Introduction: Approximately 40% of Parkinson's disease (PD) patients that take mostly dopamine receptor agonists for motor fluctuations, experience the return of symptoms between regular doses. This is a phenomenon known as 'OFF periods.' Positive allosteric modulators (PAMs) of metabotropic glutamate receptor 4 (mGluR4) are a promising non-dopaminergic mechanism with potential to address the unmet need of patients suffering from OFF periods. Foliglurax is the first mGluR4 PAM that has advanced into clinical testing in PD patients.
Areas covered: We summarize the chemistry, pharmacokinetics, and preclinical pharmacology of foliglurax. Translational PET imaging studies, clinical efficacy data, and a competitive landscape analysis of available therapies are presented to the readers. In this Perspective article, foliglurax is used as a case study to illustrate the inherent R&D challenges that companies face when developing drugs. These challenges include the delivery of drugs acting through novel mechanisms, long-term scientific investment, and commercial success and shorter-term positive financial returns.
Expert opinion: Failure to meet the primary and secondary endpoints in a Phase 2 study led Lundbeck to discontinue the development of foliglurax. Understanding the evidence supporting compound progression into Phase 2 will enable the proper assessment of the therapeutic potential of mGluR4 PAMs.
Keywords: Allosteric drugs; drug discovery and development; foliglurax; mGluR4 PAM; nondopaminergic mechanisms; off periods; parkinson’s disease; pharmaceutical business models; preclinical efficacy models; translational PET imaging.