Disease Analysis: Parkinson’s Disease

Parkinson’s disease (PD) is a chronic disorder characterized by movement abnormalities and other non-motor symptoms, such as dementia, depression, visual hallucinations, and autonomic dysfunction. Although not fatal, there is currently no cure for the disease, and its chronicity is associated with significant morbidity and disability.

Latest key takeaways

• Datamonitor Healthcare estimates that in 2021, there were 10.3 million prevalent cases of Parkinson’s disease (PD) in adults aged 40 years and older worldwide, and forecasts that number to increase to 12.4 million prevalent cases by 2027.
• Standards of care in this space are predominantly mature brands with decades of clinical use and physician familiarity, with levodopa products continuing to dominate the market. Prescriptions for generic products constitute the vast majority of market volume.
• There have been an array of impactful events within the PD space so far in 2022. Amneal submitted an NDA to the FDA for its novel carbidopa/levodopa (CD/LD) asset, IPX203, in August 2022. Following positive topline Phase III results in October 2021, AbbVie has also filed an NDA for its subcutaneous foslevodopa/foscarbidopa drug, ABBV-951, in advanced PD. In April 2022, supportive long-term Phase II safety data were released for NeuroDerm/Mitsubishi Tanabe’s ND0612, which is competing with ABBV-951. Additionally, highly positive Phase IIb data were recently released for Enterin’s ENT-01 for the treatment of PD-related constipation.
• AbbVie’s Duopa is among the most lucrative drugs currently available in the PD market. A contributing factor to the drug’s successful market penetration is the clinical efficacy data achieved in trials, where Duopa treatment significantly reduced “off” periods in PD patients compared to the standard of care, Sinemet (CD/LD). Duopa, also a CD/LD combination, is delivered directly and continuously into the intestines by a pump for up to 16 hours per day, thus reducing or even eliminating fluctuations and “off” periods. The procedure, however, is one of the most invasive in this market and comes with the usual risks of surgical complications.
• Acadia’s Nuplazid, the first and only US-approved drug for Parkinson’s disease psychosis (PDP), scores well commercially in Datamonitor Healthcare’s drug assessment model. In pivotal trials, Nuplazid demonstrated significant efficacy in reducing the hallucinations and delusions associated with PDP, and through its non-dopaminergic mechanism it has shown no negative impacts on motor function. Acadia reported $484.1m in sales for Nuplazid in 2021, and this is expected to increase substantially over the coming decade given the lack of competition in this segment and the drug’s ongoing clinical development in other indications.
• Neupro has performed well commercially since its US approval in 2007, but a looming patent cliff will likely reduce the brand’s future revenues in the PD market. Several factors have contributed to the drug’s performance, including a transdermal, continuous delivery system, its targeting of both early- and late-stage PD patients, monotherapy use, and its availability across the US, EU, and Japan.
• Despite levodopa’s status as the drug of choice in PD, long-term use frequently results in diminished efficacy and the development of motor fluctuations and dyskinesia. Advanced PD, therefore, has the greatest opportunities for drug developers. Competition in the rescue therapy space began to heat up when Inbrija was approved in the US in 2018. Kynmobi provided competition after its US approval in 2020, but is now being discontinued due to poor sales and safety issues. Many other newly launched therapies for “off” periods are approved only as adjunctive treatments to levodopa. Continuous infusions have also emerged to tackle this issue, mimicking the continuous release of dopamine in non-pathological conditions. These therapies have been the most efficacious in reducing “off” time and increasing quality “on” time. Developers have also incorporated complex devices/formulations to extend market exclusivity and combat generic imitations.
• Both Prothena (partnered with Roche) and Enterin are racing to potentially bring the first disease-modifying therapy to the PD market by targeting the pathological hallmark of PD, Lewy bodies, which consist of α-synuclein aggregates. In early trials thus far, Prothena’s prasinezumab, a monoclonal antibody, has signaled strong proof of concept by inducing a mean reduction of free serum α-synuclein levels of 96% in healthy volunteers. Results from a Phase II randomized, controlled trial in early PD patients displayed statistical superiority in improvements on the Movement Disorder Society Unified PD Rating Scale (MDS-UPDRS) versus placebo, though these improvements were modest at best.
• Phase IIb data from Enterin’s ENT-01, an orally administered cationic aminosterol targeting PD-related constipation, were positive. The study met the primary endpoint of change in complete spontaneous bowel movement, with statistical significance (p=0.0001). The exploratory endpoints, which included psychosis and dementia improvement, also showed promising results. Constipation is one of the earliest symptoms associated with PD and can present up to 15 years before PD diagnosis.
• For the first time since its US approval in 2015, AbbVie’s Duopa could experience direct competition from less invasive pipeline subcutaneous continuous infusions, which will potentially avoid the risks and tolerability issues associated with surgery. An apomorphine infusion pump is in development by Supernus Pharmaceuticals for the continuous treatment of on-off episodes in patients whose motor control is unsatisfactory with oral levodopa. Mitsubishi Tanabe’s novel asset ND0612 is comparably a pump formulation administering medication subcutaneously. It is the only investigational subcutaneous continuous CD/LD treatment with safety data extending beyond one year. Finally, ABBV-951, a foslevodopa/foscarbidopa formulation for advanced PD administered via continuous subcutaneous infusion, is the highest rated out of the three in Datamonitor Healthcare’s assessment model.
• Other pipeline drugs include Anavex Life Sciences’ ANAVEX 2-73, which is targeting the cognitive impairments associated with PD dementia; Amneal’s IPX203, a novel oral formulation of both immediate-release and extended-release CD/LD granules aiming to provide a rapid onset of effects and a more sustained duration than immediate-release CD/LDs alone; and Cerevel Therapeutics’ tavapadon, a monotherapy option for early-stage PD. Additionally, Pharma Two B’s P2B001 combines low-dose pramipexole and rasagiline (which have complementary mechanisms of action) in a slow-release formulation.
• As has been the case for many years, and despite new drug entrants, one of the greatest unmet pharmacological needs in the treatment of PD is for neuroprotective therapies to prevent disease progression. In addition to this, more tolerable drugs and regimens are needed, as well as more effective drugs for non-motor symptoms, and improved control of motor fluctuations/“off” periods.
• Reimbursement issues are a common barrier to uptake in the US PD market. Newer, more expensive drugs are often not approved by insurance companies, making market penetration difficult. The market is slightly more accessible in Europe and Japan.
• The majority of high-impact upcoming catalysts in the PD space comprise later-stage trial readouts for pipeline PD drugs. Cerevel is expecting topline readouts from four Phase III tavapadon trials in 2023. ABBV-951 will be reviewed for approval by the FDA in May 2023, while Pharma Two B is expected to file an NDA for P2B001 in November 2022