FDA Accepts PBPK Modeling to Replace Ten Clinical Trials for CML Drug Asciminib
Key Insights
Certara's Simcyp Simulator enabled physiologically-based pharmacokinetic modeling predictions that were accepted by the U.S. FDA (search) in lieu of clinical studies to support asciminib's new drug application.
The PBPK modeling replaced at least ten dedicated clinical pharmacology studies for asciminib, a first-in-class allosteric inhibitor targeting the BCR::ABL1 (search) myristoyl pocket (search) for chronic myeloid leukemia (search) treatment.
This regulatory acceptance demonstrates the growing impact of model-informed drug development approaches, with the modeling work spanning over a decade to optimize dosing regimens and drug interaction profiles.
Certara, Inc. announced that the U.S. FDA (search) has accepted physiologically-based pharmacokinetic (PBPK) modeling predictions from its Simcyp Simulator in lieu of clinical studies to support the new drug application for asciminib (Scemblix), marking a significant milestone in model-informed drug development. The PBPK modeling replaced at least ten dedicated clinical pharmacology studies, demonstrating the growing regulatory acceptance of virtual biological systems to predict drug behavior in the human body.
Revolutionary Approach to Drug Development
PBPK modeling uses virtual biological systems to predict how drugs are absorbed, distributed, metabolized, and eliminated by the body, and is increasingly being applied in place of certain clinical studies where appropriate. The results, published in "Physiologically Based Pharmacokinetic Modeling and Simulations in Lieu of Clinical Pharmacology Studies to Support the New Drug Application of Asciminib" by Loisios-Konstantinidis et al., highlight the growing impact and business benefits of model-informed drug development approaches for regulatory decision-making.
Asciminib represents a breakthrough as the first-in-class allosteric inhibitor that specifically binds the BCR::ABL1 (search) myristoyl pocket (search) used to treat patients with chronic myeloid leukemia (search) (CML (search)). The global incidence rate of CML was close to one case in 100,000 population in 2018, and it accounts for approximately 15% of newly diagnosed cases of leukemia (search) in adults.
Comprehensive Modeling Results
Given asciminib's potential for drug-drug interactions and the need to evaluate multiple dosing regimens, PBPK modeling with the Simcyp Simulator enabled a mechanistic assessment of the drug's pharmacokinetics across diverse patient populations, dosing regimens and clinical scenarios. These simulations provided evidence that complemented and, in some cases, replaced clinical pharmacology studies in the NDA.
Key results from the PBPK modeling included bridging between clinically tested and untested scenarios, replacement of at least ten dedicated clinical pharmacology studies, accurate characterization of asciminib pharmacokinetics across healthy volunteers and cancer patients, and predicting how medicines work in real-life patients taking other medications.
Industry Partnership and Scientific Rigor
"As a member of the Simcyp Consortium, we have firsthand experience with Simcyp's capabilities and value its leading scientific rigor essential for enabling regulatory acceptance of PBPK models," said Ioannis Loisios-Konstantinidis, Senior Principal Scientist, PK Sciences, Novartis Biomedical Research.
Rob Aspbury, President, Certara Predictive Technologies, emphasized the collaborative nature of the achievement: "This collaboration exemplifies the scientific partnership that the Simcyp Simulator enables. The modeling work for asciminib evolved over a decade and contributed to richer understanding its optimal dosing regimen and drug interaction profile, ultimately supporting regulatory approval and an important new treatment for patients with CML (search)."
Implications for Future Drug Development
The FDA's acceptance of PBPK modeling results for asciminib represents a paradigm shift in drug development, demonstrating how biosimulation can save time and money while maintaining scientific rigor. This approach enables pharmaceutical companies to reduce the number of human clinical trials required for regulatory approval, potentially accelerating the delivery of new treatments to patients while reducing development costs and timeline risks.