Introduction
In the absence of a disease-modifying or curative therapy for Parkinson’s Disease (PD), management of this progressive neurodegenerative condition currently relies on effective symptomatic treatments to control motor and non-motor symptoms, to ensure patients have the best possible quality of life, and to minimise the burden on caregivers. Thanks to research and development efforts over the past 25 years, we now have a range of effective oral, non-oral and surgical therapeutic options to offer to patients and meet the differing needs of individual patients as their disease progresses.
While early stage PD can generally be managed effectively for several years with dopaminergic drugs, as the disease progresses to the advanced stage (APD), emerging motor and non-motor complications, the tapering off of therapeutic effect, and other treatment-related challenges such as gastrointestinal absorption issues, require a change of therapeutic strategy [1, 2].
At this point, methods of non-oral continuous drug delivery (CDD) that aim to provide continuous dopaminergic stimulation are used for sustained clinical efficacy, improvements in ON times without troublesome dyskinesias, and a reduction in OFF periods [3].
Given the wide range of device-aided advanced therapies (DAT) that are now available, the use of expert opinion-based clinically-driven personalised therapies in PD is an important concept that needs to be implemented, as the ‘one size fits all’ approach is not considered appropriate for the modern management of advanced PD [4].
Choosing the right DAT for each individual is, therefore, crucial to treatment success. Clear patient profiles of the individual characteristics that might best be addressed with a particular therapy are important to aid informed discussion with patients and carers and make the most appropriate treatment selection. A pragmatic and evidence-based clinical pathway, recently published as stepped care for PD, includes firstly confirmation of a diagnosis of APD, a process that can be aided by various screening tools [5], and secondly a decision as to which is the best DAT option based on the clinical profile supported by appropriate biomarkers where required (e.g. wearable sensors), patient choice, side effects profile, and age, as well as the stage of PD, the motor and non-motor burden, and patient lifestyle [6]. The patient’s own viewpoint is critical in making any therapeutic choice and their preference for, or hesitancy about, particular DATs need to be considered and discussed [7].
To assist clinicians in correctly diagnosing APD, several validated screening tools are available for use in clinical practice [8]. Commonly used tools are the 5-2-1 criteria (≥ 5 doses of oral levodopa per day and/or ≥ 2 hours of OFF time per day and/or ≥ 1 hour of troublesome dyskinesia) which is based a consensus statement of European PD experts along with several non-motor symptoms such as non-motor fluctuations and sleep dysfunction as well as functional consequences affecting quality of life [9]. The MANAGE-PD paradigm has been developed based on these criteria, and is an online tool which can help determine whether current treatment needs further optimisation or if a device-aided option should be considered [10]. A recent comparison of the application of the 5-2-1 criteria and MANAGE-PD in clinical practice found that while both are valuable tools in the clinic, MANAGE-PD has a better screening potential for determining suitability for DAT than do the relatively simplistic 5-2-1 criteria [11]. The Dutch DAT Screening tool (D-DATS) has also been developed recently, and seems promising in promoting timely referral and appropriate treatment with DAT in APD [12].
When it comes to treatment selection, a range of DATs with proven efficacy and tolerability are now available in many countries for APD patients [13]. Since levodopa is the recognised ‘gold standard’ PD therapy, there has been particular focus on strategies to improve its delivery to overcome the limitations of oral and transdermal administration [14, 15].
While recent and ongoing developments in therapies for APD are to be welcomed, regulatory approval and marketing authorisation of treatments does not always equate to access or reimbursement at a national level in many countries, despite the availability of positive pivotal licencing studies-based data. In Poland, for instance, the prevalence of PD has significantly increased in recent decades, which aligns with global trends suggesting the disease burden has more than doubled over that time, possibly due to the increasing elderly population [16]. Despite this rise in PD cases, more costly and effective APD treatments are not routinely available to all and must be approved for national reimbursement in accordance with each country’s specialist therapeutic programme. In addition, while particular medications themselves may be reimbursed, the newer delivery devices with inherent mechanical advantages may not. Classic examples of this are the non-availability of different formulations of apomorphine infusion, where one delivery system may be more bespoke to a patient’s needs than another, or the availability of different types of intrajejunal levodopa infusion, where smaller, lighter and relatively silent devices may be preferred by patients [17].
Having taken account of all these challenges to providing effective treatment for patients, a group of key movement disorders experts from Poland, along with other European PD experts, convened to discuss the gaps in the current care pathway for APD in Poland and make recommendations as to how to improve this situation.
This article summarises that expert group’s discussions and recommendations, which are intended to aid clinicians and their patients in making appropriate treatment choices from the existing pool of therapies as well as from the newer options discussed in this paper.
Material and methods
Polish movement disorders specialists and external stakeholders (the authors of this article) participated in an expert advisory meeting in June 2024 based on their extensive experience in clinical management of APD at tertiary centres within Poland or other European countries, and also their involvement in clinical research into both established DATs and those currently in development.
This article presents a narrative review of their discussions of the current, global APD treatment landscape, and their identification of gaps in the Polish market in terms of treatment options. It includes recommendations based on their expert opinion for an optimal APD management pathway in Poland.
