Asciminib

Asciminib is a potent inhibitor of the ABL/BCR::ABL1 tyrosine kinase, sometimes called a STAMP inhibitor (Specifically Targeting the ABL Myristoyl Pocket). In most chronic myeloid leukaemia (CML), the Philadelphia chromosome creates the BCR::ABL1 fusion gene, whose protein has permanently raised tyrosine kinase activity that drives the growth of leukaemia cells. Asciminib inhibits that activity by acting at the myristoyl pocket of the ABL portion of the protein rather than at the catalytic site.

Mechanism of Action

• Allosteric inhibition: asciminib binds the myristoyl pocket of the ABL1 portion of BCR::ABL1 and locks the kinase in an inactive conformation, which prevents its oncogenic activity.
• Potency in vitro: it inhibits ABL1 kinase activity at mean IC50 values below 3 nanomolar. In patient-derived cells carrying BCR::ABL1 it specifically blocks proliferation (IC50 1–25 nanomolar). In cells engineered to express wild-type or T315I-mutant BCR::ABL1, it inhibits growth with mean IC50 values of 0.61 and 7.64 nanomolar.
• T315I mutation: in mouse models of CML, tumours with wild-type BCR::ABL1 regressed at doses above 7.5 mg/kg twice daily and tumours with the T315I mutant at doses above 30 mg/kg twice daily. This is why the T315I indication uses a higher dose (200 mg twice daily) than the standard 80 mg total daily dose.
• Cardiac electrophysiology: asciminib prolongs the QT interval in relation to exposure. In 239 patients with Ph+ CML or Ph+ acute lymphoblastic leukaemia, the estimated mean change in QTcF was 3.35 ms for 40 mg twice daily, 3.64 ms for 80 mg once daily and 5.37 ms for 200 mg twice daily.

Pharmacokinetics

• Absorption: rapid; median time to peak concentration is 2 to 3 hours, independent of dose. At steady state, peak concentration and 12- or 24-hour exposure (AUC) were 793 ng/mL and 5,262 ng·h/mL for 40 mg twice daily, 1,781 ng/mL and 15,112 ng·h/mL for 80 mg once daily, and 5,642 ng/mL and 37,547 ng·h/mL for 200 mg twice daily. Absorption is predicted to be about 100% and bioavailability about 73%.
• Food effect: food lowers bioavailability. AUC fell by 62.3% with a high-fat meal and by 30% with a low-fat meal compared with fasting, so the tablets are taken without food.
• Cyclodextrin effect: bioavailability may be reduced by medicines that contain hydroxypropyl-β-cyclodextrin as an excipient; an itraconazole oral solution containing it lowered asciminib AUC by 40.2%.
• Distribution: apparent volume of distribution at steady state is about 111 L; asciminib is mainly in plasma (blood-to-plasma ratio 0.58 in vitro) and is 97.3% bound to plasma proteins.
• Metabolism: CYP3A4-mediated oxidation and UGT2B7- and UGT2B17-mediated glucuronidation. Unchanged asciminib is the main circulating component in plasma (92.7%).
• Elimination: mainly in faeces, with biliary secretion involving the BCRP transporter, and to a minor extent in urine. After a single 80 mg radiolabelled dose, 80% was recovered in faeces and 11% in urine. The terminal half-life is reported as about 5.5 hours at 40 mg twice daily and 9.0 hours at 200 mg twice daily.
• Special populations: no dose adjustment is needed for patients aged 65 years or over. See Administration and Dosage for kidney and liver impairment.

• Ph+ CML-CP: adults with Philadelphia chromosome-positive chronic myeloid leukaemia in chronic phase.
• Ph+ CML-CP with the T315I mutation: adults who are resistant to, intolerant to or ineligible for ponatinib.

• Hypersensitivity to asciminib or to any of the excipients.

