A case study of foliglurax, the first clinical mGluR4 PAM for symptomatic treatment of Parkinson’s disease: translational gaps or a failing industry innovation model?

ABSTRACT

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

Article highlights

• Novel Parkinson’s disease medications working through nondopaminergic mechanisms have potential to improve clinical outcomes for PD patients.

• mGluR4 positive allosteric modulators (PAMs) have shown efficacy in preclinical models generally used in the discovery of Parkinson’s disease medications.

• Progress has been made with issues of chemical tractability of mGluR PAMs, but clinically successful translational strategies remain challenging.

• Further preclinical and clinical work is required to assess the potential therapeutic utility of compounds working through the mGluR4 PAM mechanism.

• As for-profit R&D business models continue shifting toward earlier stage external partnerships and acquisitions, ‘proof of concept’ must include increasingly rigorous criteria for commercial success.

This box summarizes key points contained in the article.

Declaration of interest

D Doller is an employee of Sunovion Pharmaceuticals. He was an employee of Lundbeck Research USA between 2006 and 2015, where he conducted research on mGluRs, and is a co-inventor of several mGluR patents. A Bespalov is an employee and shareholder at PAASP GmbH, PAASP US LLC, Exciva GmbH, Synventa, LLC, and Ritec Pharma. R Miller is currently the Chief Business Officer of PAASP US, LLC. M Kalinichev is currently an employee of Ipsen Innovation, France. He was an employee of H. Lundbeck A/S between 2014 and 2015. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

One referee was involved with Prexton in a preclinical electrophysiological study in a rat model of Parkinson’s disease on the synaptic and antidyskinetic effects of foliglurax. Peer reviewers on this manuscript have no other relevant financial or other relationships to disclose.

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Additional information

Funding

This paper was not funded.