Source: European Medicines Agency (EU) Revision Year: 2022 Publisher: Novartis Europharm Limited, Vista Building, Elm Park, Merrion Road, Dublin 4, Ireland
Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitors
ATC code: L01EA06
Asciminib is a 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 pocket.
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 engineered to express either the wild-type or the T315I mutant form of BCR::ABL1, asciminib inhibits cell growth with mean IC50 values of 0.61 ± 0.21 and 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 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.
Asciminib treatment is associated with an exposure-related prolongation of the QT interval.
The correlation between asciminib concentration and the estimated 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 asciminib 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 asciminib 40 mg twice-daily dose. See section 4.4.
The clinical efficacy and safety of asciminib in the treatment of patients with Philadelphia chromosome-positive myeloid leukaemia in chronic phase (Ph+ CML-CP) with treatment failure or intolerance to two or more tyrosine kinase inhibitors were evaluated in the multicentre, randomised, active-controlled and open-label phase III study ASCEMBL. Resistance to last TKI was defined as any of the following: failure to achieve either haematological or cytogenetic response at 3 months; BCR::ABL1 (on the International Scale, IS) >10% at 6 months or thereafter; >65% Ph+ metaphases at 6 months or >35% at 12 months or thereafter; loss of complete haematological response (CHR), partial cytogenetic response (PCyR), complete cytogenetic response (CCyR) or major molecular response (MMR) at any time; new BCR::ABL1 mutations which potentially cause resistance to study medicinal product or clonal evolution in Ph+ metaphases at any time. Intolerance to last TKI was defined as non-haematological toxicities unresponsive to optimal management, 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 to receive either asciminib 40 mg twice daily (N=157) or bosutinib 500 mg once daily (N=76). Patients with known presence of T315I and/or V299L mutations at any time prior to study entry were not included in ASCEMBL. Patients continued treatment until unacceptable toxicity or treatment failure occurred.
Patients with Ph+ CML-CP were 51.5% female and 48.5% male, with median age 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 Caucasian (74.7%), Asian (14.2%) and Black (4.3%). Of the 233 patients, 80.7% and 18% had Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1, respectively. Patients who had previously received 2, 3, 4, 5 or more prior lines of TKIs were 48.1%, 31.3%, 14.6% and 6%, respectively.
The median duration of the randomised treatment was 103 weeks (range: 0.1 to 201 weeks) for patients receiving asciminib and 31 weeks (range: 1 to 188 weeks) for patients receiving bosutinib.
The primary endpoint of the study was MMR rate at 24 weeks and the key secondary endpoint was MMR rate at 96 weeks. MMR is defined as BCR::ABL1 IS ratio ≤0.1%. Other secondary endpoints were CCyR rate at 24 and 96 weeks, defined as no Philadelphia-positive metaphases in bone marrow with a minimum of 20 metaphases examined.
The main efficacy outcomes from the ASCEMBL study are summarised in Table 3.
Table 3. Efficacy results in patients treated with two or more tyrosine kinase inhibitors (ASCEMBL):
| Asciminib 40 mg twice daily | Bosutinib 500 mg once daily | Difference (95% CI)1 | p-value | |
|---|---|---|---|---|
| N=157 | N=76 | |||
| MMR rate, % (95% CI) at 24 weeks | 25.48 (18.87, 33.04) | 13.16 (6.49, 22.87) | 12.24 (2.19, 22.30) | 0.0292 |
| MMR rate, % (95% CI) at 96 weeks | 37.58 (29.99, 45.65) | 15.79 (8.43, 25.96) | 21.74 (10.53, 32.95) | 0.0012 |
| N=1033 | N=623 | |||
| CCyR rate, % (95% CI) at 24 weeks | 40.78 (31.20, 50.90) | 24.19 (14.22, 36.74) | 17.30 (3.62, 30.99) | Not formally tested |
| CCyR rate, % (95% CI) at 96 weeks | 39.81 (30.29, 49.92) | 16.13 (8.02, 27.67) | 23.87 (10.3, 37.43) | Not formally tested |
1 On adjustment for the baseline major cytogenetic response status
2 Cochran-Mantel-Haenszel two-sided test stratified by baseline major cytogenetic response status
3 CCyR analysis based on patients who were not in CCyR at baseline
The primary and key secondary endpoints were the only ones formally tested for statistical significance according to protocol.
In ASCEMBL, 12.7% of patients treated with asciminib 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 asciminib with or without any BCR::ABL1 mutation at baseline, respectively. MMR at 24 weeks was observed in 25% and 11.1% of patients receiving bosutinib with or without any mutation at baseline, respectively. The MMR rate at 24 weeks in patients in whom the randomised treatment represented the third, fourth, or fifth or more line of TKI was 29.3%, 25%, and 16.1% in patients treated with asciminib and 20%, 13.8%, and 0% in patients receiving bosutinib, respectively.
The Kaplan-Meier estimated proportion of patients receiving asciminib and maintaining MMR for at least 72 weeks was 96.7% (95% CI: 87.4, 99.2).
The European Medicines Agency has deferred the obligation to submit the results of studies with Scemblix in one or more subsets of the paediatric population in CML (see section 4.2 for information on paediatric use).
Asciminib is rapidly absorbed, with median maximum plasma level (Tmax) reached 2 to 3 hours after oral administration, independent of the dose. The geometric mean (geoCV%) of Cmax and AUCtau at steady state is 793 ng/ml (49%) and 5262 ng*h/ml (48%), respectively, following administration of asciminib at the 40 mg twice-daily dose. PBPK models predict that asciminib absorption is 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 an itraconazole oral solution containing hydroxypropyl-β-cyclodextrin at a total of 8 g per dose with a 40 mg dose of asciminib decreased asciminib AUCinf by 40.2% in healthy subjects.
