By Drug Modality

Preclinical testing is essential for new therapeutic modalities to evaluate their safety, efficacy, pharmacokinetics, and pharmacodynamics before human trials. It helps identify potential risks and optimize formulations, ensuring that only the most promising and safe candidates progress to clinical trials. This step minimizes the likelihood of adverse effects and increases the chances of successful outcomes in human studies.

New therapeutic modalities often present unique challenges, such as ensuring stability, efficient delivery, and targeted action. Each modality, whether it’s a PROTAC, oligonucleotide, ADC, peptide, peptide drug conjugate, CAR-T, or mRNA, has specific properties that require tailored approaches for evaluating its pharmacological and toxicological profiles. Additionally, addressing immunogenicity, off-target effects, and scalability for clinical production are significant challenges.

Stability and bioavailability are ensured through rigorous testing across a range of conditions, including temperature, pH, and enzymatic exposure. Formulation studies are conducted to develop stable delivery systems (e.g., lipid nanoparticles for mRNA or ADC linkers). Bioavailability is assessed through pharmacokinetic studies that measure the absorption, distribution, metabolism, and excretion (ADME) of the therapeutic.

Preclinical testing must adhere to regulatory guidelines set by agencies such as the US regulatory agencies, the EMA (European Medicines Agency) in Europe, and other relevant authorities. These guidelines include conducting Good Laboratory Practice (GLP)-compliant studies, performing comprehensive toxicology assessments, and documenting all findings in detail. Specific guidance documents outline requirements for different modalities.

Key considerations include:

• Target specificity: Ensuring the therapeutic precisely interacts with its intended target.
• Stability: Developing formulations that maintain stability in physiological conditions.
• Delivery: Creating effective delivery systems that reach target cells or tissues.
• Efficacy: Demonstrating the therapeutic effect in relevant disease models.
• Safety: Identifying and mitigating potential toxicities and adverse effects.

Potential off-target effects are addressed through comprehensive in vitro and in vivo studies. High-throughput screening and bioinformatics tools are used to predict and identify unintended interactions. Functional assays and advanced imaging techniques help monitor off-target effects. Proteomics and genomics analyses are conducted to assess the broader impact on biological systems.

For biologics, considerations include immunogenicity, stability, and complex manufacturing processes. Biologics often require specialized assays to assess protein folding, glycosylation, and biological activity. For small molecules, the focus is on chemical stability, metabolic pathways, and potential drug-drug interactions. Both require robust pharmacokinetic and toxicological evaluations, but biologics may need additional immunotoxicity and bioanalytical assessments.

The transition is handled by compiling and submitting all preclinical data into an Investigational New Drug (IND) application in the US or a Clinical Trial Application (CTA) in Europe. This includes detailed reports on safety, efficacy, pharmacokinetics, and toxicology studies. Collaboration with clinical experts ensures the design of early-phase clinical trials that address potential risks identified in preclinical testing. A well-defined manufacturing and quality control process is also established to ensure consistent production of the therapeutic for human studies.

Small molecule development requires characterization of pharmacological activity, selectivity, absorption, distribution, metabolism, and excretion (ADME), as well as potential safety risks. Integrated in vitro and in vivo pharmacology, DMPK, bioanalysis, and toxicology studies help characterize candidate properties, guide dose selection, and support progression toward IND-enabling development.

Large molecule development requires tailored approaches to characterize biological activity, pharmacokinetics, biodistribution, immunogenicity, and potential safety risks. Species relevance and fit-for-purpose bioanalytical methods are also important considerations. Integrated pharmacology, DMPK, bioanalysis, and safety assessment can support candidate characterization and progression toward IND-enabling development.

Targets considered difficult or historically “undruggable” by conventional approaches may become accessible through alternative therapeutic modalities. Depending on the target biology and mechanism of action, approaches such as antibodies, peptides, oligonucleotides, targeted protein degraders, and other emerging modalities can expand the range of therapeutically addressable targets. Selecting the appropriate modality and experimental strategy is therefore an important part of translating target biology into a viable drug discovery program.