In pooled data from 556 patients with Ph+ CML (ASCEMBL, X2101 and ASC4FIRST), the most common reactions of any grade (≥20%) were musculoskeletal pain (34.4%), thrombocytopenia (28.1%), fatigue (25.4%), upper respiratory tract infections (24.8%), headache (22.8%), neutropenia (21.8%), arthralgia (20.7%) and diarrhoea (20.7%). The most common reactions of grade 3 or higher (≥5%) were thrombocytopenia (16.5%), neutropenia (13.8%), increased pancreatic enzymes (9.4%) and hypertension (9.2%). Serious reactions occurred in 9.9% of patients, most often pleural effusion (1.6%), lower respiratory tract infections (1.6%), thrombocytopenia (1.3%), pancreatitis (1.1%) and pyrexia (1.1%).

Very common (≥1/10): upper respiratory tract infections, thrombocytopenia, neutropenia, anaemia, dyslipidaemia, headache, dizziness, hypertension, cough, increased pancreatic enzymes, vomiting, diarrhoea, nausea, abdominal pain, constipation, increased hepatic enzymes, rash, pruritus, musculoskeletal pain, arthralgia, fatigue.

Common (≥1/100 to <1/10): lower respiratory tract infections, influenza, hypothyroidism, decreased appetite, hyperglycaemia, dry eye, blurred vision, palpitations, pleural effusion, dyspnoea, non-cardiac chest pain, pancreatitis, increased blood bilirubin, urticaria, oedema, pyrexia, increased blood creatine phosphokinase.

Uncommon (≥1/1,000 to <1/100): febrile neutropenia, pancytopenia, hypersensitivity, QT prolongation on the electrocardiogram.

Grouped terms: upper respiratory tract infections include nasopharyngitis, pharyngitis and rhinitis; lower respiratory tract infections include pneumonia, bronchitis and tracheobronchitis; dyslipidaemia includes raised triglycerides and cholesterol.

In the 48 patients with the T315I mutation taking 200 mg twice daily, the most common reactions (≥20%) were musculoskeletal pain (41.7%), fatigue (35.4%), increased pancreatic enzymes (31.3%), diarrhoea (27.1%), nausea (27.1%), increased hepatic enzymes (25.0%), arthralgia (25.0%), cough (22.9%), thrombocytopenia (20.8%), vomiting (20.8%) and headache (20.8%). Reactions of grade 3 or higher in at least 5% were increased pancreatic enzymes (22.9%), thrombocytopenia (16.7%), neutropenia (12.5%), increased hepatic enzymes (10.4%), hypertension (8.3%), anaemia (6.3%), vomiting (6.3%) and abdominal pain (6.3%). Serious reactions occurred in 12.5%. This dataset is small, so safety at this dose is less certain.

Serious reactions to watch for are myelosuppression (thrombocytopenia, neutropenia), pancreatitis and raised pancreatic enzymes, hypertension, QT prolongation, and reactivation of hepatitis B, which has been seen with other BCR::ABL1 inhibitors.

• Medicines with a known risk of torsades de pointes (for example bepridil, chloroquine, clarithromycin, halofantrine, haloperidol, methadone, moxifloxacin, pimozide): use caution with the 80 mg total daily dose; avoid with 200 mg twice daily.
• Strong CYP3A4 inhibitors (clarithromycin, telithromycin, troleandomycin, itraconazole, ketoconazole, voriconazole, ritonavir, indinavir, nelfinavir, saquinavir): use caution with 200 mg twice daily. No dose adjustment of asciminib is needed.
• Strong CYP3A4 inducers (carbamazepine, phenobarbital, phenytoin, St John’s wort): use caution at all doses, as efficacy may be lower. Rifampicin lowered asciminib AUC by 15% and raised its peak concentration by 9% after a single 40 mg dose; phenytoin lowered AUC by 34% and peak concentration by 22% after a single 200 mg dose.
• CYP3A4 substrates with a narrow therapeutic index (fentanyl, alfentanil, dihydroergotamine, ergotamine): use caution at all doses. A sensitive CYP3A4 probe substrate showed 28% higher exposure with asciminib 40 mg twice daily.
• CYP2C9 substrates (phenytoin, warfarin): use caution with the 80 mg total daily dose. With 200 mg twice daily, avoid CYP2C9-sensitive substrates and those with a narrow therapeutic index and consider alternatives; if the combination cannot be avoided, reduce the substrate dose, and with warfarin check the INR more often because its anticoagulant effect may be enhanced. S-warfarin exposure rose by 41% with 40 mg twice daily.
• BCRP and OATP1B substrates (sulfasalazine, methotrexate, rosuvastatin): use caution at all doses and check the SmPC of the other medicine for dose-reduction advice. Rosuvastatin exposure rose 2.18-fold with 80 mg once daily; atorvastatin exposure rose only 1.14-fold, so clinically relevant OATP1B interactions are unlikely.
• P-glycoprotein substrates with a narrow therapeutic index (digoxin, dabigatran, colchicine): use caution with 200 mg twice daily. Digoxin peak concentration rose 1.30-fold and exposure 1.18-fold with 80 mg once daily.
• Hydroxypropyl-β-cyclodextrin: medicines that contain it as an excipient (for example some itraconazole oral solutions) can lower asciminib exposure.
• Food: take asciminib on an empty stomach; avoid food for at least 2 hours before and 1 hour after each dose.

