Foliglurax Failed in Trial to Ease Side Effects of Long-term Levodopa

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by Steve Bryson, PhD |

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In a final report on the Phase 2 AMBLED trial, scientists detailed the failure of Foliglurax (PTX002331) — once an investigational therapy for Parkinson’s disease — to significantly reduce some of the side effects associated with the long-term use of levodopa.

“There was no evidence in this study that foliglurax has efficacy in improving levodopa-induced motor complications in [Parkinson’s disease],” the researchers wrote.

Those results led Lundbeck, which was developing the oral therapy, to terminate its foliglurax program in March 2020.

Now, the clinical trial findings were published in the journal Movement Disorders, in a report titled “A Randomized, Double-Blind, Controlled Phase II Study of Foliglurax in Parkinson’s Disease.”

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Levodopa is one of the main medications used to ease Parkinson’s disease symptoms, such as stiffness and slowness of movement. It is the precursor of dopamine, a neurotransmitter or nerve cell signaling molecule, which is abnormally low in people with Parkinson’s.

However, long-term use of levodopa can lead to “off” periods, in which the medication is less effective at preventing symptoms, and also can induce involuntary muscle movements called dyskinesia. As a result, considerable research has focused on developing therapeutics that target non-dopamine systems.

Foliglurax, first developed by Prexton Therapeutics and then acquired by Lundbeck, was an oral therapy designed to lessen symptoms by targeting the brain receptor mGluR4. The treatment showed promise in reducing motor symptoms in several animal studies.

Building on those findings, a Phase 1 trial (NCT02639221) was conducted, which demonstrated that foliglurax was safe and well-tolerated in 64 healthy individuals. The medicine had an excellent pharmacological profile.

Then, a proof-of-concept Phase 2 study (NCT03162874), called AMBLED, was launched to evaluate foliglurax in 157 Parkinson’s patients as an add-on therapy to levodopa, with the aim of reducing off periods and levodopa-induced dyskinesia.

However, Lundbeck reported that foliglurax failed to significantly reduce the effects of long-term levodopa use, and announced it was terminating the therapy’s development and writing down foliglurax’s estimated value of €100 million (about $108 million).

Scientists at Lundbeck, with researchers at the University of Toulouse, in France, described more fully in this report the details of the AMBLED trial. Participants, who had been treated with levodopa for at least three years, were randomly assigned to receive either foliglurax (10 or 30 mg) or a placebo, given twice daily, for 28 days.

The study’s primary goal was to reduce the daily awake off time, based on patients’ diary entries, across the treatment period. Secondary measures included changes in levodopa-induced dyskinesia, evaluated by the Unified Dyskinesia Rating Scale (UDysRS) score.

According to the main analysis, although there was a numerical decrease in the daily awake off time in a dose-dependent manner compared with a placebo, the difference was not statistically significant.

After 28 days of treatment, off time had reduced by 0.55 hours in the foliglurax 10 mg group and by 0.72 hours in the 30 mg group versus 0.29 in the placebo group. Overall, 44.7% of patients who received 30 mg of foliglurax had a decrease in daily awake off time of one or more hours compared with 31.1% in the 10 mg group and 30.4% with placebo.

In addition, there were no differences in UDysRS scores between either foliglurax dose and placebo or in any other diary measures.

Treatment-emergent adverse effects (TEAEs) were experienced by 52.8% of those treated with 10 mg foliglurax, 50% of patients in the 30 mg group, and 42.3% of placebo participants. Most TEAEs were mild or moderate in severity and were resolved during the study. All seven serious TEAEs that occurred were considered not related to treatment.

The most common TEAEs were on and off symptoms, dyskinesia, and headache. Eight participants withdrew from the study due to TEAEs. There were no relevant changes between treatment groups concerning standard lab tests, heart measures, or other vital signs.

“In this proof-of-concept study, no significant effect on off time was seen with either dose of foliglurax versus placebo, and hence the study did not meet its primary endpoint [goal],” the researchers concluded, adding, “We also could not demonstrate positive results for other endpoints, including dyskinesia severity or good on time.”