Scemblix Mechanism of Action

ATC code: L01EA06.
Pharmacology: Mechanism of action: Asciminib is an oral and potent inhibitor of ABL/BCR::ABL1 tyrosine kinase. Asciminib inhibits the ABL1 kinase activity of the BCR::ABL1 fusion protein by specifically targeting the ABL myristoyl-binding pocket.
Pharmacodynamics: In vitro, asciminib inhibits the tyrosine kinase activity of ABL1 at mean IC₅₀ values below 3 nanomolar. In patient-derived cancer cells asciminib specifically inhibits the proliferation of cells harbouring BCR::ABL1 with IC₅₀ values between 1 and 25 nanomolar. In cells expressing the wild-type form or the T315I mutant form of BCR::ABL1, asciminib inhibits cell growth with mean IC₅₀ values of 0.61 ± 0.21 nanomolar or 7.64 ± 3.22 nanomolar, respectively.
In mouse xenograft models of CML asciminib dose-dependently inhibited the growth of tumours harbouring either the wild-type form or the T315I mutant form of BCR::ABL1, with tumour regression being observed at doses above 7.5 mg/kg or 30 mg/kg twice daily, respectively.
Cardiac electrophysiology: Scemblix treatment has been associated with an exposure-related prolongation of the QT interval. The correlation between asciminib concentration and the estimated maximum mean change from baseline of the QT interval with Fridericia's correction (ΔQTcF) was evaluated in 239 patients with Ph+ CML or Ph+ acute lymphoblastic leukaemia (ALL) receiving Scemblix at doses ranging from 10 to 280 mg twice daily and 80 to 200 mg once daily. The estimated mean ΔQTcF was 3.35 ms (upper bound of 90% CI: 4.43 ms) for the Scemblix 40 mg twice-daily dose, 3.64 ms (upper bound of 90% CI: 4.68 ms) for the 80 mg once-daily dose, and 5.37 ms (upper bound of 90% CI: 6.77 ms) for the 200 mg twice daily dose.
Clinical efficacy: Newly diagnosed Ph+ CML‑CP: The clinical efficacy and safety of Scemblix in the treatment of patients with newly diagnosed Philadelphia chromosome-positive myeloid leukaemia in chronic phase (Ph+ CML‑CP) were demonstrated in the multicentre, randomised, active-controlled and open-label phase III study ASC4FIRST.
In this study a total of 405 patients were randomised in a 1:1 ratio to receive either Scemblix or investigator-selected tyrosine kinase inhibitors (IS TKIs). Prior to randomisation, the investigator selected the TKI (imatinib or second-generation [2G] TKI) to be used in the event of randomisation in the comparator arm based on patient characteristics and comorbidities. Patients were stratified by EUTOS long-term survival (ELTS) risk group (low, intermediate, high) and pre-randomisation selection of TKI (imatinib or 2G TKI stratum). Patients received either Scemblix or IS TKIs and continued to receive treatment until unacceptable toxicity or treatment failure occurred.
Patients were 36.8% female and 63.2% male with a median age of 51 years (range: 18 to 86 years). Of the 405 patients, 23.5% were aged 65 years or older, while 6.2% were aged 75 years or older. Patients were white (53.8%), Asian (44.4%) and black (1%), and 0.7% were of unknown ethnicity. Demographic characteristics within the imatinib (N=203) and 2G TKI strata (N=202) were as follows: median age: 55 years and 43 years, respectively; ELTS high-risk group: 8.4% and 13.9%, respectively; Framingham group with high risk for cardiovascular disorders: 35.5% and 17.8%, respectively.
Demographic characteristics were balanced between Scemblix and IS TKIs and between both arms within the imatinib and 2G TKI strata.
Of the 405 patients, 200 received Scemblix and 201 received IS TKIs. Of the 201 patients who received IS TKIs, 99 were treated with imatinib, 49 with nilotinib, 42 with dasatinib and 11 with bosutinib. 4 patients did not receive any treatment.
