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.

• Datamonitor Healthcare estimates that in 2018, there were 9.4 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.
• In the last year there have been an array of impactful events that have occurred in the PD space. Roche released Phase II data for its novel alpha-synuclein monoclonal antibody prasinezumab, which exhibited modest efficacy, while Anavex also released data readouts from a Phase II trial investigating its novel PD dementia drug, ANAVEX 2-73, on the associated cognitive deficits experienced by patients. Data showed clinically meaningful cognitive improvements on multiple cognitive assessment parameters, as well as a reduction in motor and non-motor symptoms. In a recent Phase III study, Amneal’s IPX203, a novel formulation of both immediate-release and extended-release carbidopa and levodopa (CD-LD) granules, showed the potential of IPX203 to increase “good on” time in PD patients – higher-quality hours without troublesome and non-troublesome dyskinesia (a side effect of existing CD-LD formulations). The product decreased “off” time in patients compared to immediate-release CD/LD and showed an increase in “good on” time per dose.
• 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. Duopa also has one of the highest price tags in the PD market, but since payers view its cost-effectiveness ratio positively, AbbVie looks set to maintain fruitful returns on the drug.
• 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. Furthermore, most other atypical antipsychotics are contraindicated for PDP, with none approved by the FDA for this specific condition. Acadia reported $441.8m in sales for Nuplazid in 2020, 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 jeopardizes 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. In trials, the drug showed slightly lower efficacy compared to Mirapex, though despite this has established itself firmly in the PD treatment algorithm. UCB has fended off generic rivals thus far, and is currently tied up in patent litigation, but will likely face generic competition before 2023. Actavis Laboratories has received a tentative ANDA approval for its rotigotine generic, and as soon as this and any other rival generics can be launched, Neupro sales will undoubtedly see a dramatic decrease.
• 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 has begun to heat up, with Inbrija and Kynmobi both approved over the past couple of years, and this segment will continue to grow as developers look to target the rapid treatment of “off” periods. 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.
• Prothena has partnered with Roche to potentially bring the first disease-modifying therapy to the PD market. The drug, known as prasinezumab, is a monoclonal antibody targeting the pathological hallmark of PD, Lewy bodies, which consist of alpha-synuclein aggregates. In early trials thus far, prasinezumab has signaled strong proof of concept by inducing a mean reduction of free serum alpha-synuclein levels of 96% in healthy volunteers. Recent 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. This could be explained by the early PD cohort utilized in this study, presumably selected due to the lower likelihood of patients exhibiting severe and irreversible dopaminergic neuronal loss; however, the size of effect would understandably be reduced in this less severe population. The Phase IIb trial of prasinezumab in early PD patients was initiated in May 2021.
• Other promising pipeline therapies include the apomorphine infusion pump, in development by Supernus Pharmaceuticals, for the continuous treatment of on-off episodes in patients whose motor control is unsatisfactory with oral levodopa, and at least one other non-invasive PD therapy. Additionally, Datamonitor Healthcare views Mitsubishi Tanabe’s ND0612 as the antiparkinsonian agent that has the most clinical potential, and consequently it also has one of the highest-rated commercial profiles out of the drugs assessed. The drug is similar to Duopa in that it uses a constant infusion pump; however, as a subcutaneous device the treatment spares the adverse events and potential issues associated with a surgically administered device. In a Phase II trial, ND0612 demonstrated a 2.8-hour reduction in “off” periods, and 42% of patients experienced a complete reduction in “off” time (to 0 hours).
• 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.
• The majority of high-impact upcoming catalysts in the PD space comprise later-stage trial readouts for pipeline PD drugs. Topline results are expected from Pharma Two B’s Phase III trial of P2B001. Likewise, AbbVie expects Phase III trial data in Q4 2021 for its subcutaneous carbidopa/levodopa formulation, ABBV-951.