Treatment is started by a physician experienced in the diagnosis and treatment of leukaemia. Scemblix is taken by mouth. The tablets are swallowed whole with a glass of water and are not broken, crushed or chewed. They are taken without food: no food for at least 2 hours before and 1 hour after the dose. Treatment continues for as long as there is clinical benefit or until unacceptable toxicity occurs.

Ph+ CML-CP

• The recommended total daily dose is 80 mg, taken either as 80 mg once daily at about the same time each day or as 40 mg twice daily about 12 hours apart. The choice of regimen is at the prescriber’s discretion.
• Switching from 40 mg twice daily to 80 mg once daily: start once-daily dosing about 12 hours after the last twice-daily dose.
• Switching from 80 mg once daily to 40 mg twice daily: start twice-daily dosing about 24 hours after the last once-daily dose, then continue about 12 hours apart.

Ph+ CML-CP with the T315I Mutation

• Adults who are resistant to, intolerant to or ineligible for ponatinib take 200 mg twice daily, about 12 hours apart. The 100 mg tablets are restricted to this group.

Dose Adjustments for Side Effects

• Reduced doses: 40 mg once daily or 20 mg twice daily (from 80 mg once daily or 40 mg twice daily); 160 mg twice daily (from 200 mg twice daily in T315I disease). Asciminib is stopped permanently if the patient cannot tolerate 40 mg once daily, 20 mg twice daily or, in T315I disease, 160 mg twice daily.
• Thrombocytopenia or neutropenia (neutrophil count below 1.0 × 10⁹/L and/or platelet count below 50 × 10⁹/L): withhold until the neutrophil count is at least 1 × 10⁹/L and/or platelets at least 50 × 10⁹/L. If this happens within 2 weeks, resume at the starting dose; after more than 2 weeks, resume at the reduced dose. For recurrent severe thrombocytopenia or neutropenia, withhold again until resolved, then resume at the reduced dose.
• Asymptomatic amylase or lipase elevation (above 2.0 × the upper limit of normal): withhold until below 1.5 × the upper limit. If resolved, resume at the reduced dose; stop permanently if it recurs at the reduced dose. If not resolved, stop permanently and run tests to exclude pancreatitis.
• Non-haematological reactions of grade 3 or higher: withhold until grade 1 or lower. If resolved, resume at the reduced dose; if not, stop permanently.
• Monitoring: complete blood counts every 2 weeks for the first 3 months and monthly afterwards; serum lipase and amylase monthly; an electrocardiogram before starting; regular blood-pressure checks.

Special Populations

• Elderly (65 years and over): no dose adjustment.
• Renal impairment: no starting-dose adjustment in mild or moderate impairment at any recommended dose, nor in severe impairment at the 80 mg total daily dose. There are no clinical data in severe impairment at 200 mg twice daily, so no dose advice can be given and caution is needed.
• Hepatic impairment: the same pattern as for renal impairment: no starting-dose adjustment in mild or moderate impairment, nor in severe impairment at the 80 mg total daily dose; no data and caution in severe impairment at 200 mg twice daily.
• Children and adolescents: safety and efficacy below 18 years have not been established; no data are available.

