IRL790 Showed a Reduction in Levodopa-Induced Dyskinesia in Parkinson

December 20, 2018

The results of the study found that those taking IRL790 had a mean reduction of 8.2% in dyskinesia scores compared to placebo.

Per Svenningsson, MD, PhD

A phase 1b trial investigating IRL790 as a treatment for Parkinson disease with levodopa-induced dyskinesia demonstrated that the investigational therapy was safe and reduced levodopa-induced dyskinesia.

The results of the study found that those taking IRL790 had a mean reduction of 8.2% in dyskinesia scores compared to those taking placebo.

When asked about the clinical implications of this phase 1b study, one of the study authors, Per Svenningsson, MD, PhD, professor/specialist physician, Karolinska Institutet, told NeurologyLive, IRL790 is a “a novel mechanism and therapy to treat L-DOPA-induced dyskinesias, primarily targeting the dopamine D3 receptor. Patients with Parkinson have a very good anti-dyskinetic response already at very low doses of IRL790.”

The study (NCT03531060) included 15 participants with Parkinson disease, 9 men and 6 women, who were randomized to oral administration of 10 mg IRL790 (11 participants) or an oral placebo (4 participants) for 4 weeks. The study drug was given as an adjunct treatment to participants’ regular stable antiparkinsonian medication. Dosing was individually titrated for 14 days.

The main objective was to assess IRL790’s safety measured through the number of adverse effects, physical examination, electrocardiogram recordings, heart rate, blood pressure, and additional safety laboratory measures after 4 weeks. Secondary measures included changes from baseline in the Unified Dyskinesia Rating Scale, Unified Parkinson’s Disease Rating Scale, Parkinson Kinetigraph, Clinical Global impression of change, and pharmacokinetic assessment.

On the Unified Dyskinesia Rating Scale, a median reduction of 11.5 points vs. placebo and a mean reduction of 8.2 points vs. placebo was observed for the IRL790-treated group, and among those treated with the study drug, 55.5% were assessed as having an improved global clinician condition compared to baseline. There were no changes in symptoms in either the Unified Dyskinesia Rating Scale or Parkinson’s Kinetigraph­ assessments.

Thirteen participants completed the 4-week study, with IRL790 given at an average daily dose of 18 mg. Adverse effects were mostly reported during the titration phase of the trial (48 adverse effects) and were mainly central nervous system related and are expected to be due to the pharmacology of IRL790. Overall, 14 participants (93.3%) reported 62 adverse effects and were mild to moderate and mitigated by dose adjustments. There were no serious adverse effects reported; and no cardiovascular adverse effects were reported or detected. Two participants (18.2%) in the IRL790 group withdrew due to adverse effects assessed as possibly related to study treatment. A slight increase in prolactin levels was observed after treatment with IRL790, where the mean relative change from baseline to the completion of the study was 71.5 (71.8%) (median 58.5) in the intent-to-treat group, compared to 28.4 (59%) (median 7.1) in the placebo-treated participants. No individual abnormal prolactin values were assessed as clinically significant.

There were no clinically significant changes in vital signs, electrocardiogram and lab parameters due to treatment. The average dose in the stable dose phase was 18 mg (10­—30 mg) daily. Assessments for motor function showed a numeric reduction in dyskinesia

The phase 1b trial concluded that IRL790 can safely be administered to patients with advanced Parkinson disease, but, according to researchers, the optimal dose for the intended patient population appears to be lower than anticipated from dose titration studies in healthy male volunteers which demonstrated that IRL790 was well-tolerated in single doses up to 120 mg and multiple daily doses up to 80 mg.

These study data were the guidance for design of the current phase 2b trial (NCT03368170) in which IRL790 is currently being assessed in to study the efficacy and tolerability in a larger population of 74 participants. This trial will also help establish optimal dosing.

REFERENCE

Svenningsson P, Johansson A, Nyholm D, et al. Safety and tolerability of IRL790 in Parkinson’s disease with levodopa-induced dyskinesia—a phase 1b trial.

npj

Parkinson’s Disease. 2018;4:35.

doi

: 10.1038/s41531-018-0071-3.