Affecting more than 10 million people worldwide, parkinsonian movement disorders are best known for impaired motor function, gait and balance problems and disturbances in cognition, sleep, behaviour and bowel function. The non-motor symptoms cause significant morbidity in these patients and in the atypical forms of parkinsonism, they are among the most troublesome symptoms to treat. Treatment of atypical parkinsonism is symptomatic and has limited benefit. There are no approved treatments that modify disease progression.
PBT434 is novel small molecule that acts as an iron chaperone. In disease, “reactive” iron promotes protein aggregation and causes increased oxidative stress, factors which contribute to the neuronal injury and cell death that underpins the vast array of symptoms experienced by patients with parkinsonian movement disorders. PBT434 exports reactive intracellular iron and redistributes it to the normal cellular machinery where it can be utilised for critical functions such as energy production and oxygen transport. Patients with diseases of α-synuclein and tau aggregation have increased levels of reactive iron in affected brain regions which drive the formation of protein deposits and contribute to the underlying pathology.
PBT434 does not interfere with the iron involved in normal cellular function but preferentially binds the reactive iron that would otherwise interact with important intracellular proteins such as alpha-synuclein and tau. In doing so, PBT434 can restore iron equilibrium, reduce protein aggregation and improve cellular function.
PBT434 blocks the formation of alpha-synuclein and tau clusters, thus preventing the buildup of fibrils and downstream effects that lead to cellular dysfunction and death. There is evidence in several animal models of neurodegeneration that PBT434 prevents neuronal loss and improves motor and/or cognitive impairments.
PBT434 has received ethics committee approval and has commenced recruitment for its Phase 1 clinical trial evaluating safety, tolerability and pharmacokinetics. Multiple System Atrophy (MSA) and Progressive Supranuclear Palsy (PSP) are two rare but devastating and fatal forms of atypical parkinsonism and Prana’s initial targets for PBT434. Both MSA and PSP are orphan diseases that would benefit from the favorable treatment extended by regulators to encourage drug development for illnesses that are rare.
Prana’s research collaboration with Takeda Pharmaceuticals International covers the study of PBT434’s ability to prevent neurodegeneration in the gastrointestinal system, an important non-motor feature of Parkinson's disease, that may cause severe disability. The partnership follows the recently published results demonstrating that PBT434 caused a significant reduction of alpha-synuclein accumulation in various pre-clinical models of Parkinson’s disease.