Missed Dose

• Once-daily regimen: if the dose is less than 12 hours late, take it and take the next dose as scheduled. If it is more than about 12 hours late, skip it and take the next dose as scheduled.
• Twice-daily regimen: if the dose is less than 6 hours late, take it and take the next dose as scheduled. If it is more than about 6 hours late, skip it and take the next dose as scheduled.

Higher Dose in T315I Disease

For patients with the T315I mutation taking 200 mg twice daily, close monitoring should be considered. The safety data are limited to 48 patients (34 with a treatment intensity above 90%), so a higher safety risk than with 80 mg total daily dose cannot be excluded.

Myelosuppression

Thrombocytopenia, neutropenia and anaemia occur, and severe (grade 3 or 4) thrombocytopenia and neutropenia have been reported. They were generally reversible and managed by temporarily withholding treatment. Complete blood counts are done every 2 weeks for the first 3 months and then monthly, or as clinically indicated, and patients are watched for signs of myelosuppression.

Pancreatic Toxicity

Pancreatitis and symptom-free rises in serum lipase and amylase, including severe ones, occurred. Lipase and amylase are checked monthly, or as clinically indicated, and more often in patients with a history of pancreatitis. If enzyme rises come with abdominal symptoms, treatment is withheld and tests to exclude pancreatitis are considered.

QT Prolongation

QT prolongation occurred. An electrocardiogram is advised before treatment and during treatment as clinically indicated. Low potassium and magnesium levels should be corrected before the first dose and monitored. Caution is needed with medicines that carry a known risk of torsades de pointes at the 80 mg total daily dose, and such combinations should be avoided with 200 mg twice daily.

Hypertension

Hypertension, including severe hypertension, occurred. Blood pressure and other cardiovascular risk factors should be monitored regularly and managed with standard therapy.

Hepatitis B Reactivation

Hepatitis B virus has reactivated in chronic carriers during treatment with other BCR::ABL1 inhibitors. Patients are tested for hepatitis B infection before starting asciminib; those who test positive need specialist advice and monitoring for signs of active infection (see section 4.4 of the SmPC).

Pregnancy, Breastfeeding and Fertility

• Pregnancy test and contraception: the pregnancy status of women who could become pregnant should be verified before treatment starts. Sexually active women who could become pregnant should use effective contraception (a method with a pregnancy rate below 1%) during treatment and for at least 3 days after stopping.
• Pregnancy: there are no or few data in pregnant women, and animal studies showed reproductive toxicity. Asciminib is not recommended in pregnancy or in women who could become pregnant and are not using contraception. A patient who becomes pregnant while taking it should be told of the possible risk to the foetus.
• Breastfeeding: it is unknown whether asciminib or its metabolites pass into human milk. Because of the potential for serious reactions in the infant, breastfeeding should stop during treatment and for at least 3 days afterwards.
• Fertility: there are no human data. In rats, reproductive function was not affected, but sperm motility and count were reduced at 200 mg/kg/day; the relevance for humans is unknown.

Lactose

The tablets contain lactose monohydrate (43 mg, 86 mg and 216 mg in the 20 mg, 40 mg and 100 mg tablets). Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take them.

Effect on Driving

Asciminib has no or a negligible influence on the ability to drive and use machines. Patients with dizziness, fatigue or other side effects that could affect safe driving should refrain from driving or using machines for as long as these persist.

Do not store above 25 °C. Keep the tablets in the original package to protect them from moisture. No cold chain is needed.

3 years. Do not use after the expiry date on the pack.

Prescription only (Rx), on the prescription of a specialist experienced in the diagnosis and treatment of leukaemia, who starts the treatment. Asciminib is taken at home, so it is supplied to the patient or to the treating clinic on prescription. Scemblix comes in blister packs of 20 or 60 tablets (20 mg and 40 mg), multipacks of 180 tablets (40 mg) and packs of 60 or 120 tablets (100 mg); not all pack sizes may be marketed.