The Growing Value of Quantitative Systems Pharmacology (QSP)

QSP combines computational modeling and experimental data to examine the relationships between a drug, the biological system, and the disease process (Figure 1). With the ability to leverage big data (biological and pharmacological), QSP allows R&D teams to identify and test therapeutic strategies in virtual trials with virtual patients. It improves confidence in both the compound and the target and can be used for a variety of purposes including new modalities, dose selection and optimization, combination therapy, disease triage, and more.

When integrated into R&D, QSP delivers key insights into many of the most pressing questions drug developers face, such as:

• In a given biological pathway, what is the best target and modality for pharmacological intervention to treat a disease?
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• Can we predict the effect of a drug in a special population or other indication?
• Can we individualize the dosing regimen based on patient characteristics?
• Can we predict human response (dose) to a novel mechanism based on pre-clinical data?
• Which biomarkers do we require to answer the above questions?

In addition to driving better decision-making, QSP helps researchers streamline their work and use resources more efficiently.

At Certara, we’re applying QSP to several specific areas of expertise:

Immunogenicity (IG)

As defined by the US FDA, IG is the ability of a therapeutic product to trigger an immune response in the body. IG can be a showstopper in biologic drug development, with 89% incidence rate and 49% of those impacting efficacy. IG management is a complex, multifactorial problem in need of a solution. Certara facilitates a consortium of major pharma companies and has developed a technology platform that is used to enable compound prioritization and inform go/no-go decisions. The FDA has also licensed this model, which can use first-in-human data to design Phase II/III trials, predict impact of disease and co-medication, extrapolate to new populations, and predict if IG can be managed via dosing regimens. Read more about our work in immunogenicity in this white paper.

Immuno-Oncology (IO)

IO uses a patient’s own immune system to fight their cancer. Cancer IO drug therapy has had a huge impact in patient care, expected to reach $39B by 2024. Certara manages a consortium with leading pharma companies focused on developing an IO Simulator to test combination cancer therapies, evaluate different dose regimens, and select biomarkers in computer-generated, virtual patients.

The IO Simulator incorporates the pertinent biology, pharmacology, and variation between individuals to guide clinical development of IO therapies. It is being used today on a range of pivotal development programs. Read this blog to learn how using virtual patients can refine the search for safe and effective IO combination therapies.

ワクチン

QSP is being used to simulate vaccine responses in virtual patients early in the development cycle and throughout all subsequent phases via virtual trials. Certara developed a QSP vaccine platform for novel COVID-19 vaccines that are in patient use today. That platform is derived from our unique IG Simulator and will be used to develop other vaccines. Read this press release on how the Vaccine Simulator predicted optimal timing for COVID-19 vaccine doses.

Neurodegenerative Diseases (NDD)

NDDs are complex and usually involve dysregulation in multiple biochemical pathways. Understanding the disease and potential treatments requires the combination of genetics, expression and mRNA, cell diversity, cellular networks, brain networks, and science networks into one comprehensive model. Microglia, as the immune cells in the CNS, play crucial roles in neuroinflammation and many other CNS diseases. QSP is being applied to understanding the dynamics of microglial phenotypes and the effects on treatments targeting microglia. Check out this AAPS Newsmagazine article on using this approach to address the challenges of NDDs.

By providing integrated approaches to assessing new drug modalities and mechanisms of action, QSP can be applied very early in the evaluative process to determine the first dose and understand potential toxicity issues along with longer-term therapeutic value. At Certara, we have been applying QSP to understand the potential for a range of new modalities, including:

• Genetic therapies, including AAV, lysosomal storage disease, glycogen storage disorder, enzyme replacement, and genetically engineered antibodies.
• Protein degradation. By harnessing the body’s own natural protein disposal system to degrade and remove disease-causing proteins, this approach is being leveraged to identify new drug targets.
• Bi, tri and multi-specifics. Bispecific and trispecific antibodies are essentially antibodies bioengineered to contain two or three distinct antigen-binding domains, which allow these recombinant molecules to bind specifically to more than one target. QSP enables the in silico biological exploration of these complexities to achieve desired therapeutic response.
• CAR-T – read more about our collaboration with the Memorial Sloan Kettering Cancer Center. This new biosimulation platform initially aims to address key questions on the optimal dose and regimen for CAR T-cell therapies in patients with multiple myeloma and will leverage de-identified MSK clinical data.
• Gene Editing. This Nobel Prize winning technology approach allows genetic material to be added, removed, or altered at particular locations in the genome. Certara is using its QSP platforms to guide dose selection and decision-making across several different types of gene editing, including CRISPR/CAS9 and base editing.

Certara has differentiated its QSP consulting by building robust, regulatory-ready software platforms for reproducible model development. The software is available in a proprietary and proven editor tool with an easy-to-use interface. This unique approach has been shared with US, EU, and Japanese regulators, all committed to advancing the use of QSP in drug discovery, development, and regulatory review.