A new pharmacokinetic and exposure-response analysis provides evidence supporting alternative dosing regimens for the chronic myeloid leukemia (CML) drug asciminib. The study, published in September 2024 in Clinical Pharmacokinetics, aimed to demonstrate the similarity in efficacy and safety between 80 mg once daily (q.d.) and 40 mg twice daily (b.i.d.) dosing of asciminib in patients with Philadelphia chromosome-positive CML without the T315I mutation. It also sought to support the use of 200 mg b.i.d. dosing in patients harboring the T315I mutation.
The analysis was based on data from two clinical trials: a phase I dose-finding study (NCT02081378) and the phase III ASCEMBL study (NCT03106779). The phase I study included 199 patients who received asciminib at doses ranging from 10-200 mg b.i.d. or 10-400 mg q.d. The ASCEMBL study included 154 patients who received asciminib 40 mg b.i.d. In total, data from 353 patients were pooled for the analysis. The study was funded by Novartis Pharmaceuticals, the developer of asciminib.
Using model-informed drug development techniques, the researchers conducted population pharmacokinetic (PopPK) and exposure-response analyses for both efficacy and safety. The PopPK analysis showed comparable exposure, measured by area under the curve (AUC0-24h), for 40 mg b.i.d. and 80 mg q.d. dosing (12,638 vs 12,646 ng*h/mL). The maximum plasma concentration (Cmax) for 80 mg q.d. was 1.61-fold higher than 40 mg b.i.d., while the minimum concentration (Cmin) was 0.72-fold that of 40 mg b.i.d.
For efficacy, the exposure-response analysis predicted similar major molecular response (MMR) rates at 24 weeks (27.6% vs 24.8%) and 48 weeks (32.3% vs 30.6%) for 40 mg b.i.d. and 80 mg q.d. dosing, respectively. These predictions aligned closely with observed clinical data. For patients with the T315I mutation, the analysis supported the adequacy of the 200 mg b.i.d. dose, with predicted MMR rates of 20.7% at 24 weeks and 23.7% at 48 weeks.
Safety analyses revealed no clinically meaningful relationships between asciminib exposure and the majority of laboratory abnormalities or adverse events examined. This suggests a similar safety profile across the dose regimens studied, including 200 mg b.i.d. for T315I mutation-positive patients.
The study had some limitations. The number of patients with safety data for the 80 mg q.d. regimen was relatively small (n=18). However, the authors argue that this is counterbalanced by the substantial total amount of safety data collected over several years of treatment with daily doses of 80 mg or higher (n=150).
The researchers concluded that the 80 mg q.d. and 40 mg b.i.d. dosing regimens of asciminib demonstrate similar efficacy and safety profiles in CML patients without the T315I mutation. They also determined that the 200 mg b.i.d. dose is both safe and effective for patients harboring the T315I mutation.
These findings have potential clinical implications for the treatment of CML. The once-daily 80 mg dosing option could improve patient compliance, as it may be more convenient than twice-daily dosing. This is particularly relevant given that asciminib must be taken under fasting conditions, which can pose practical challenges for many patients in managing their daily meals and schedules. Improved compliance could potentially enhance the long-term clinical benefit of asciminib therapy.
Additionally, the support for the 200 mg b.i.d. dosing in T315I mutation-positive patients provides valuable evidence for treating this subgroup, which has historically had limited treatment options and poorer outcomes.
It's worth noting that based partly on this analysis, both the 40 mg b.i.d. and 80 mg q.d. dosing regimens have been approved for use in several countries, including the United States. The 200 mg b.i.d. regimen for T315I-positive patients has also gained regulatory approval in multiple jurisdictions.
This study demonstrates the value of model-informed drug development in optimizing dosing strategies for targeted therapies like asciminib. By leveraging pharmacokinetic and pharmacodynamic modeling, researchers were able to provide robust evidence supporting alternative dosing regimens without the need for additional large-scale clinical trials. This approach can potentially accelerate the development and approval of more patient-friendly dosing options for critical medications.
As with any modeling study, these findings should be further validated through real-world clinical experience and additional studies. Clinicians should consider these results in the context of individual patient factors when making treatment decisions. Nonetheless, this analysis provides important evidence supporting flexible dosing options that may improve the long-term management of CML for many patients.
References
Combes FP, Sy SKB, Li YF, et al. Dose Justification for Asciminib in Patients with Philadelphia Chromosome-Positive Chronic Myeloid Leukemia with and Without the T315I Mutation. Clin Pharmacokinet. 2024;63(9):1301-1312. doi:10.1007/s40262-024-01411-1
