Selection and optimisation of the lead therapeutic candidate
To support you in the planning of a pharmaceutical project, we here describe the different steps in the drug development process.
Independent of therapeutic modality, initial leads are required to begin the process of therapeutic development. These leads can be identified through screening of appropriate chemical or biological libraries. For instance, an antibody library contains variable segments from different antibodies, expressed in different biological or molecular systems. Leads can also be designed and/or synthesised or be derived from a certain cell or tissue type. In common to all these lead identification processes is the requirement for appropriate assays, both for the detection of promising leads or hits and disqualification of others of less interest.
The difference between a hit from a particular assay and a lead series lies in the identification of structure-activity relationships within the series. These include parameters such as activity on the target, solubility, permeability, metabolic stability, and others. Many hits never mature into lead series, either as one or more of these important parameters cannot be optimized well enough, or as this leads to potentiated safety liabilities.
The lead series is then iteratively optimized through small structural changes, directed at improving the structure towards a viable therapeutic candidate, able to meet regulatory demands. This process is termed lead optimisation and, in terms of conventional chemical drugs, this is aimed at yielding a structure which unifies all characteristics necessary to achieve therapy with appropriate safety.
Lead optimisation is also required in the refinement of other therapeutic modalities, for example peptides/proteins, antibodies and cell- and gene-based therapies, and is based on the same rationale as for chemical agents, but uses other techniques to introduce structural changes in each case.
This complex preclinical work includes the use of in silico, in vitro and in vivo methods/experiments, as well as the use of patient-derived material in some cases.
In summary, the preclinical work should yield knowledge of how the therapeutic candidate affects its disease target, the underlying mechanism in the therapeutic effect, and a clear understanding of dose-response relationships. The work should also provide an understanding of the therapeutic window of exposure, as well as ideas of how the mode of action may be determined and proven to be translated in the clinical setting. This is generally termed proof of concept.
Translational science plan
Transferring preclinical data to clinical application is challenging. A translational plan is based on indication and patient group for your medical product. With a strategic approach, prior to the start of a clinical study, preclinical data can be used as guidance in predicting the route of administration and dosage, and e.g. for the identification of biomarkers that demonstrate efficacy and safety. Thereafter, a regulatory plan can be established with a view to market approval.