Neurodegenerative diseases (ND) are significant causes of mortality and morbidity worldwide, especially in the elderly population. Among these, Parkinson’s disease (PD) is the second most common ND after Alzheimer’s disease (AD)1 and affects around 160,000 people in Spain2. As PD prevalence increases with age, and given the growing life expectancy, the number of people affected by PD is expected to rise substantially in the future3. In fact, within the ND considered in the Global Burden of Disease, Injuries and Risk Factors Study, PD showed the fastest growth in terms of prevalence, disability and deaths4.

The average age of onset is 60 years old and the mean duration of the disease from diagnosis to death is 15 years1. PD is clinically defined by the presence of bradykinesia and other cardinal motor symptoms. However, most PD patients suffer from non-motor symptoms as well, which significantly contribute to overall burden. Cognitive dysfunction, depression and autonomic failure are some of the most common and relevant non-motor related problems5.

Oral dopaminergic replacement, including levodopa (LD) and/or other antiparkinsonian drugs, is considered the gold standard first line for the treatment of PD. However, as the disease progresses, plasma bioavailability of oral antiparkinsonian drugs may be altered, which leads to an unpredictable response to treatment. Consequently, motor and/or non-motor fluctuations may occur whereby patients alternate between achieving adequate symptom control (“ON” time) or inadequate control (“OFF” time). LD-related fluctuations in PD are associated with disease progression and non-physiological, discontinuous, or pulsatile stimulation of striatal dopaminergic receptors; and may result in unwanted motor symptoms known as dyskinesias6. At this time of the evolution of the disease, infusion therapies become an alternative to oral medication for patients with advanced PD when symptoms are inadequately controlled, as recent European Academy of Neurology/Movement Disorder Society guidelines indicate7.

In these cases, management of the disease requires the use of second-line therapies or Device-Aided Therapies (DAT) such as apomorphine (APO) or foslevodopa/foscarbidopa (FLD/FCD) subcutaneous infusions, among others.

PD, as the second most prevalent ND, leads to high health care costs in the Spanish population. The severity of the disease and the degree of disability caused by both motor and non-motor symptoms contribute significantly to an increase in health-related costs. In this context, the evaluation of the use of advanced therapies in PD becomes critical8. Thus, the aim of this analysis was to assess the budget impact considering the drug costs of APO compared to that of FLD/FCD in patients with advanced stage of PD in Spain.

According to our model, treating patients with advanced PD with APO is a cost-efficient strategy, as SNHS could save and average amount of €42,218 per patient/year considering the administration of APO instead of FLD/FCD and potential annual savings of more than €2,500 million. In the scenario that price reductions of 20% / 30% were applied over current EXF price of FLD/FCD, savings will be of €30,179 / €24,658 per patient/year, respectively. In these scenarios, the total annual savings will range between €1,875-€1,532 million per year.

It is noteworthy that a post-hoc analysis of data from APO pivotal clinical trials was conducted along with an analysis of real-world experience from 13 movement disorders specialists using a questionnaire that focused on starting patients on APO infusion. The specifications of the clinical trial protocols limited individual decision making, as centres were not allowed to proceed with dose adjustments after the first four weeks of double-blind treatment. Nevertheless, real-world data reported that a stable dose of APO was achieved in most patients within 3 weeks18.

APO remains the only drug with efficacy comparable to that of LD. In a crossover open-label study, no difference was observed between APO and LD in all outcome variables, including hand tapping scores, walking time, severity of tremor, dyskinesia score, and a PD disability scale. This study demonstrated for the first time that APO shows the same efficacy on motor symptoms compared with LD, but with a significantly faster onset effect19.

Although data are available to support the efficacy and safety of both APO and FLD/FCD, not all scientific societies or regulatory organizations position them equally. In fact, according to the National Institute of Health Care and Excellence (NICE) of United Kingdom (UK) latest guidelines, and in line with the conclusions of our study, FLD/FCD is recommended only when available medicines for advanced PD are not working well enough, patients cannot be treated with APO or deep brain stimulation (DBS), or if these treatments no longer control symptoms20. Similar conclusions have been reached by the Haute Autorité de Santé (HAS) in France21.

In Spain, despite the efficacy of APO and FLD/FCD, which could be considered clinically equivalent in terms of reduction in hours of OFF time (2.47 vs 2.75, 12 weeks; 3.66 vs 3.50, 52 weeks; respectively) and increase in hours of ON time without disabling dyskinesias (2.77 vs 2.72, 12 weeks; 3.31 vs 3.80, 52 weeks; respectively), treatment-costs show significant differences.

A comparative analysis of the safety data published from the pivotal clinical trials, considered comparable in terms of patients´ profile, primary endpoints, and other clinically relevant parameters, reveals differences that could be significantly favourable to APO in terms of reduced incidences of severe/serious long-term adverse effects, treatment withdrawal due to adverse effects, infusion site erythema, and hallucinations.

