Talon is developing oral small molecule drugs to treat Parkinson’s gait dysfunction and L-DOPA-induced dyskinesia.
Parkinson's Gait - TPS-100
- What is it? Multi-targeted, fixed-dosed drug combination 1 enhances brain cholinergic activity (acetylcholine) to improve gait in PD
- Safety – The components of TPS-100 are safe in humans
- Efficacy – TPS-100 improves balance and gait in models of Parkinsonism
- What’s Next? Dose optimization studies to support Phase I clinical trials.
Gait impairment and postural instability are common motor symptoms leading to falls and significant morbidity in Parkinson’s disease not adequately treated by L-DOPA (dopamine) therapy, suggesting other neurotransmitter systems are involved in gait. Recent studies suggest that the loss of both dopamine in the striatum and acetylcholine in the pedunculopontine and basal forebrain contribute to freezing of gait and falls.2
Fixed-ratio drug combinations such as TPS-100 that target both dopamine and acetylcholine (multiple disease mechanisms) are expected to result in improved efficacy and reduced cost without increasing the risk of adverse effects.1
L-DOPA-Induced Dyskinesia (LID) - Glycine Enhancers
- What is it? Glycine reuptake inhibitor (GLYT1) combined with L-DOPA therapy to improve Parkinson’s treatment. 3,4
- Safety – Extensive clinical safety data for GLYT1 inhibition
- Efficacy – Candidate reduces L-DOPA-mediated side effects such as dyskinesia and psychosis in Parkinson’s
- What’s Next? Studies to optimize the dose are underway in non-human primates to allow clinical trials.
Levodopa (L-DOPA) is main drug used to treat Parkinson’s tremor and rigidity by increasing dopamine in the brain. Long term use of L-DOPA is associated with psychosis and dyskinesia, a side effect characterized by rapid involuntary movement, or slow and extended muscle spasms. L-DOPA-induced dyskinesia LID) and psychosis are linked to changes in neurotransmitters such as glutamate and drugs like Amantadine that directly block glutamate neurotransmission can reduce symptoms of dyskinesia but can worsen psychosis in PD. In contrast, enhancing glutamate activity by increasing the level of glycine in the brain reduce dyskinesia and psychosis. 3,4
This work is supported by the Michael J Fox Foundation.
- Makhoba XH, Viegas C Jr, Mosa RA, Viegas FPD, Pooe OJ. Potential Impact of the Multi-Target Drug Approach in the Treatment of Some Complex Diseases. Drug Des Devel Ther. 2020 Aug 11;14:3235-3249.
- Bohnen et al. Cholinergic System Changes of Falls and Freezing of Gait in Parkinson’s Disease. Ann Neurol. 2019;85:538–549
- Frouni I, Belliveau S, Maddaford S, Nuara SG, Gourdon JC, Huot P. Effect of the glycine transporter 1 inhibitor ALX-5407 on dyskinesia, psychosis-like behaviours and parkinsonism in the MPTP-lesioned marmoset. Eur J Pharmacol. 2021 Nov 5;910:174452
- Collaboration with The Neuro (McGill University)