The median duration of treatment was 69.8 weeks (range: 0.7 to 107.7 weeks) for patients receiving Scemblix and 64.3 weeks (range: 1.3 to 103.1 weeks) for patients receiving IS TKIs. By 48 weeks 90% of patients on Scemblix and 80.6% of patients on IS TKIs were still receiving treatment.
The study had 2 primary objectives for the assessment of major molecular response (MMR) at 48 weeks. One primary objective evaluated Scemblix compared to IS TKIs. The other primary objective evaluated Scemblix compared to IS TKIs within the imatinib stratum. A secondary objective evaluated MMR at 48 weeks, with Scemblix having been evaluated compared to IS TKIs within the 2G TKI stratum.
The key efficacy outcomes of ASC4FIRST are summarised in Table 1. (See Table 1.)

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The median time to MMR in patients who received Scemblix, IS TKIs, IS TKIs within the imatinib stratum and IS TKIs within the 2G TKI stratum was: 24.3 weeks (95% CI: 24.1 to 24.6 weeks), 36.4 weeks (95% CI: 36.1 to 48.6 weeks), 48.6 weeks (95% CI: 36.1 to 59.6 weeks) and 36.1 weeks (95% CI: 24.4 to 48.1 weeks), respectively.
BCR::ABL1 mutations were observed in 4% of patients treated with Scemblix and in 2% of patients treated with IS TKIs.
Pretreated Ph+ CML‑CP: The clinical efficacy and safety of Scemblix in the treatment of patients with Ph+ CML‑CP with treatment failure or intolerance to two or more tyrosine kinase inhibitors were investigated in the multicentre, randomised, active-controlled and open-label phase III study ASCEMBL.
Resistance to the last TKI was defined as: Lack of haematological or cytogenetic response at 3 months; BCR::ABL1 on the International Scale [IS] >10% at 6 months or thereafter; >65% Philadelphia-positive (Ph+) metaphases at 6 months or >35% at 12 months or thereafter; Loss of complete haematological response (CHR), of partial cytogenetic response (PCyR), of complete cytogenetic response (CCyR) or of major molecular response (MMR) at any time; New BCR::ABL1 mutations which potentially cause resistance to the study medicinal product or clonal evolution in Ph+ metaphases at any time.
Intolerance to the last TKI was defined as non-haematological toxicities unresponsive to optimal treatment or as haematological toxicities recurring after dose reduction to the lowest recommended dose.
In this study a total of 233 patients were randomised in a 2:1 ratio and stratified according to major cytogenetic response (MCyR) status at baseline for treatment with either 40 mg Scemblix twice daily (N=157) or 500 mg bosutinib once daily (N=76). There are only limited clinical data on the 80 mg once-daily dosage.
Pharmacological analyses indicate that both dosages have a comparable clinical profile. Patients continued treatment until unacceptable toxicity or treatment failure occurred. Patients with a known T315I and/or V299L mutation at any time prior to study entry were not included in the ASCEMBL study.
Patients with Ph+ CML‑CP previously treated with two or more TKIs were 51.5% female and 48.5% male with a median age of 52 years (range: 19 to 83 years). Of the 233 patients, 18.9% were 65 years or older, while 2.6% were 75 years or older. Patients were white (74.7%), Asian (14.2%) and black (4.3%). Of the 233 patients, 80.7% and 18% had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, respectively. The proportion of patients who had previously received 2, 3, 4, 5 or more prior treatment lines of TKIs were 48.1%, 31.3%, 14.6% and 6%, respectively. The median duration of treatment was 156 weeks (range: 0.1 to 256.3 weeks) for patients receiving Scemblix and 30.5 weeks (range: 1 to 239.3 weeks) for patients receiving bosutinib.
The primary endpoint of the study was the MMR rate at 24 weeks and MMR rate at 96 weeks was the key secondary endpoint. MMR rate is defined as a BCR::ABL1 ratio ≤0.1% on the International Scale [IS]. Other secondary endpoints were complete cytogenetic response rate (CCyR) at 24 and 96 weeks, defined as no Philadelphia-positive metaphases in bone marrow with a minimum of 20 metaphases examined.
