Abstract
The clinical failure rate for disease-modifying treatments (DMTs) that slow or stop disease progression has been nearly 100% for the major neurodegenerative disorders (NDDs), with many compounds failing in expensive and time-consuming phase 2 and 3 trials for lack of efficacy. Here, we critically review the use of pharmacological and mechanistic biomarkers in early phase clinical trials of DMTs in NDDs, and propose a roadmap for providing early proof-of-concept to increase R&D productivity in this field of high unmet medical need. A literature search was performed on published early phase clinical trials aimed 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 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 fail approach in an area that has seen a nearly 100% failure rate to date.
Highlights
While there have been successes in neuropharmacology, most central nervous system (CNS) pharmaceutical approaches treat symptoms rather than disease cause
There is an urgent need for better treatments that can slow or stop disease progression of neurodegenerative disorders (NDDs), especially since the burden of these debilitating diseases on patients and society is on the rise as populations age [1]
The ability of an investigational compound to “interfere in the underlying pathophysiological mechanisms leading to cell death” on the other hand, is something that could be demonstrated with the use of pharmacodynamic biomarkers in short-duration early phase trials, even in healthy subjects
Summary
While there have been successes in neuropharmacology, most central nervous system (CNS) pharmaceutical approaches treat symptoms rather than disease cause. In a field where nearly 100% of investigational drugs fail to make it to market, the use of such biomarkers can offer an indirect yet relatively quick strategy to confirm (peripheral) target and pathway-engagement and provide early proof-of-concept in short-duration mechanistic early-phase trials in both healthy volunteers and patients [23,24]. This quick win/fast fail approach can increase research and development (R&D) productivity and help guide dosing-decisions for maximizing success rates in later stage trials [25]. We summarize and conclude this overview with a proposal for a roadmap for designing mechanistic, data-rich early phase clinical pharmacology studies for disease-modifying therapies in neurodegenerative disorders
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