Experimental Parkinson’s disease therapies
Experimental Parkinson’s disease therapies
Results of a number of experimental therapies were presented. Among them: PBT434, a novel, brain-penetrating, inhibitor of α-synuclein aggregation; opicapone, a catechol-O-methyltransferase (COMT) inhibitor; venglustat, a CNS-penetrating glucosylceramide (GL-1) synthase inhibitor; and SYN120, an antagonist of serotonin receptors (5-HT6 and 5-HT2A).
PBT434 demonstrated approximately proportional pharmacokinetics up to 300 mg in a randomised, double-blind, placebo-controlled first-in-human study . A total of 18 healthy volunteers received oral single ascending doses (n=8) or multiple ascending doses (n=10) of PBT434. The treatment was well-tolerated. Adverse events were mild and infrequent; no serious adverse events were reported. The authors concluded that PBT434 has potential for treating synucleinopathies such as Parkinson’s disease and multiple system atrophy.
Opicapone is a novel, highly selective, peripheral COMT inhibitor under development as an adjunct therapy to levodopa for Parkinson’s disease with motor fluctuations. In two international placebo-controlled phase 3 studies (BIPARK-1 and BIPARK-2), once-daily opicapone increased ON time without troublesome dyskinesia in this category of patients . In both studies, opicapone 50 mg was associated with a significant increase from baseline to week 14/15 in absolute ON time without troublesome dyskinesia versus placebo (P=0.002 and P=0.025 for BIPARK-1 and BIPARK-2, respectively). These improvements were sustained in long-term extension studies. In the pooled safety population (n=631), dyskinesia was reported in 17.4% and 6.2% of patients in the opicapone and placebo group, respectively; rarely resulting in discontinuation.
Once-daily venglustat at 3 escalating doses was tested in 17 Parkinson’s disease patients with a GBA mutation and symptoms ≥2 years in part 1 of the MOVES-PD trial . Participants were randomised to placebo (n=4) or venglustat (n=13). All patients except 1 in the venglustat group reported at least 1 treatment-emergent adverse event; most were mild or moderate and resolved without corrective treatment during the study. The most common were psychiatric, neurological, and gastrointestinal events. No serious adverse events or deaths occurred. Dose-dependent plasma and CSF exposure were observed. CSF glucosylceramide (GL1) decreased 74.3% (high dose). Part 2 of MOVES-PD is ongoing.
SYN120 was shown to improve cognition in preclinical models. In a phase 2a study, safety and preliminary efficacy of SYN120 in patients with Parkinson’s disease dementia were evaluated . Eligible patients were randomised to SYN120 100 mg daily or placebo; they all used a cholinesterase inhibitor as well. There were 36 and 41 patients in the modified intention-to-treat groups of SYN120 and placebo, respectively. SYN120 did not improve cognition in patients with Parkinson’s disease dementia, but it may have improved cognition-based daily function. SYN120 was generally well-tolerated. Adverse events were experienced by 74% and 77% of participants in the SYN120 and placebo group, respectively; 11% (in both groups) were serious. A worsening of motor symptoms was observed.
A survey of Parkinson’s disease patients in a medical cannabis program in the USA confirmed that medical cannabis, typically in combination with other Parkinson’s disease therapies, is a well-tolerated option to improve both motor and non-motor symptoms . Medical cannabis may be helpful in relieving some adverse events of Parkinson’s disease medications, such as nausea and insomnia. Of 63 participants, 77% reported improvement in motor symptoms, most commonly tremor and spasticity; improvements in rigidity, gait instability, dyskinesia, and bradykinesia were also found. Over half of the Parkinson’s disease patients had improvements in non-motor symptoms, including sleep disturbance, anxiety, depression, and nausea. Adverse events included somnolence, disorientation, and dizziness, with 6.4% discontinuing due to adverse events.
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