chills, sore throat, and/or other infection-related symptoms.

• Breathing difficulties.

• Rapid pulse rate.

• Headache.

• Pale skin.

• Confusion.

• Fatigue.

Storage and Handling

Medication should be kept at room temperature, securely closed, and out of children's reach. Put the medication in a secure place, and secure the safety caps. Use specific methods to eliminate unnecessary prescriptions, like medicine take-back programs. For information on take-back programs, speak with the recycling or waste agency in the community or the pharmacy.

For Doctors

Pharmacodynamics

Asciminib works as a therapeutic agent by blocking an oncogenic protein that causes CML to spread. Depending on the treated condition, it may be taken orally once or twice a day. It has been used to treat Ph+ CML with the T315I mutation, an often treatment-resistant type of illness, by raising the total daily dose five times as opposed to normal therapy (80 mg daily vs. 400 mg daily). Treatment with Asciminib may cause thrombocytopenia and neutropenia, among other forms of myelosuppression, similar to the effects of many other chemotherapy drugs. Throughout treatment, patients should have periodic laboratory monitoring, and dose modifications can be necessary depending on how severe the side effects are. Additionally, patients may develop pancreatic and/or cardiovascular damage, which both call for regular observation and possibly even need dose adjustments based on the prescribing information.

Chemical Taxonomy

The IUPAC name of Asciminib is N-4-[chloro(difluoro)methoxy]phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamide;hydrochloride. The chemical formula of Asciminib is C20H18ClF2N5O33, and its CAS number is 1492952-76-7.

Mechanism of Action

Most individuals with Chronic Myeloid Leukemia (CML) experience a translocation of the Philadelphia chromosome, which results in the creation of the oncogenic fusion gene BCR-ABL1, which unites the ABL1 and BCR genes. This fusion gene results in the fusion protein BCR-ABL1, which promotes the growth of CML by exhibiting increased tyrosine kinase and transforming activity. Asciminib functions as an allosteric inhibitor of the tyrosine kinase BCR-ABL1. It stops the fusion protein's oncogenic activity by attaching to the ABL1 portion's myristoyl pocket and locking it into an inactive conformation.

Pharmacokinetics

• Absorption: The median half-life of Asciminib is 2.5 hours following oral intake. The T315I mutant therapy resulted in the following steady-state Cmax and AUCtau values: 1781 ng/mL (nanograms per milliliter) and 15112 ng.h/mL (nanograms per hour per milliliter) at 80 mg once daily, 793 ng/mL and 5262 ng.h/mL at 40 mg twice daily, and 5642 ng/mL and 37547 ng.h/mL at 200 mg twice daily. The AUC and Cmax were reduced by 62 percent and 68 percent, respectively, and by 30 percent and 35 percent, respectively, when co-administration was combined with high-fat and low-fat meals.

• Distribution: The apparent volume of distribution of Asciminib at steady-state is 151 L (liters). Asciminib attaches to plasma proteins 97 percent of the time in vitro, yet it is unknown which particular protein(s) it binds to explicitly.

• Metabolism: Asciminib undergoes minimal metabolism; its parent drug remains unaltered, making up most of the drug in plasma (about 93 percent) and excreted in feces (about 57 percent). In that order, M30.5, M44, and M29.5 are the primary metabolites in circulation, making up roughly 5 percent, 2 percent, and 0.4 percent of the entire dose provided. CYP3A4 mediates Asciminib's oxidative metabolism, while UGT2B7 and UGT2B17 mediate Asciminib's glucuronidation.

• Excretion: Breast cancer-resistant protein (BCRP) transporters enhance the biliary secretion process that eliminates Asciminib. After taking Asciminib orally, the amount recovered in the urine and feces was around 11 percent and 80 percent, respectively. Of the drug material collected in the urine and feces, the unchanged parent drug made up about 2.5 percent and 57 percent, respectively. Asciminib has a terminal elimination half-life of 5.5 hours when taken twice daily at a dose of 40 mg and 9.0 hours when taken at a dose of 200 mg. When taking 80 mg of Asciminib daily, the total apparent clearance is 6.7 L/h (liters per hour), and when taking 200 mg twice daily, it is 4.1 L/h.

