Foliglurax Fails to Minimize Long-term Use Side Effects of Levodopa, Phase 2 Trial Shows

Despite being safe and well-tolerated, foliglurax (PTX002331), an investigational therapy for Parkinson’s disease, failed to significantly reduce some of the effects associated with long-term use of levodopa, including its “wearing-off” effect and motor complications, according to data from a Phase 2 clinical trial.

As a result, Lundbeck, the company that currently holds the therapy’s development and commercial rights, has decided to terminate its development program and to write-down foliglurax’s current value of €100 million (about $108 million).

“We are disappointed that foliglurax did not demonstrate sufficient efficacy for patients living with Parkinson’s disease. We have made the difficult decision to discontinue the development of the foliglurax program to focus our resources on more promising programmes,” Johan Luthman, executive vice president and head of research and development at Lundbeck, said in a press release.

Levodopa, a dopamine replacement therapy, is the mainstay of treatment used to ease the symptoms of Parkinson’s. However, its long-term use can have multiple side effects, including a “wearing-off” effect (off periods), in which the medication ceases to be effective at preventing symptoms, and levodopa-induced dyskinesia (LID), a condition in which patients start having involuntary muscle movements.

Foliglurax, originally developed by Prexton Therapeutics and then acquired by Lundbeck, is an experimental treatment for Parkinson’s that is intended to lessen  the symptoms of the disease using an alternative strategy that does not involve the brain’s dopaminergic system targeted by levodopa.

Instead, foliglurax activates metabotropic glutamate receptor 4 (mGluR4), a type of brain receptor that is thought to be a promising therapeutic candidate to alleviate both motor and non-motor symptoms of Parkinson’s.

The recently-completed, proof-of-concept, Phase 2 trial (NCT03162874), called AMBLED, investigated the safety, tolerability, and effectiveness of foliglurax when used as an add-on therapy to levodopa at reducing LID and off periods in 157 patients with Parkinson’s who had been treated with levodopa for at least three years.

During AMBLED, participants were assigned randomly to receive either foliglurax, at a dose of 10 or 30 mg, or a placebo, both administered orally, twice daily, for a period of 28 days. Then came a follow-up period of 14 days.

The main goal of the study was to assess changes in the daily awake off time, based on patients’ diary entries, from the beginning of the trial (baseline) to the end of the 28-day treatment period. Secondary goals included assessing changes in LID, which was evaluated based on the Unified Dyskinesia Rating Scale (UDysRS) score, within the same time-frame.

Findings from the trial now announced by Lundbeck showed both doses of foliglurax failed to meet the study goals of demonstrating a significant positive effect at reducing levodopa’s “wearing-off” effect and LID compared to a placebo.

Foliglurax had an acceptable safety and tolerability profile, which was consistent with data from a previous Phase 1 trial (NCT02639221) assessing the safety, tolerability, and pharmacokinetic properties of the medication in a group of healthy volunteers. (Pharmacokinetics is the study of how a medicine is absorbed, distributed, metabolized, and eliminated from the body.)

The company is still conducting additional analyses to understand the full extent of these findings. Data from AMBLED will be published in a medical journal in the coming months.