Parkinson’s therapy shows promise for motor function: Trial data
GT-02287 led to stable motor function, lower levels of disease biomarkers
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- GT-02287, an oral Parkinson's therapy, stabilized motor function.
- It reduced DOPA decarboxylase (DDC) and improved GCase activity.
- Benefits were greater in patients with high glucosylsphingosine (GluSph).
GT-02287, an oral Parkinson’s disease therapy from Gain Therapeutics, showed promising results in a Phase 1b trial. Over three months of treatment, patients had lower levels of DOPA decarboxylase (DDC) in their cerebrospinal fluid — a biomarker linked to Parkinson’s activity.
Motor function remained stable over five months of treatment. GT-02287 appeared to have greater effects in patients with high levels of glucosylsphingosine (GluSph), a marker of reduced GCase enzyme activity, which helps cells break down waste and is involved in Parkinson’s biology.
The results were detailed in a presentation, “An Open-Label Phase 1b Study of GT-02287 in Parkinson’s Disease,” by Jonas Hannestad, MD, PhD, Gain’s chief medical officer, at the AD/PD Alzheimer’s & Parkinson’s Diseases Conference, held March 17-21 in Copenhagen.
“We are encouraged by the evolving biomarker evidence in the Phase 1b clinical study of GT-02287 in Parkinson’s disease that suggests GT-02287 is targeting the causative biology of [Parkinson’s],” Gene Mack, president and CEO of Gain, said in a company press release. “The totality of the data continues to support the potential of GT-02287 in both idiopathic [of unknown cause] and GBA1 Parkinson’s disease and we hope to one day shift the treatment paradigm away from symptomatic relief and to disease modification.”
Parkinson’s disease is caused by the progressive loss of dopaminergic neurons, the nerve cells that produce dopamine, a chemical messenger involved in motor function. The accumulation of toxic clumps of misfolded alpha-synuclein protein in the brain is thought to contribute to the loss of these neurons.
Restoring GCase activity
Mutations in the GBA1 gene are a known genetic cause of Parkinson’s, leading to the production of misfolded or dysfunctional GCase, an enzyme needed to break down fatty molecules such as GluSph. This is thought to contribute to the buildup of alpha-synuclein in dopaminergic neurons.
GT-02287 is a small-molecule therapy designed to enter the brain and restore GCase activity, aiming to reduce the buildup of misfolded alpha-synuclein.
The treatment was found to be safe and well tolerated and to cross the blood-brain barrier, a protective membrane that surrounds the brain and spinal cord, in healthy volunteers in a Phase 1 trial. GT-02287 also increased GCase activity.
In the Phase 1b trial (NCT06732180), 20 people with Parkinson’s, including those with idiopathic disease or Parkinson’s associated with GBA1 mutations, were treated with GT-02287. Participants had a mean age of 63.5. Most of them (85.7%) were men, and most had been diagnosed with Parkinson’s for a mean of three years.
The trial was divided into two parts. In the first part, all participants received daily doses of GT-02287 for about three months. Participants could then enter an extension phase in which they received GT-02287 for an additional nine months. Of the 19 participants who completed treatment in the first part, 16 opted to continue into the nine-month extension study.
Previous results showed that after three months of treatment, participants experienced a significant improvement in motor function and a reduction of GluSph levels in the CSF.
The newly presented results demonstrate that motor function, assessed using the MDS Unified Parkinson’s Disease Rating Scale (MDS-UPDRS), remained stable in 14 participants who completed five months of treatment in the ongoing second part of the trial.
Preliminary data also suggested that participants with elevated baseline GluSph continued to benefit more than those with lower levels, with a 6.7-point difference in the sum of MDS-UPDRS Part II (activities of daily living) and Part III (motor function) scores between the two groups.
In patients with high GluSph levels, DDC levels in the cerebrospinal fluid (CSF) decreased after three months of treatment. DDC is an enzyme responsible for converting levodopa into dopamine in the brain and is elevated in the CSF of people with Parkinson’s, possibly due to dopaminergic neuron dysfunction.
“Building on our previously reported reduction of GluSph in CSF, this additional data shows a correlation between decreased levels of GluSph, decreased levels of DDC, and improvements in MDS-UPDRS scores associated with treatment with GT-02287,” Mack said. “Importantly, MDS-UPDRS scores remained stable and durable across the overall study population after 150 days of treatment with GT-02287, which we view as an encouraging signal in this progressive neurological disorder.”
Hannestad said the company expects the extension study to finish in September and plans to present additional data “at scientific conferences throughout the balance of the year.”
Gain also presented preclinical data on another treatment candidate, GT-04686, identified using the company’s proprietary Magellan drug discovery platform. In a poster titled, “Novel Allosteric GCase Modulators, Different From the Clinical Stage GT-02287, for the Treatment of Parkinson’s Disease,” the company showed that the compound increased GCase levels in patient-derived cells.
GT-04686 was also shown to enter the brain and to improve motor and nonmotor function in a mouse model of GBA1 Parkinsons’s.
“Our proprietary Magellan drug discovery platform has yielded novel GCase allosteric modulators that have generated promising preclinical data in Parkinson’s disease models. We look forward to further development of these novel, structurally distinct compounds and continued deployment of Magellan to identify leads targeting other neurodegenerative and rare diseases,” said Joanne Taylor, PhD, Gain’s senior vice president of research.
