Modeling & simulation ×biomarker exploration
– Model Based Drug Development –

We enable improvement of drug development efficiency and seamless translational research!

To improve the probability of success and to speed-up the process of clinical studies, it is important to look ahead to clinical studies even when formulating strategies for the preclinical phases.
We, Axcelead Drug Discovery Partners (hereinafter referred to as Axcelead DDP), contribute to a smooth transition to clinical development through further quantitative evaluation of projects by combining pharmacometrics, such as modeling & simulation (hereinafter referred to as M&S), in addition to PK/PD assays and analyses.
For the biomarkers exploration that enable M&S, we utilize various platform technologies, including an omics analysis, to offer comprehensive support from exploratory biomarkers to validation.

Summary of M&S

M&S is a method that analyzes the correlation between drug exposure (pharmacokinetics: PK), pharmacological effects (pharmacodynamics: PD), and the final output of the disease process (efficacy). A model is formulated using a huge volume of study data and information and knowledge accumulated in the past, and the precision of project evaluation improves based on the prediction obtained from the results of the analysis.

Breimer DD and Danhof M et al., Clinical Pharmacokinetics, 32 (4): 259-267 (1997), partially modified

Breimer DD and Danhof M et al., Clinical Pharmacokinetics, 32 (4): 259-267 (1997), partially modified

Axcelead DDP adopts for each phase, and provides total support from optimization of a chemical compound to, using so-called model-based drug development (MBDD).
We work closely with LAP&P, who offers consultations focused on M&S, to offer seamless support for your translational . Axcelead DDP mainly supports the preclinical stages, including PK/PD , and LAP&P performs the M& once the project advances to the clinical stage.

*Relevant news release:
navigate_nextAnnouncement of Start of Business Partnership between Axcelead DDP and LAP&P for Modeling and Simulation in Pharmaceutical Research

Overview of biomarker discovery

A biomarker is an indicative of pathophysiological process or response to a therapeutic intervention, and improves the efficiency of drug development. Multiple steps and technologies are needed for the biomarker discovery and validation.

Axcelead DDP utilizes a variety of technologies to explore biomarkers according to a drug target and customer needs. Those include multiple omics platforms such as metabolomics, proteomics, lipidomics and transcriptomics using next generation sequencing (NGS), flow cytophotometry, immunohistochemistry (IHC), in situ hybridization (ISH) and etc. In addition, bioinformatics is used for analysis of the omics data

In vitro and in vivo models are also available for various disease areas such as oncology, immunology, CNS, cardiovascular/metabolic, gastrointestinal diseases.Furthermore,can generate genetically modified mouse and rats in a short period of time using CRISPR/Cas9 technology.

In addition to the biomarker discovery, we support development of methods for biomarker measurement and more robust assay systems for clinical studies. Axcelead DDP offers a one-stop service to enable seamless translational research

M&S is useful in the following

Preclinical stage

M&S is utilized…

 To elucidate the mode of action of the chemical compound at the preclinical stage.

To discuss the target dose and blood concentration.

To provide quantitative information for inferring the results of the clinical study.
Making it possible to identify candidate products for development based on quantitative information, supporting internal projects prioritization, and decision making on investments!

Contributing to faster and more efficient development through seamless translational research!

Clinical stage

M&S is utilized…

To confirm whether the chemical compound has hit the target based on changes in the biomarkers, the optimal clinical dose, and the reference values for biomarker measurement the phase 1 clinical study,.
Enabling quick Go/No-go decisions at an early stage of the clinical study!

Improving the precision of the dosing plan based on the results of M&S, contributing to achieving the goal of the clinical study!

M&S Case Study

– Value added to an anticancer drug project
by M&S using biomarkers –

It is difficult to measure tumor volume in clinical studies. In nonclinical studies, a correlation between tumor volume, biomarkers, and exposure dose can be obtained by M&S, enabling an estimate of the tumor suppression rate based on changes in the biomarkers, and selecting an optimal dose in clinical studies.

As a result of using PK/PD/Efficacy M&S in the Hedgehog inhibitor project, the results suggested that if the expression of dermal Gli1 mRNA, a biomarker, was suppressed by at least 83%, 90% of the maximum tumor growth suppression effect was achieved, and that the required blood concentration was 0.68 μg/mL.

Because the inhibition of dermal Gli1 mRNA was measurable in the Phase 1 clinical study, it was possible to confirm it hit the target in phase 1. This contributed greatly to the stage up in the company.

[Source of the graph] Akifumi Kogame, Drug Metabolism and Disposition, 41 (4) 727-734 (2013), partially modified)

Frequently asked questions

Q:Are there any modalities to which M&S cannot be applied?

A:Any modality is OK. M&S analysis can be adopted as long as PK, biomarkers, and efficacy have been measured.

Q:Is PK/PD analysis meaningless if the biomarker cannot be measured in clinical settings?

A:Even if the biomarkers cannot be measured in clinical settings, we consider that a similar effect can be achieved by PK/ efficacy analysis because there should be some endpoints in drug discovery. In our past experience, numerous chemical compounds have been generated by modeling PK/ efficacy.
We, Axcelead DDP, also support studies on special drug efficacy and biomarker measurement in collaboration with our pharmacology divisions.

Q:Tell us about your experience with M&S

A:In my previous position, I worked under the policy that a certain level of potential should be demonstrated by M&S in order to proceed to a clinical study, and M&S was introduced to almost all programs, through which I gained a lot of experience.
We work closely with LAP&P, a consulting company specializing in modeling. I studied the technology and knowhow of modeling at Leiden University.

Q:What are the time and cost requirements for M&S?

A:That depends on your chemical compound, data, and request, but we usually provide the results of analysis that could lead to some form of subsequent decision about from 2 weeks to 1 month. The expenses are also quite reasonable, but vary depending on the conditions. Please contact us directly.
If you wish to start with exploratory biomarkers, both the duration and cost will change. Ask us for details.