foliglurax (PXT2331) / Lundbeck, Domain Therap - LARVOL DELTA

Metabotropic Glutamate Receptor 4 (mGlu4) Positive Allosteric Modulators Lack Efficacy in Rat and Marmoset Models of L-DOPA-Induced Dyskinesia. (PubMed, J Parkinsons Dis) - "Given the weak efficacy and side-effect profile of amantadine, alternative strategies to reduce glutamate transmission are being investigated...We hypothesized that two mGlu4 positive allosteric modulators, Lu AF21934 ((1 S,2 R) N1-(3,4-dichlorophenyl)cyclohexane-1,2-dicarboxamide) and ADX88178 (5-Methyl-N-(4-methylpyrimidin-2-yl)-4-(1H-pyrazol-4-yl)thiazol-2-amine), would provide relief in rat and primate models of L-DOPA-induced dyskinesia...This study found no benefit of mGlu4 positive allosteric modulators in tackling L-DOPA-induced dyskinesia. These findings are concordant with the recent failure of foliglurax in phase II clinical trials supporting the predictive validity of these pre-clinical dyskinesia models, while raising further doubt on the anti-dyskinetic potential of mGlu4 positive allosteric modulators."

Journal • Preclinical • CNS Disorders • Movement Disorders • Parkinson's Disease

Effect of ADX-88178, a highly-selective mGlu4 PAM, on parkinsonism, dyskinesia and psychosis-like behaviours in the MPTP-lesioned marmoset (MDS Congress 2023) - "Recently, the development of the mGlu PAM foliglurax was discontinued, after it failed to meet endpoints pertaining to off time and dyskinesia in a clinical trial...ADX-88178 is a highly-selective mGlu PAM that previously reversed catalepsy induced by haloperidol in the rat and enhanced the anti-parkinsonian action of L-DOPA in the 6-hydroxydopamine-lesioned rat... These results provide additional evidence of the anti-parkinsonian effect of ADX-88178 as an adjunct to L-DOPA and also indicate that ADX-88178 may alleviate L-DOPA-induced dyskinesia. However, they also suggest that ADX-88178 may not be suitable for PD patients with psychotic manifestations; whether it is a drug-specific or a class effect warrants further investigation."

CNS Disorders • Parkinson's Disease • Psychiatry

Foliglurax, a positive allosteric modulator of the metabotrophic glutamate receptor 4, protects dopaminergic neurons in MPTP-lesioned male mice. (PubMed, Brain Res) - "There was a negative correlation between dopamine content and GFAP levels. Our results show that positive allosteric modulation of mGlu4 receptors with foliglurax provided neuroprotective effects in the MPTP mouse model of PD."

Journal • Preclinical • CNS Disorders • Inflammation • Movement Disorders • Parkinson's Disease • GFAP

Clinical investigations of compounds targeting metabotropic glutamate receptors. (PubMed, Pharmacol Biochem Behav) - "PET ligands for mGlu5Rs have been studied in a range of patient populations and several mGlu5R antagonists have been tested for potential efficacy in patients including mavoglurant, diploglurant, basimglurant, GET 73, and ADX10059...Fenobam was approved for use as an anxiolytic prior to its recognition as an mGlu5R antagonist. mGlu2/3R agonists (pomaglumated methionil) and mGlu2R agonists (JNJ-40411813, AZD 8529, and LY2979165) have been studied in patients with schizophrenia with promising but mixed results. Antagonists of mGlu2/3Rs (decoglurant and TS-161) have been studied in depression where TS-161 has advanced into a planned Phase 2 study in treatment-resistant depression...The mGlu4R potentiator, foliglurax, did not meet its primary endpoint in patients with Parkinson's disease. Ongoing efforts to develop mGluR-targeted compounds continue to promise these glutamate modulators as medicines for psychiatric and neurological disorders."

Journal • CNS Disorders • Depression • Developmental Disorders • Epilepsy • Fragile X Syndrome • Gastroenterology • Gastroesophageal Reflux Disease • Genetic Disorders • Mental Retardation • Mood Disorders • Movement Disorders • Pain • Parkinson's Disease • Psychiatry • Schizophrenia

A positive allosteric modulator of mGlu4 receptors restores striatal plasticity in an animal model of l-Dopa-induced dyskinesia. (PubMed, Neuropharmacology) - "This study aimed to clarify the effects of foliglurax, a selective mGlu4-PAM, on the loss of bidirectional synaptic plasticity associated with l-DOPA-induced dyskinesia (LID)...Moreover, this co-treatment rescued striatal bidirectional plasticity and attenuated the intensity of l-DOPA-induced dyskinesia. This is the first demonstration in an animal model of PD and dyskinesia that a mGlu4 PAM can restore striatal synaptic plasticity."

