• Current treatment addresses symptoms without modifying disease.
• Rexaceract restores GCase functionality to reduce alpha-synuclein aggregation.
• Treatment-emergent adverse events were considered mild.

Scores on a clinical evaluation tool for motor symptoms of Parkinson’s disease stabilized with rexaceract, according to data presented at the International Congress of Parkinson’s Disease and Movement Disorders.

In addition to stable scores on the Movement Disorder Society-Sponsored Revision of the Unified Parkinson’s Disease Rating Scale, oral treatment with the brain-penetrant small molecule also was well-tolerated, Joanne Taylor, PhD, chief scientific officer, Gain Therapeutics, and colleagues wrote.

“The current standard of care for Parkinson’s disease is symptomatic treatment, which is basically based on the dopamine neurotransmitter system,” Taylor told Healio.

Levodopa makes more dopamine available as the nerve cells that contain dopamine die with the disease, she explained.

“It’s pretty effective in the beginning, but then it doesn’t work anymore after a while because it depends on the surviving neurons being able to make more dopamine,” Taylor said. “As they die, it doesn’t work anymore.”

Dopamine agonists can mimic dopamine’s effects, but these drugs also wear off with time without stopping the underlying cause of the disease.

“Rexaceract is hoping to be one of the first, if not the first, disease-modifying drugs currently in development,” she said. “We’re hoping to stop the nerve cells from dying in the first place.”

The GBA1 gene encodes for glucocerebrosidase (GCase), a lysosomal enzyme, the researchers noted. But when GBA1 variants cause misfolding and impairment of GCase, endoplasmic reticulum stress, lysosomal and mitochondrial dysfunction, reductions in GCase activity, alpha-synuclein aggregation and neuroinflammation may follow.

According to Taylor, even patients who do not have a GBA1 mutation experience deficits in this functioning, for reasons that have yet to be determined.

“GCase is an enzyme which is very important in the lysosome, which is a structure in the cell which is responsible for clearing junk out of the cell,” she said.

Rexaceract corrects molecular pathway abnormalities while stabilizing GCase and chaperoning it to lysosomes and mitochondria to restore its function, the researchers said, potentially slowing the progression of disease.

“We get rid of that toxic substrate, and we also prevent the aggregation of alpha-synuclein, and we’ve shown this very, very clearly in our preclinical models that this is actually what happens,” Taylor said.

The phase 1b study included 90 days of dosing in its first part and 9 months of additional dosing during an optional extension, which 12 patients with Parkinson’s disease (age range, 42 to 83 years) for up to 7 years have completed so far. The cohort included patients with and without the GBA1 mutation.

“It was quite a broad population,” Taylor said.

Dosing included 13.5 mg/kg each day, with an option for 11 mg/kg each day when tolerability was inadequate.

Movement Disorder Society-Sponsored Revision of the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) motor scores were stable from baseline through 360 days.

There also was no meaningful progression in motor symptoms based on part II of the scale, which involves patient-reported assessments of motor function in daily activities, or on part III, which is an assessment of motor function by the clinician.

Gain Therapeutics said that scores on parts II and III typically increase by about six points each year, indicating disease progression.

“It remained flat,” Taylor said. “The UPDRS scores didn’t go up over the year.”

In fact, she said, patients with high levels of glucosylsphingosine, a GCase substrate, in their cerebral spinal fluid at baseline unexpectedly saw motor improvement at 90 days as these levels fell, unlike patients with lower glucosylsphingosine levels at baseline that remained constant. 

“But as we’ve gone out to 360 days, everybody is stabilized,” Taylor said. “There isn’t this difference anymore.”

Additionally, although some patients experienced transient elevations in liver enzymes in the first part of the study, there were no such elevations during the second part, nor were there any other new safety signals.

“The number of safety signals in the second part of the trial were fewer than in the first part of the trial, which is really good news if you’re looking at a treatment which is going to go on over years,” Taylor said. “The drug seems to be quite safe.”

Taylor and colleagues classified most of the treatment-emergent adverse events as mild, adding that there were fewer such events in the second part compared with the first part, including four patients who experienced headaches related to treatment. There also was a musculoskeletal event that the researchers said may have been related.

Based on these findings, the researchers said that MDS-UPDRS scores stabilized with rexaceract, which patients tolerated well with no new safety signals in patients that were included in the nine-month extension study.

“Some of the patients in our study have reported anecdotal improvement in things like taste and smell, which are impaired in Parkinson’s disease, and movement, balance and concentration,” Taylor said.

Next, the researchers will explore the drug in a phase 2 clinical trial, which will include a placebo-controlled arm.

“We’ll be very interested in looking at safety in the treatment arm compared with the placebo arm,” Taylor told Healio. “We’ll be looking at clinical outcomes and biomarkers as well.”

For more information:

Joanne Taylor, PhD, can be reached at neurology@healio.com.