For example, peripheral receptor occupancy on cell surfaces can be measured with the use of flow cytometry on fresh blood [180]. at the evaluation of NDD DMT compounds using MESH terms in PubMed. Publications were selected that reported an early phase clinical trial with NDD DMT compounds between 2010 and November 2020. Attention was given to the reported use of pharmacodynamic (mechanistic and physiological response) biomarkers. A total of 121 early phase clinical trials were identified, of which 89 trials (74%) incorporated one or multiple pharmacodynamic biomarkers. However, only 65 trials (54%) used mechanistic (target occupancy or activation) biomarkers to demonstrate target engagement in humans. The most important categories of early phase mechanistic and response biomarkers are discussed and a roadmap for incorporation of a robust biomarker strategy for early phase NDD DMT clinical trials is proposed. As our GS-9451 understanding of NDDs is improving, there is a rise in potentially disease-modifying treatments being brought to the clinic. Further increasing the rational use of mechanistic biomarkers in early phase trials for these (targeted) therapies can increase R&D productivity with a quick win/fast GS-9451 fail approach in an area that has seen a nearly 100% failure rate to date. [38]. Other types of biomarkers can include (detecting or confirming the presence of a disease), (presence or change in the biomarker predicts an GS-9451 individual or group to experience a favorable or unfavorable effect from the exposure to a medical product), (identify the likelihood of a clinical event, disease recurrence, or disease progression in untreated patients), and (indicates the likelihood, presence, or extent of a toxicity as an adverse event) [38,39]see Table 1. In some cases, a biomarker can be used as surrogate to substitute for a clinical endpoint, but to qualify as a surrogate, a biomarker must correlate with the clinical outcome and the change in the biomarker must also explain the change in the clinical outcome [38]; evidence that is currently lacking for the majority of biomarkers. Table 1 Biomarker categories and examples of use in NND DMT drug development (adapted from Cummings and Amur et al. [39,45]). (molecular target occupancy and activation) ([patho]physiological response) Efficacy response marker as a surrogate for a clinical endpointBraak staging with tau PET as a surrogate biomarker for clinical AD (though no validated surrogate biomarkers are available yet for NDDs).DiagnosticPatient selectionGBA1 gene mutation in PD patientsEIMCSF cytokines (TGF-b1, TGF-b2, TGF-b3, IL-6, IL-10, MCP-1)(patho)physiological responsePatients[101,102,103,104,105,106,107,108,109,110,111,112,113]Gene therapyHepatocyte growth factor 1/1 (100%)Serum HGF; Leukocyte actin-normalized SOD1 CSF SOD1 protein and enzymic activityTarget activationPatients[120,121]SupplementLysosomal Cathepsins B and L0/1 (0%)—Patients[122]Stabilize the mitochondrial transition pore, buffer intracellular energy stores, stimulate synaptic glutamate uptake, and scavenge reactive oxygen species1/1 (100%)-MRS brain glutamate and glutamine (Glx)Physiological response Patients[123]Overall use of mechanistic biomarkers in early phase ALS trials14/27 (52%) *ATTR amyloidosisAntisense oligonucleotideTransthyretin (TTR)1/1 (100%)Plasma TTR-Target activationHVs[124]RNA interferenceTransthyretin amyloid1/1 (100%)Serum transthyretin, retinol-binding protein and vitamin A-Target occupancy and activationHVs and patients[125]Overall use of mechanistic biomarkers in early phase ATTR trials2/2 (100%)FRDASmall moleculeFXN gene expression1/1 (100%)Whole blood FXN mRNA, frataxin protein; mechanistic biomarkers that are primarily used to demonstrate and (target engagement), and and (distal) biomarkers (Table 1) [25,46]. Overall, 89 out of 121 (74%) NDD DMT early phase trials that were published over the past decade reported the use of one or more pharmacodynamic response biomarkers (Figure 1). Given the significant added value of using pharmacodynamic response biomarkers in early phase trials, this might not be surprising. Less than half of all trials (46%) reported the use of central pharmacodynamic biomarkers. The use of peripheral pharmacodynamic biomarkers was slightly higher at 50%. Only 65 trials (54%) reported the use of proximal mechanistic biomarkers (Figure 1) and there are clear differences in the use of biomarkers between different disorders and different types of drugs (Table 2). Open in a separate window Figure 1 Percentage of early clinical phase reporting the use of different categories of pharmacodynamic biomarkers and clinical outcomes. Thirty-one trials (26%) reported the use of target occupancy biomarkers and forty-eight trials (40%) reported the use of a target activation biomarkers. Sixty-five trials included at least 1 proximal (mechanistic) biomarker (target occupancy and/or activation). Twenty-eight trials (23%) reported the use of physiological ETV4 response biomarkers. Thirty-two trials used pathophysiological response biomarkers, which comes down to 33% of all early phase NDD DMT trials (98) that were performed in patients. Forty-seven trials (39%) reported the use of at least 1 distal biomarker. In total, 89 of 121 trials reported at least one pharmacodynamic biomarker and seventy-three trials reported clinical outcomes, which comes down to 74% of all early phase NDD DMT trials (98).