The most important efficacy results from the ASCEMBL study are summarised in Table 2. (See Table 2.)

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In the ASCEMBL study 12.7% of patients treated with Scemblix and 13.2% of patients receiving bosutinib had one or more BCR::ABL1 mutations detected at baseline. MMR at 24 weeks was observed in 35.3% and 24.8% of patients receiving Scemblix with or without any BCR::ABL1 mutation at baseline, respectively.
The clinical efficacy and safety of Scemblix in the treatment of patients with Ph+ CML‑CP in whom treatment with a tyrosine kinase inhibitor failed or who did not tolerate such treatment were investigated in a cohort of the ongoing multicentre, single-arm, open-label, phase II dose escalation study ASC2ESCALATE.
The primary endpoint of the study is the MMR rate at 12 months in the second-line cohort (2L).
At the time of the interim analysis, 71 patients had been enrolled in the 2L cohort, with a median duration of Scemblix treatment of 19 weeks (range: 6.1 to 29.6 weeks). The MMR at 24 weeks was achieved in 42.9% of evaluable patients (N=28) in the 2L cohort (95% CI: 24.5% to 62.8%).
Ph+ CML‑CP harbouring a T315I mutation: The clinical efficacy and safety of Scemblix in the treatment of patients with Ph+ CML‑CP harbouring the T315I mutation were investigated in a multicentre, open-label, phase I human study, X2101.
In this study, a total of 185 patients with Ph+ CML‑CP without (N=115) or with (N=70) the T315I mutation received Scemblix at doses from 10 to 200 mg twice daily or 80 to 200 mg once daily. 48 of these patients with Ph+ CML‑CP harbouring the T315I mutation received Scemblix at a dose of 200 mg twice daily. The patients continued the treatment until unacceptable toxicity or until treatment failure.
Among the patients with Ph+ CML‑CP with the T315I mutation who received Scemblix at a dose of 200 mg twice daily, 77.1% were male and 22.9% were female with a median age of 56.5 years (range: 26 to 86 years). Of the 48 patients, 33.3% were aged 65 years or older and 8.3% were aged 75 years or older. The patients were white (47.9%), Asian (25%), and black (2.1%). 75% of the patients had an ECOG performance status of 0 and 25% had an ECOG performance status of 1. The proportion of patients who had previously received 1, 2, 3, 4, and 5 or more TKIs was 16.7%, 31.3%, 35.4%, 14.6%, and 2.1%, respectively. The median treatment duration was 181.7 weeks (range: 2 to 312 weeks).
MMR at 24 weeks was achieved in 42.2% of the evaluable patients (N=45) treated with Scemblix (95% CI: 27.7-57.8%).
MMR at 96 weeks was achieved in 48.9% of the evaluable patients (N=45) treated with Scemblix.
Elderly patients: Of the 556 patients treated with Scemblix in the ASC4FIRST, ASCEMBL and X2101 studies, 130 (23.4%) were aged 65 years or older and 31 (5.6%) were aged 75 years or older. No clear overall differences in the efficacy of Scemblix were observed between patients aged 65 years or older and younger patients.
Paediatric population: No studies on safety and efficacy have been performed in children and adolescents aged under 18 years.
Pharmacokinetics: Absorption: Asciminib is rapidly absorbed, with median maximum plasma levels (T_max) reached 2 to 3 hours after oral administration, independent of the dose. The geometric mean (geoCV%) of C_max at steady state is 1,781 ng/ml (23%) and 793 ng/ml (49%) following administration of Scemblix at 80 mg once daily and 40 mg twice daily, respectively. The geometric mean (geoCV%) of C_max at steady state is 5642 ng/ml (40%) following administration of Scemblix at 200 mg twice daily. The geometric mean (geoCV%) of AUC_tau is 5262 ng*h/ml (48%) following administration of Scemblix at 40 mg twice daily. According to model calculations, asciminib absorption is estimated at approximately 100%, while bioavailability is approximately 73%.
