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Drug repurposing in neurological diseases: an integrated approach to reduce trial and error
  1. Alexander E Clout1,
  2. Oscar Della Pasqua2,3,
  3. Michael G Hanna4,5,
  4. Mine Orlu1,
  5. Robert D S Pitceathly4,5
  1. 1 Department of Pharmaceutics, UCL School of Pharmacy, London, UK
  2. 2 Clinical Pharmacology and Therapeutics Group, UCL School of Pharmacy, London, UK
  3. 3 Clinical Pharmacology Modelling and Simulation, GlaxoSmithKline, Uxbridge, UK
  4. 4 MRC Centre for Neuromuscular Diseases, UCL Queen Square Institute of Neurology and National Hospital for Neurology and Neurosurgery, London, UK
  5. 5 Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK
  1. Correspondence to Dr Robert D S Pitceathly; r.pitceathly{at}; Dr Mine Orlu; m.orlu{at}


Identifying effective disease-modifying therapies for neurological diseases remains an important challenge in drug discovery and development. Drug repurposing attempts to determine new indications for pre-existing compounds and represents a major opportunity to address this clinically unmet need. It is potentially more cost-effective and time-efficient than de novo drug development and has yielded notable successes in neurological disorders. However, across all medical disciplines, only 30% of repurposed drugs, and 10% of novel candidate molecules, gain market approval. One potentially significant contributor towards this limited success rate is an incomplete knowledge of the exposure–response relationships for the compounds of interest, and how these relate to the new indication, prior to commencing a new trial. We provide an overview of the current approach to early-stage drug repurposing and consider the issues contributing to inconclusive, or possibly falsely negative, Phase II and III trial outcomes in neurological diseases by highlighting examples that illustrate the limitations of empirical evidence generation without a strong scientific basis for the dose rationale. We conclude with a framework suggesting a translational, iterative approach, that integrates pharmacological, pharmaceutical and clinical expertise, towards preclinical and early clinical drug development. This ensures appropriate dosing regimen, route of administration and/or formulation are selected for the new indication before their evaluation in prospective clinical trials.

  • repurposing
  • repositioning
  • neurological diseases
  • dose rationale
  • formulation
  • clinical trials
  • Pharmacokinetics
  • Pharmacodynamics
  • Pharmacokinetic-Pharmacodynamic

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  • MO and RDSP contributed equally.

  • Contributors AEC, ODP, MGH, MO and RDSP contributed to the conception and design of the work, and were involved in drafting the work, revising it critically and reviewing for the final approval.

  • Funding AEC is funded by the Lily-Stoneygate Research Awards Programme ‘Treatments for Mitochondrial Disease’ 2016/2017. RDSP is supported by a Medical Research Council Clinician Scientist Fellowship (MR/S002065/1).

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Provenance and peer review Not commissioned; externally peer reviewed.