Food consumption decreases asciminib bioavailability, with a high-fat meal having a higher impact on asciminib pharmacokinetics than a low-fat meal. Asciminib AUC is decreased by 62.3% with a high-fat meal and by 30% with a low-fat meal compared to the fasted state (see section 4.2).
Asciminib apparent volume of distribution at steady state is 111 litres based on population pharmacokinetic analysis. Asciminib is mainly distributed to plasma, with a mean blood-to-plasma ratio of 0.58, independent of the dose based on in vitro data. Asciminib is 97.3% bound to human plasma proteins, independent of the dose.
Asciminib is primarily metabolised via CYP3A4-mediated oxidation, and UGT2B7- and UGT2B17-mediated glucuronidation. Asciminib is the main circulating component in plasma (92.7% of the administered dose).
Asciminib is mainly eliminated via faecal excretion, with a minor contribution of the renal route. Eighty and 11% of the asciminib dose were recovered in the faeces and in the 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 breast cancer-resistant protein (BCRP).
The oral total clearance (CL/F) of asciminib is 6.31 l/hour, based on population pharmacokinetic analysis. The elimination half-life of asciminib is 5.2 hours at 40 mg twice daily.
Asciminib exhibits a slight dose over-proportional increase in steady-state exposure (AUC and Cmax) across the dose range of 10 to 200 mg administered once or twice daily.
The geometric mean accumulation ratio is approximately 2-fold. Steady-state conditions are achieved within 3 days at the 40 mg twice-daily dose.
In vitro, asciminib reversibly inhibits CYP3A4/5, CYP2C9 and UGT1A1 at plasma concentrations reached at a 40 mg twice-daily dose.
Asciminib is a substrate of BCRP and P-gp.
Asciminib inhibits BCRP and P-gp with Ki values of 24.3 and 21.7 micromolar, respectively.
Asciminib is metabolised by several pathways, including the CYP3A4, UGT2B7 and UGT2B17 enzymes and biliary secreted by the transporter BCRP. Medicinal products inhibiting or inducing CYP3A4, UGT and BCRP pathways may alter asciminib exposure.
Asciminib systemic exposure is not affected by gender, race or body weight to any clinically relevant extent.
A dedicated renal impairment study including 6 subjects with normal renal function (absolute glomerular filtration rate [aGFR] ≥90 ml/min) and 8 subjects with severe renal impairment not requiring dialysis (aGFR 15 to <30 ml/min) has been conducted. Asciminib AUCinf and Cmax were increased by 56% and 8%, respectively, in subjects with severe renal impairment compared to subjects with normal renal function, following oral administration of a single 40 mg dose of asciminib (see section 4.2). Population pharmacokinetic models indicate an increase in asciminib median steady-state AUC0-24h by 11.5% in subjects with mild to moderate renal impairment, compared to subjects with normal renal function.
A dedicated hepatic impairment study including 8 subjects each with normal hepatic function, mild hepatic impairment (Child-Pugh A score 5-6), moderate hepatic impairment (Child-Pugh B score 7-9) or severe hepatic impairment (Child-Pugh C score 10-15) was conducted. Asciminib AUCinf was increased by 22%, 3% and 66% in subjects with mild, moderate and severe hepatic impairment, respectively, compared to subjects with normal hepatic function, following oral administration of a single 40 mg dose of asciminib (see section 4.2).
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, likely at AUC exposures 12-fold higher than those achieved in patients at the recommended dose (RD) of 40 mg twice daily.
Pancreatic effects (serum amylase and lipase increases, acinar cell lesions) occurred in dogs at AUC exposures below those achieved in patients at the RD of 40 mg twice daily. A trend towards recovery was observed.
Elevations in liver enzymes and/or bilirubin were observed in rats, dogs and monkeys. 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 12- to 18-fold (dogs and monkeys, respectively) higher than those achieved in patients at the RD of 40 mg twice daily. These changes were fully reversible.
Effects on the haematopoietic system (reduction in red blood cell mass, increased splenic or bone marrow pigment and increased reticulocytes) were consistent with a mild and regenerative, extravascular, haemolytic anaemia in all species. These changes occurred at AUC exposures either equivalent to (rats) or 12- to 14-fold (dogs and monkeys, respectively) higher than those achieved in patients at the RD of 40 mg twice daily. These changes were fully reversible.
Minimal mucosal hypertrophy/hyperplasia (increase in thickness of the mucosa with frequent elongation of villi) was present in the duodenum of rats at AUC exposures 30-fold higher than those achieved in patients at the RD of 40 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-fold (rats) higher than those achieved in patients at the RD of 40 mg twice daily. These changes were fully reversible.
Asciminib did not have mutagenic, clastogenic or aneugenic potential either in vitro nor in vivo. Carcinogenicity studies have not been conducted with asciminib.
Animal reproduction studies in pregnant rats and rabbits demonstrated that oral administration of asciminib during organogenesis induced embryotoxicity, foetotoxicity and teratogenicity.
In embryo-foetal development studies, a slight increase in foetal malformations (anasarca and cardiac malformations) and increased visceral and skeletal variants were observed in rats. 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 no observed adverse effect level (NOAEL) of 25 mg/kg/day, the AUC exposures were equivalent to those achieved in patients at the RD of 40 mg twice daily. In rabbits, at the foetal NOAEL of 15 mg/kg/day, the AUC exposures were equivalent to those achieved in patients at the RD of 40 mg twice daily.
In the rat fertility study, asciminib did not affect reproductive function in male and female rats. 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 higher than those achieved in patients at the RD of 40 mg twice daily.
A pre- and postnatal developmental toxicity study was not performed.
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 Cmax in plasma was 15-fold higher than the exposure in patients at the RD of 40 mg twice daily
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