Toxicity

Clinical trials and real-world clinical practice have shown that Asciminib, a BCR-ABL1 inhibitor, has an excellent safety profile. On the other hand, it may cause toxicities such as tiredness, vomiting, pancreatitis, hematologic toxicity, and cardiovascular events.

Drug Interactions

1. Strong CYP3A4 Inhibitors: When using Asciminib concurrently at a dose of 200 mg twice a day, closely watch for adverse effects.

2. Itraconazole Oral Solution With Hydroxypropyl-Beta-Cyclodextrin: Avoid using Asciminib concurrently at all prescribed dosages.

3. Some CYP3A4 Substrates: Closely watch for negative responses when concurrently using Asciminib at a dose of 80 mg per day. Asciminib at 200 mg twice a day should not be used.

4. CYP2C9 Substrates: Do not use Asciminib concurrently at any suggested dosage.

• A Daily Total Dose of 80 MG: Lower the dosage of the CYP2C9 substrate as needed if it is unavoidable.

• 200 mg Taken Twice Daily: If it is impossible to prevent, think of non-CYP2C9 substrate alternative therapy.

5. Specific P-gp Substrates: Keep a close eye out for any negative side effects when using Asciminib concurrently at all prescribed dosages.

Clinical Studies

• Ph+ CML-CP, Previously Treated With Two or More TKIs: This open-label, multicenter, randomized, active-controlled trial assessed Asciminib's efficacy in treating Ph+ CML in patients in the chronic phase who had received two or more tyrosine kinase inhibitors in the past. A 2:1 ratio of patients, stratified according to the degree of significant cytogenetic response (MCyR), comprised the 233 participants in the trial. For Asciminib, the mean length of treatment was 67 weeks, while for Bosutinib, it was 30 weeks. Patients receiving Asciminib had a median MMR rate of 29 percent at 48 weeks, while those getting Bosutinib had a median MMR rate of 13 percent. Although the patients with MMR had not yet achieved the median duration of response, the follow-up period was 20 months on average.

• Ph+ CML-CP with the T315I mutation: An open-label, multicenter study assessed Asciminib's efficacy in treating Ph+ CML-CP with the T315I mutation. The study had 45 patients aged 65 to 86 years, with 80 percent male and 20 percent female participants. The treatment lasted 108 weeks on average. According to the study, 42 percent of the patients reached MMR by week 24 and 49 percent by week 96. The study emphasizes how crucial it is to comprehend the T315I mutation to treat cancer.

Use in Specific Populations

• Pregnancy: Studies on animals suggest that this medication may be harmful to fetuses. Women who are or may become pregnant should be informed of the possible risks, and the pregnancy status should be confirmed before beginning treatment. During treatment and for one week following the last dosage, effective contraception should be taken. Studies on animals reveal harmful effects on development, such as deformities and embryo-fetal death. The medication may reduce female fertility, but it is unclear if this impact can be reversed. The US FDA has updated the pregnant labeling rule for prescription drug products to include a requirement for a statement of risk, evidence to support that summary, and pertinent information.

• Breastfeeding: Due to possible undesirable reactions, unclear effects on the breastfed child, and decreased milk production, breastfeeding is not advised during therapy or for one week following the last dosage.

• Pediatric Use: Asciminib's effectiveness and safety in treating pediatric patients are unknown.

• Geriatric Use: Elderly individuals take Asciminib, a medicine that has not been identified to have issues unique to older adults.

• Renal Impairment: For those who have mild to severe renal impairment (estimated glomerular filtration rate [eGFR] 15 to 89 mL/min (milliliters per minute)/1.73 m2 (square meter) who are taking Asciminib without requiring dialysis, there is no need to alter the dose.

• Hepatic Impairment: Patients with mild to severe hepatic impairment can use Asciminib without changing the dosage.