Journal • Preclinical • CNS Disorders • Movement Disorders • Parkinson's Disease

A Randomized, Double-Blind, Controlled Phase II Study of Foliglurax in Parkinson's Disease. (PubMed, Mov Disord) - "There was no evidence in this study that foliglurax has efficacy in improving levodopa-induced motor complications in PD."

Clinical • Journal • P2 data • CNS Disorders • Movement Disorders • Parkinson's Disease

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? (PubMed, Expert Opin Investig Drugs) - "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."

Clinical • Journal • CNS Disorders • Movement Disorders • Parkinson's Disease

[VIRTUAL] Research Outcomes in Parkinson Disease Emerging Therapies: Impact of a Medical Education Program on Neurologists’ Knowledge (ANA 2020) - "The following areas showed significant (P <0.05) pre- vs posteducational improvements: primary outcome for a trial that examined the early vs delayed use of levodopa/carbidopa in patients with early PD (60% relative pre-vs post education improvement), primary outcome for a clinical trial of isradipine in patients with newly diagnosed PD (60% relative pre-vs post education improvement), and identification of primary PD symptoms assessed in a clinical trial of foliglurax (34% relative pre-vs post education improvement). The results suggested that the CME-certified 30-minute video discussion between physician experts was effective at improving knowledge in PD related emerging therapies. Future educational efforts should continue to address findings from clinical and other research in PD."

CNS Disorders • Parkinson's Disease

Improved Synthesis of the Thiophenol Precursor N-(4-Chloro-3-mercaptophenyl)picolinamide for Making the mGluR4 PET Ligand. (PubMed, Tetrahedron) - "Recently [C]mG4P012 (previously [C]KALB012 and presently named as [C]PXT012253 by Prexton Therapeutics) had been used as a biomarker during the preclinical development of a potential therapeutic drug, PXT0002331 (an mGluR4 PAM), for PD and L-dopa-induced dyskinesia...To support the translational research of [C]mG4P012 and the other potential applications, we have developed a new route for synthesis of the thiophenol precursor and optimized the reaction conditions. The synthesis of N-(4-chloro-3-mercaptophenyl)picolinamide from 1-chloro-4-nitrobenzene has been greatly improved from 8% to 52% total yield with easy handling and in gram scales."

Journal • Movement Disorders

Study Investigating Effects of Foliglurax in Patients With Parkinson's Disease (PD) and Healthy Subjects (clinicaltrials.gov) - P1; N=6; Terminated; Sponsor: H. Lundbeck A/S; N=30 ➔ 6; Recruiting ➔ Terminated; Study termination due to efficacy results of another study

Clinical • Enrollment change • Trial termination • CNS Disorders • Gene Therapies • Movement Disorders • Parkinson's Disease

Binding of Foliglurax to Regions in the Brain in Healthy Participants and in Patients With Parkinson's Disease (PD) (clinicaltrials.gov) - P1; N=6; Terminated; Sponsor: H. Lundbeck A/S; N=17 ➔ 6; Recruiting ➔ Terminated; New efficacy data from another study

Clinical • Enrollment change • Trial termination • CNS Disorders • Gene Therapies • Movement Disorders • Parkinson's Disease

Discovery, characterization and anti-Parkinsonian effect of a novel mGluR4 PAM chemical series (ACS-Fall 2018) - "Moreover, we described the identification of a close analog with improved PK profile after oral administration. Based on its favorable and unique profile, compound PXT002331 or foliglurax could be a good candidate for clinical development."

Biosimilar • CNS Disorders • Gene Therapies • Genetic Disorders • Parkinson's Disease

A NOVEL MGLUR4 COMPOUND ALLEVIATES MOTOR SYMPTOMS IN PRIMATE MODELS OF PARKINSON'S DISEASE (WCN 2017) - "This is the first demonstration in non-human primates that a mGluR4 PAM can alleviate the motor symptoms of PD and the motor complications induced by levodopa. Supported by its unique profile, foliglurax has been the first mGluR4 PAM entering the clinics and is now being tested in Phase IIa studies."

