Parkinson’s disease (PD) is a complex, multi-system neurodegenerative disorder that affects movement control. It is characterized by progressive degeneration of the neurons of the substantia nigra pars compacta, which reduces the levels of dopamine available for neurotransmission in the corpus striatum. Current treatments centre on the management of dopamine levels in the brain. Levodopa-based therapies have been the standard of care in the PD market for the past 50 years. However, the effectiveness of levodopa declines with time, and both motor and non-motor complications arise. This creates a significant opportunity for new entrants into the PD market.
In the early stages of the disease, motor symptoms are well managed by levodopa. However, as the disease progresses, reliable dosing becomes more difficult. Levodopa is a particularly difficult compound due to limitations in its absorption combined with a short half-life. Effective treatment for motor symptoms, including levodopa-induced dyskinesia, off-episodes, gait, and imbalance, remains an ongoing challenge in PD. According to key opinion leaders (KOL) interviewed by GlobalData, as many as one-third of PD patients experience dyskinesia and almost all of them will eventually have off-episodes.
In addition to the debilitating motor symptoms suffered by PD patients, an array of non-motor symptoms is also a recognised part of the disease progression. Among the non-motor complications of PD, the most difficult to treat are PD psychosis and PD dementia, which are primarily seen in advanced-stage patients. Acadia’s Nuplazid (pimavanserin) marks the first and only medication approved for the treatment of PD psychosis in the US since 2016. KOLs stated that although Nuplazid is effective in managing symptoms for many patients, there is still a significant number who do not respond. Additionally, similar to off-label antipsychotic products, Nuplazid has a boxed warning for the potential of increased risk of death in elderly people with dementia, which limits its use. As such, KOLs considered the treatment of PD psychosis an area of unmet need. KOLs emphasized that dementia is a common problem in PD patients that further affects medication compliance and remains difficult to treat. KOLs also stated that 15%–25% of PD patients report experiencing hallucinations or delusions and 80% of patients with PD psychosis also have cognitive impairment.
The current medications used for the treatment of PD are limited to those providing symptomatic relief, leaving ample opportunities for new entrants into the PD market. The need for disease-modifying therapies (DMTs) is one of the highest unmet needs and was consistently highlighted by KOLs. They agreed that if a curative or disease-modifying agent was approved for PD, it could bring about a major shift in the way that patients are treated.
Several pipeline drugs that are in late-stage development may help address these longstanding unmet needs. KOLs expressed excitement over continuous subcutaneous levodopa infusion systems offered by AbbVie’s ABBV-951 (foscarbidopa/foslevodopa) and NeuroDerm’s ND0612 (levodopa/carbidopa) to control motor fluctuations in a non-invasive way. Sunovion’s ulotaront, a novel oral non-D2 receptor antagonist that acts by modulating the activity of trace amine-associated receptor 1 through a different mechanism of action than current antipsychotic drugs, is being investigated for PD psychosis. Anavex’s blarcamesine is a sigma-1 receptor agonist and muscarinic receptor modulator that is being studied for PD dementia. Roche’s prasinezumab and Annovis’s buntanetap are suggested to possess disease-modifying properties by targeting α-synuclein protein, and in turn, halting the disease progression. Additionally, KOLs suspect glucagon-like peptide-1 receptor agonists, Novo Nordisk’s Victoza (liraglutide) and Neuraly’s NLY01, of offering neuroprotection.
Any new medication that can improve motor symptom control, target PD dementia, or target PD psychosis could have a huge clinical impact. However, due to the availability of only symptomatic treatment options in the PD market, it is likely that any late-stage pipeline agents would revolutionise PD treatment if they demonstrated any neuroprotective or disease-modifying properties in the pivotal trial.