Asciminib – 模型简化了研发过程，避免了 10 多项临床试验

Chronic myeloid leukemia (CML) is a clonal myeloproliferative neoplasm characterized by the uncontrolled proliferation of immature granulocytes in the bone marrow and peripheral blood. This abnormal cell population disrupts normal hematopoiesis, leading to cytopenias (reduced production of mature blood cells) and potential leukemic transformation (progression to acute leukemia).

The underlying driver of CML is a specific mutation called BCR-ABL, a constitutively active tyrosine kinase enzyme that fuels the uncontrolled growth and survival of CML cells.

Asciminib (Scemblix®) is a novel drug with a unique mechanism of action for treating CML. It specifically targets the BCR-ABL tyrosine kinase, offering a targeted approach to the disease.

In November 2021, the US FDA granted accelerated approval for asciminib for two specific indications of CML, a milestone followed by endorsements from EMA and PMDA in 2022. Asciminib represents a significant leap in CML therapy.

Developing a new drug typically involves extensive clinical trials to determine safe and effective dosing regimens. Asciminib presented several challenges for traditional clinical trial design:

• Multiple Dosing Regimens: The developers wanted to establish safe and effective doses of 80mg and 200mg.
• Drug-Drug Interactions (DDI): It was crucial to assess how asciminib interacts with other medications.
• Food Effect: The potential impact of food on asciminib absorption needs evaluation.
• Patient Population Variations: The safety and efficacy in patients with impaired liver function required investigation.

A unique approach utilizing model-informed drug development (MIDD) was employed to bridge efficacy and safety data between dosing regimens. This innovative strategy involved using PBPK (physiologically-based pharmacokinetic) modeling to bridge DDI clinical assessments from one dose to other untested doses. Importantly, PBPK predictions were used to inform the drug label, replacing the need for more than 10 traditional clinical pharmacology studies.

Simcyp’s ADAM-PBPK model simulations demonstrated that changes in stomach acid (gastric pH) wouldn’t significantly affect asciminib exposure. This is because asciminib’s high solubility in bile salts, attributed to supersaturation, overrides the potential impact of pH. As a result, the drug label concludes that elevated gastric pH is unlikely to have a clinically meaningful effect on asciminib’s pharmacokinetics (PK) following a single dose of 200 mg.

By utilizing PBPK modeling, the developers achieved significant benefits:

• Reduced Clinical Trials: Over 10 potentially time-consuming and expensive clinical pharmacology studies were waived based on PBPK simulations.
• Efficient Dosing Regimen Approval: The FDA approved 80 mg and 200 mg dosing based on PBPK data, eliminating the need for further trials.
• Streamlined Development Process: PBPK modeling expedited the overall development timeline of asciminib.

By replacing traditional clinical trials with simulations in certain areas, PBPK modeling can significantly reduce costs, expedite approvals, and ultimately benefit patients by bringing new drugs to market faster.