Treatment with IRLAB Therapeutics‘ small molecule IRL752 is safe and well-tolerated by Parkinson’s disease patients with dementia, and may help manage symptoms that are unresponsive to levodopa, results from a Phase 2a trial show.
In particular, the treatment was found to reduce apathy, improve balance, and decrease the risk of falls. Planning and executive function also seem to improve with IRL752. Notably, no severe adverse events related to treatment were reported.
IRL752 is a small molecule that has the ability to enhance communications between nerve cells in the frontal cortex, a major brain area that controls cognitive functions. It does so by increasing the availability of two important chemical messengers (neurotransmitters) — norepinephrine and dopamine — and by activating specific genes involved in nerve cell communication.
Both of these chemical messengers are needed for cells to communicate properly but their levels are reduced in those with Parkinson’s disease, leading to the motor and cognitive deficits characteristic of the condition.
After showing that IRL752 is safe and well-tolerated in a group of 40 healthy volunteers included in a Phase 1 trial, with no cardiovascular effects reported, IRLAB designed a Phase 2a trial (2017-001673-17) to evaluate the treatment’s safety, tolerability, and preliminary signs of efficacy in people with Parkinson’s and dementia taking their normal antiparkinsonian medications.
“The aim with IRL752 is to improve balance and reduce the risk of falls in patients with Parkinson’s disease, which is the current top priority within the treatment of Parkinson’s disease,” Joakim Tedroff, MD, PhD, chief medical officer of IRLAB, said in a press release.
The trial included 32 patients, median age of 72 years, from Sweden and Finland who were randomly assigned IRL752 or a placebo. The treatment’s dose was adjusted for each patient during the first 14 days, after which dosing was kept stable for an additional 14 days of treatment. The average dose achieved in the stable dose phase was 600 mg daily.
The trial’s main goal was to determine the safety and efficacy of repeat IRL752 dosing in these patients. Secondary efficacy measures included IRL752’s effects on Parkinson’s symptoms, postural control and walking speed, freezing of gait, cognitive function, neuropsychiatric symptoms, and global function.
During the four-week treatment period, 72% of patients reported at least one treatment-emergent adverse event, 58% of which were possibly related to treatment. Most adverse events were mild, affected the central nervous system, and occurred predominantly in the first two weeks, when the dose was still being adjusted for each patient.
The most common adverse events related to IRL752 included abdominal pain, headache, tremor, increase in liver enzymes (indicating possible liver damage), and cognitive disorder.
Two patients reported severe adverse events during the study, but none were deemed related to treatment. Also, no patient experienced changes in vital signs or in cardiovascular parameters.
Regarding efficacy, patients taking IRL752 showed significant lessening of axial motor symptoms such as postural instability and falls, as well as reductions in apathy and cognitive impairment. These symptoms are known to be largely unresponsive to levodopa treatment.
Notably, “the possible effect of adjunct IRL752 treatment on postural dysfunction seemed not to be a result of a general effect on parkinsonism because none of the other classical hallmark symptoms of Parkinson’s disease were affected by the treatment,” the researchers wrote.
Instead, they believe that an increase in norepinephrine likely explains the improvements, as symptoms such as poor balance and apathy have been associated with lower levels of this neurotransmitter.
The researchers also showed that IRL752 reached concentrations in the blood believed to have a therapeutic effect, suggesting that “IRL752 may be dosed at potentially clinically effective dosing in this patient population.”
The company is now planning a Phase 2b clinical trial to continue evaluating the effects of IRL752 on the frequency of falls in Parkinson’s patients.
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