Asciminib bioavailability may be reduced by co-administration of oral medicinal products containing hydroxypropyl-β-cyclodextrin as an excipient. Co-administration of multiple doses of itraconazole as oral solution containing hydroxypropyl-β-cyclodextrin at a total of 8 g per dose with a 40 mg dose of asciminib decreased the asciminib AUC_inf by 40.2% in healthy subjects.
Food effect: Food consumption decreases asciminib bioavailability, with a high-fat meal having a higher impact on asciminib pharmacokinetics than a low-fat meal. Asciminib AUC and C_max are decreased by 62.3% and 68.2%, respectively, with a high-fat meal and by 30% and 34.8%, respectively, with a low-fat meal compared to the fasted state (see Dosage & Administration and Interactions).
Distribution: The apparent volume of distribution of asciminib at steady state is 111 l based on a population pharmacokinetic analysis. Asciminib is mainly distributed in the plasma, with a mean blood-to-plasma ratio of 0.58, independent of the dose. Asciminib is 97.3% bound to human plasma proteins, independent of the dose.
Metabolism: Asciminib is primarily metabolised via CYP3A4-mediated oxidation, UGT2B7-mediated glucuronidation and UGT2B17-mediated glucuronidation. Asciminib is the main circulating component in plasma (92.7% of the administered dose).
Elimination: Asciminib is mainly eliminated via the faeces, with only a minor proportion eliminated renally. 80% and 11% of the asciminib dose were recovered in the faeces and urine of healthy subjects, respectively, following oral administration of a single 80 mg dose of [¹⁴C]-labelled asciminib. Faecal elimination of unchanged asciminib accounts for 56.7% of the administered dose. Asciminib is eliminated by biliary secretion via the breast cancer resistant protein (BCRP).
The oral total clearance (CL/F) of asciminib is 6.31 l/hour based on a population pharmacokinetic analysis. The accumulation half-life of asciminib is 5.2 hours at dosages of 40 mg twice daily and 80 mg once daily.
Linearity/non-linearity: Asciminib exhibits a slight dose over-proportional increase in steady-state exposure (AUC and C_max) across the dose range of 10 to 200 mg administered once or twice daily.
The geometric mean accumulation ratio is approximately 2-fold, independent of the dose. Steady-state conditions are achieved within 3 days at the 40 mg twice-daily dose.
Kinetics in special populations: Asciminib systemic exposure is not affected by gender, age (20 to 88 years), ethnicity or body weight (42 to 184 kg) to any clinically relevant extent.
Hepatic impairment: A dedicated hepatic impairment study including 8 participants each with normal hepatic function, mild hepatic impairment (Child-Pugh A score 5 to 6), moderate hepatic impairment (Child-Pugh B score 7 to 9) or severe hepatic impairment (Child-Pugh C score 10 to 15) was conducted. The asciminib AUC_inf was increased by 22%, 3% and 66% in participants with mild, moderate and severe hepatic impairment, respectively, compared to participants with normal hepatic function following oral administration of a single 40 mg dose of Scemblix (see Dosage & Administration).
Renal impairment: A dedicated renal impairment study including 6 participants with normal renal function (absolute glomerular filtration rate [aGFR] ≥90 ml/min) and 8 participants with severe renal impairment not requiring dialysis (aGFR 15 to <30 ml/min) has been conducted. The asciminib AUC_inf and C_max are increased by 56% and 8%, respectively, in participants with severe renal impairment compared to participants with normal renal function following oral administration of a single 40 mg dose of Scemblix (see Dosage & Administration).
Population pharmacokinetic models show an increase in asciminib median steady-state AUC_0-24h by 11.5% in participants with mild to moderate renal impairment compared to participants with normal renal function.
Toxicology: Preclinical data: Asciminib was evaluated in safety pharmacology, repeated-dose toxicity, genotoxicity, reproductive toxicity and phototoxicity studies.
Safety pharmacology: Moderate cardiovascular effects (increased heart rate, decreased systolic pressure, decreased mean arterial pressure and decreased arterial pulse pressure) were observed in in vivo cardiac safety studies in dogs. No QTc prolongation was found in dogs up to the highest free asciminib exposure of 6.3 micromolar.