Conversely, according to the published data, FLD/FCD had a lower incidence of skin nodules at infusion site. Anyway, it is noteworthy that the skin nodules incidence related to APO treatment has been significantly reduced in recent years in routine clinical practice due to the adoption of minimally invasive Teflon needles22.

Moreover, the apparent lower incidence of hallucinations associated with APO is of outstanding clinical relevance. This finding has been postulated to be due to the pharmacological profile of APO as antagonist of the serotonergic 5-HT2A receptor, pointed in a real-world data comparative study23. This study compared APO with intrajejunal LD/CD infusion (IJLI) and deep brain stimulation of the subthalamic nucleus (STN-DBS). The results showed that APO reduced the perceptual disorders/hallucinations domain of the NMSS (Non-Motor Symptom Scale) to a greater extent than the other two advanced therapies (relative change was -50.9, -34.6 and -55.5 for IJLI, STN-DBS and APO, respectively)23. In this regard, it is also noteworthy that APO is a dopaminergic agonist with very low affinity for the dopaminergic D3 receptor, which has been associated with a lower risk of developing impulse control disorders2425.

A comparative study was published in 2020 to analyse the costs of DBS, IJLI, and APO. The methodology used was based on real-world data obtained from an integrated healthcare organization in the Basque Country (Spain) from 2016 to 2018. The study showed the annual cost over 3 years and the projected cost for 2 additional years. The total cost for 5 years’ treatment was €53,217 for DBS, €208,163 for IJLI, and €170,591 for APO, which revealed a considerable higher cost for LD/CD, compared to APO26. Moreover, although DBS seemed to be the most affordable among the three alternatives, a 5-year prospective clinical comparative study between DBS and APO reported a worsening of the Neuropsychiatric Inventory Questionnaire in the DBS group but not in the APO group27.

As a chronic progressive disease in which most patients reach an advanced stage after 7 to 10 years from diagnosis5, PD has a great impact on patients’ and caregivers’ lives. PD caused more than 200,000 deaths and 3,2 million disability-adjusted life-years (DALYs) worldwide in 2016, and more than 4,000 deaths and 54,175 DALYs in Spain4. Moreover, it also involves a substantial social burden and entails an important economic impact. According to data from Parkinson's Survey Observing the Quality of Care (EPOCA) Study conducted in Spain, more than half of the patients are diagnosed of PD between 1-5 years after the first symptom, which means a considerable delay3. These data even further emphasize the importance of having cost-effective therapies for patients in advanced stages, as many of them are diagnosed after having already gone through the early stages of the disease.

According to a survey carried out among neurologists attending PD patients in Catalonia area (Spain), 70% stated that they had some limitation for the implementation of second-line therapies, and the main cause were the lack of resources at their hospital centre (38.1%). Lack of knowledge about second-line therapies or existing circuits for this purpose were also mentioned, among others. Only 7.1% and 2.4% of the neurologists considered the following as limitations to establish second-line therapies: possible side effects or low therapeutic benefit, respectively28.

Finally, it is also noteworthy that a recently published indirect treatment comparison and cost-minimisation analysis conducted from a UK healthcare payer´s perspective has reached similar conclusions to ours in terms of comparative efficacy and safety, as well as cost savings of medication, between APO and FLD/FCD treatments29.

All these previous investigations highlight the importance of access to second-line therapies and the need for affordable treatments for PD patients in Spanish hospitals, in which cost-effectiveness treatments could significantly increase the number of patients benefited from advanced therapies.

This model presents some limitations. The clinical data used to populate the model have been extracted from the literature with different timelines and methodologies and not from real-word studies. Furthermore, the costs used in the model are those available at public databases and may not reflect the real clinical practice or may suffer changes in the future. Moreover, this model does not consider adjuvant medication costs in advanced PD such as levodopa, catechol-O-methyl-transferase inhibitors (iCOMT), monoamine oxidase inhibitors (IMAO), or amantadine, among others; healthcare costs; nor indirect costs; so the indirect savings that APO or FLD/FCD could have achieved in terms of productivity loss may not be reflected in the current results.

Overall, our APO or FLD/FCD medication cost model suggests that APO can be more efficient than FLD/FCD in the treatment of advanced Parkison´s disease from the payer´s perspective of SNHS since treating patients with APO would lead to considerable treatment savings. This goes in line with the recommendations from the guidelines on pharmacological efficiency, recently published by NICE20 or other similar studies29. Although the selection of an appropriate treatment option is mainly to be determined by clinical criteria and patient characteristics, the fact that APO is more affordable than FLD/FCD should be considered for a wise choice of treatment.

The authors would like to acknowledge Keylates Health Solutions, S.L. for their support in the performing of this study.

All authors contributed to the study. GJ wrote the outline of the manuscript. DJ and MM revised and approved the outline. All authors read and approved the final manuscript.

This study was funded by ITF Research Pharma, S.L.U.

The original data and materials that have supported the completion of this study are available.

Not applicable.

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