Clinical • CNS Disorders • Parkinson's Disease

Characterization of [C]PXT012253 as a PET Radioligand for mGlu Allosteric Modulators in Nonhuman Primates. (PubMed, Mol Imaging Biol) - "[C]PXT012253 was shown to be a promising PET radioligand for mGlu allosteric modulators in the monkey brain. MA1 would be the choice of quantitative method. Further development of [C]PXT012253 in human subjects is warranted."

Journal

Effects of Repeated Doses of Foliglurax on Drug Metabolizing Enzymes in Healthy Subjects (clinicaltrials.gov) - P1; N=20; Completed; Sponsor: H. Lundbeck A/S; Recruiting ➔ Completed

Clinical • Trial completion

Lundbeck reports headline results from phase IIa AMBLED study of foliglurax in Parkinson’s disease (Lundbeck Press Release) - "H. Lundbeck A/S...today announced that the phase IIa study (AMBLED) of its novel selective positive allosteric modulator of the glutamate 4 receptor (mGlu4 PAM), foliglurax, for the treatment of Parkinson's disease did not meet the primary study endpoint. There was no statistically significant difference in change from baseline in OFF time versus placebo after a 4-week treatment period....'We have made the difficult decision to discontinue the development of the foliglurax program to focus our resources on more promising programmes.'"

Discontinued • P2a data

Study Investigating Effects of Foliglurax in Patients With Parkinson's Disease (PD) and Healthy Subjects (clinicaltrials.gov) - P1; N=30; Recruiting; Sponsor: H. Lundbeck A/S

New P1 trial

AMBLED: Study to Evaluate the Efficacy, Safety and Tolerability of PXT002331 (Foliglurax) in Reducing Motor Complications of Levodopa Therapy in Parkinson Disease's Patients (clinicaltrials.gov) - P2a; N=157; Completed; Sponsor: Prexton Therapeutics; Active, not recruiting ➔ Completed

Clinical • Trial completion

Effects of Repeated Doses of Foliglurax on Drug Metabolizing Enzymes in Healthy Subjects (clinicaltrials.gov) - P1; N=20; Recruiting; Sponsor: H. Lundbeck A/S

Clinical • New P1 trial

AMBLED: Study to Evaluate the Efficacy, Safety and Tolerability of PXT002331 (Foliglurax) in Reducing Motor Complications of Levodopa Therapy in Parkinson Disease's Patients (clinicaltrials.gov) - P2a; N=157; Active, not recruiting; Sponsor: Prexton Therapeutics; Recruiting ➔ Active, not recruiting; Trial completion date: Oct 2019 ➔ Mar 2020; Trial primary completion date: Sep 2019 ➔ Feb 2020

Clinical • Enrollment closed • Trial completion date • Trial primary completion date

Binding of Foliglurax to Regions in the Brain in Healthy Participants and in Patients With Parkinson's Disease (PD) (clinicaltrials.gov) - P1; N=17; Recruiting; Sponsor: H. Lundbeck A/S

Clinical • New P1 trial

An mGlu4-Positive Allosteric Modulator Alleviates Parkinsonism in Primates. (PubMed, Mov Disord) - "This work provides a demonstration that a positive allosteric modulator of metabotropic glutamate receptor 4 can alleviate the motor symptoms of PD and the motor complications induced by l-dopa in primates. PXT002331 is the first compound of its class to enter phase IIa clinical trials."

Journal

Lundbeck makes a large M&A move, but the target will be somewhat controversial (SeekingAlpha) - "The most promising pipeline assets today are...foliglurax, an experimental treatment for levodopa-induced dyskinesia in Parkinson’s, where investors should see proof of concept data in Q1’2020."

What the Body Does to Foliglurax in Healthy Volunteers (clinicaltrials.gov) - P1; N=6; Completed; Sponsor: H. Lundbeck A/S; Not yet recruiting ➔ Completed

Clinical • Trial completion

DT095435: A novel “pan” group III metabotropic glutamate receptor positive allosteric modulator for Parkinson’s disease (Neuroscience 2019) - "As expected from its PK profile, our candidate exhibited robust pro-motor activity after oral administration and remained active at dose as low as 0.1 mg/kg in mouse haldol-induced catalepsy model. Using two more advanced PD models, i.e. unilateral 6-OHDA lesioned rats & monkeys lesioned with MPTP toxin (both rendered dyskinetic by prolonged L-DOPA treatment), we have also compared efficacy of our non-selective mGluR4/7/8 PAM QZ candidate with that of selective mGluR4 PAM Foliglurax and/or amantadine in reducing LID."