Repeated-dose toxicity: Histopathological hepatic changes (centrilobular hepatocyte hypertrophy, slight bile duct hyperplasia, increased individual hepatocyte necrosis and diffuse hepatocellular hypertrophy) were seen in rats and monkeys. These changes occurred at AUC exposures either equivalent to (rats) or 8- to 18-fold (dogs and monkeys) higher than those achieved in patients on 40 mg twice daily or 80 mg once daily. The AUC exposures were lower (rats), equivalent (dogs), or approximately 2-fold higher (monkeys) than the exposure in patients on 200 mg twice daily. These changes were fully reversible.
Minimal mucosal hypertrophy/hyperplasia (increase in the thickness of the mucosa with frequent elongation of villi) occurred in the duodenum of rats at AUC exposures 30-fold or 22-fold higher than those achieved in patients on 40 mg twice daily or 80 mg once daily, respectively. The AUC exposure was 4-fold higher than in patients on 200 mg twice daily. This change was fully reversible.
Minimal or slight hypertrophy of the adrenal gland and mild to moderate decreased vacuolation in the zona fasciculata occurred at AUC exposures either equivalent to (monkeys) or 19- to 13-fold (rats) higher than those achieved in patients on 40 mg twice daily or 80 mg once daily, respectively. The AUC exposures were lower (monkeys) or 2-fold higher (rats) than the exposure in patients on 200 mg twice daily. These changes were fully reversible.
Carcinogenicity and mutagenicity: Asciminib did not show mutagenic, clastogenic or aneugenic potential in vitro or in vivo.
In a 2-year rat carcinogenicity study non-neoplastic proliferative changes in the form of ovarian Sertoli cell hyperplasia were observed in female animals at a dose of ≥30 mg/kg/day. Benign Sertoli cell tumours in the ovaries were observed in female rats at the highest tested dose of 66 mg/kg/day. AUC exposures to asciminib in female rats at a dosage of 66 mg/kg/day were generally 8-fold or 5-fold higher than in patients who received a dose of 40 mg twice daily or 80 mg once daily, respectively, and are equivalent to those achieved in patients at a dose of 200 mg twice daily. However, no asciminib-related neoplastic or hyperplastic findings were observed in male rats at any dosage.
The clinical relevance of these findings is currently unknown.
Reproductive toxicity: In embryo-foetal development studies pregnant animals received oral doses of asciminib at 25, 150 and 600 mg/kg/day in rats and at 15, 50 and 300 mg/kg/day in rabbits during organogenesis. In embryo-foetal development studies a slight increase in foetal malformations (anasarca and cardiac malformations) and an increase in visceral and skeletal variants were observed in rats. An increased incidence of resorptions indicative of embryo-foetal mortality and a low incidence of cardiac malformations indicative of teratogenicity were observed in rabbits. In rats, at the foetal NOAEL of 25 mg/kg/day, the AUC exposures were equal to or less than those achieved in patients at the 40 mg twice-daily or 80 mg once-daily doses. At the foetal NOAEL of 25 mg/kg/day, the AUC exposures were lower than those achieved in patients at the 200 mg twice daily dose. In rabbits, at the foetal NOAEL of 15 mg/kg/day, the AUC exposures were equivalent to or below those achieved in patients at the 40 mg twice-daily or 80 mg once-daily doses. At the foetal NOAEL of 15 mg/kg/day, the AUC exposures were lower than those achieved in patients at the 200 mg twice daily dose.
Fertility: A slight effect on male sperm motility and sperm count was observed at doses of 200 mg/kg/day, likely at AUC exposures 19-fold, 13-fold or 2-fold higher than those achieved in patients at 40 mg twice daily, 80 mg once daily or 200 mg twice daily, respectively.
Phototoxicity: In mice asciminib showed dose-dependent phototoxic effects starting at 200 mg/kg/day. At the NOAEL of 60 mg/kg/day exposure based on C_max in plasma was 15-fold, 6-fold or 2-fold higher than the exposure in patients on 40 mg twice daily, 80 mg once daily, or 200 mg twice daily, respectively.