Drug discovery and development: Biomarkers of neurotoxicity and neurodegeneration

Abstract

Attrition in drug discovery and development remains a major challenge. Safety/toxicity is the most prevalent reason for failure with cardiovascular and CNS toxicities predominating. Non-invasive biomarkers of neurotoxicity would provide significant advantage by allowing earlier prediction of likely neurotoxicity in preclinical studies as well as facilitating clinical trials of new therapies for neurodegenerative conditions such as Parkinson's disease (PD) and multiple sclerosis (MS).

Keywords: Biomarkers; central nervous system; drug development; drug safety; neurodegeneration; toxicology.

Figure 1.

The drug discovery and development paradigm for small molecules. Target selection (TS) is followed by lead generation (LG) and lead optimization (LO). One or two candidate drugs (CDs) are selected to begin more extensive in vitro and in vivo testing, providing the data to select one molecule to go forward for good laboratory practice (GLP) toxicology testing in support of first time in human (FTIH) clinical trials. (A color version of this figure is available in the online journal.)

Figure 2.

Navigating the regulatory framework. International Council for Harmonisation (ICH) guidelines specify the different areas of testing to be undertaken to create the ‘FTIH package’. Testing is structured as general toxicology, safety and secondary pharmacology, genetic toxicology/carcinogenicity and developmental/reproductive toxicology. CD: candidate drug; CNS: central nervous system; DRF: dose range finding; EFD: embryo fetal development; FTIH: first time in human; GLP: good laboratory practice; LG/LO: lead generation/lead optimization; ICH: International Council for Harmonization; MOLY: mouse lymphoma; MTD: maximum tolerated dose; P&P: peri and post-natal; SAR: structure activity relationship; TS: target selection. *Could be different duration or cyclical dosing depending on clinical plan. (A color version of this figure is available in the online journal.)

Figure 3.

A comparison of key aspects of ICH M3 and ICH S9. See text for details. PK: pharmacokinetics; MAA: marketing authority authorization. (A color version of this figure is available in the online journal.)

Figure 4.

An analysis of reasons for attrition in drug development. (a) Safety failures during GLP toxicology testing show that CNS toxicity is infrequent. (b) Safety failures across all discovery and development stages demonstrate that CNS accounts for almost 25% of failures. (c) Clinical failures predominate over preclinical failures. The CNS therapy area predominates in the overall failure profile due to CNS toxicity but CVGI and R&I are also impacted. For original data see Cook et al.(A color version of this figure is available in the online journal.)

Figure 5.

Incidence of neurotoxicities reported in the FDALabel database. FDALabel provides a concise overview of US Food and Drug Administration (FDA) drug labeling, which details drug products, drug–drug interactions, adverse drug reactions (ADRs) and contains a set of approximately 80,000 data labels. (A color version of this figure is available in the online journal.)

Figure 6.

Correlation of biomarkers in the rat TMT model with imaging and histopathological endpoints. In MRI, magnetic pulses perturb the orientation of protons (typically hydrogen atoms) and the instrument records the time it takes for the perturbed protons to return or relax to their pre-perturbed state. Longitudinal relaxation time is referred to as T1 and transverse relaxation time as T2. Fluorojade C (FJC) is a marker for dead neurons. GFAP: green fibrillary acidic protein; MRI: magnetic resonance imaging. (A color version of this figure is available in the online journal.)