Results
Global APD treatment landscape
Approved DAT options for the management of APD along with some therapies that are not yet approved or are under investigation are set out in Figure 1. For the early stages of APD, several minimally invasive non-oral ‘on-demand’ therapies are available that can provide rapid relief of troublesome motor OFF episodes as they occur, such as subcutaneous apomorphine (APO) injection, sublingual APO, or inhaled levodopa [18]. However, these therapies are administered intermittently and when APD becomes established and their daily use becomes too frequent, one of the more invasive continuous therapies may need to be considered to provide more effective control of PD symptoms. Where available, suitable patients can be considered for deep brain stimulation (DBS) or one of the infusion therapies, delivered either subcutaneously (APO infusion [19, 20] or the recently approved foslevodopa/foscarbidopa [13]) or via intestinal infusion (levodopa–carbidopa intestinal gel, LCIG) [21] or levodopa–entacapone–carbidopa intestinal gel (LECIG) infusion [17, 22]. However, it is important to take into account patient preferences when selecting therapy. A study evaluating the most common reason patients declined DBS and LCIG found that they were concerned about surgery, while the most common reason APO infusion was declined was the requirement for regular self-injection. DBS seemed to be preferred by younger patients with less severe disease, while APO infusion was generally preferred by older patients with a longer disease duration [7].
Not licenced indicates not licenced for commercial or clinical use
Further levodopa-based continuous therapies are in development, but have not yet received regulatory authority approval. These include transdermal levodopa pump patch, subcutaneous levodopa–carbidopa infusion (ND0612) delivered via a dual syringe and needle system, and concentrated acidic solutions of levodopa administered intravenously (DIZ101) or subcutaneously (DIZ102) [13, 23]. Continuous formulations of other non-levodopa therapies are also under investigation, including subcutaneous ropinirole and rotigotine, transdermal APO pump patch, and rotigotine implant. In addition, in selected cases, incisionless but lesioning techniques, e.g. transcranial magnetic resonance imaging (MRI)-guided focused ultrasound therapy (MRgfUS) or gamma knife therapies for unilateral thalamotomy or pallidotomy, can be used. One MRgFUS system has been approved in Europe (CE marked for essential tremor, PD tremor, and neuropathic pain) since 2012 [24] and since ٢٠١٦ in the USA for the management of essential tremor [25]. Its use in parkinsonian tremor is based on a small study of only ٢٠ patients on active treatment and seven on sham treatment [26], and currently the European Association of Neurology (EAN) does not recommend this for the management of PD tremor. There is also concern about its long-term safety [27]. If proven effective and safe in robust clinical trials, these will expand the range of options available to APD patients.
Current gaps in Polish APD therapy market
In Poland, DATs for APD treatment, which are more costly than oral or transdermal medications, are reimbursed in accordance with the Ministry of Health’s Specialist Therapeutic Programme (STP). General neurologists will usually refer patients to specialist centres to determine and confirm a diagnosis of APD and, if the centres agree with the decision, an application is filed for consideration at the monthly meeting of the STP Committee to request advanced treatment which is assessed according to the 5-2-1 motor criteria along with recommended non-motor symptoms criteria and functional deficits which may affect quality of life [9].
Several therapeutic options in Poland are already available including DBS, intrajejunal LCIG infusion, and subcutaneous APO infusion. Normally, patients under the age of 70 are eligible for DBS if there is insufficient response to conventional pharmacological therapies and the emergence of clinically relevant motor fluctuations and dyskinesias along with a lack of significant cognitive impairment (excluding mild cognitive impairment), moderate-to-severe depression, significant white matter hyperintensities, or other vascular changes on brain MRI scan. Of relevance is the fact that the Polish criteria for suitability for DBS treatment mostly adopted the criteria established by a French group, as included in the recent EAN guidelines [28]. Severe dysarthria and severe gait disorder are additional exclusion criteria. Therefore, many patients who do not fulfil these criteria could potentially benefit from the available infusion-based advanced therapies, and the additional new product developments discussed in this paper.
As such, if patients are older than 70 and not eligible for DBS, then subcutaneous apomorphine infusion is considered the least invasive of all advanced therapies at this stage and can be used [19]. However, caution and vigilance about dopamine agonist-related side effects, such as impulse control disorder, somnolence and psychosis, still apply. Intrajejunal levodopa infusion was the predominant form of infusion therapy for advanced PD until the advent of subcutaneous foslevodopa/foscarbidopa, and is used globally with well-established long-term clinical efficacy [29, 30]. Foslevodopa/foscarbidopa is currently the only subcutaneous levodopa preparation available commercially and has recently become available in Poland. It is effective when used over a 24-hour period, which differentiates it from subcutaneous APO infusion which is usually administered over 16 hours in Poland. Selecting who is suitable for which therapeutic option is, therefore, a complex challenge, and a pragmatic flowchart is provided in this paper (Fig. 2) where we also consider the place of LECIG infusion as well as subcutaneous APO injection for rescue therapy.
However, if a request for advanced treatment is approved, according to the Ministry of Health’s policy only the medication is reimbursed. As a result, patients wishing to start infusion therapy, such as LCIG infusion, may be offered older, larger pump systems, such as the Smith Medical CADD Legacy 1400 pump used for LCIG infusion, which may deter particularly younger and more active patients from commencing what might be for them an effective treatment option. Such rejections can be related to the weight of the pump, problems with body image, as well as general societal inconvenience.
Rescue therapy from predictable OFF periods remains a mainstay of management of fluctuating PD, especially in younger patients. In the case of on-demand (or ‘rescue’) treatments, there is currently a notable gap in the APD treatment pathway in Poland, with the only reimbursed options being soluble sustained-release levodopa tablets. Subcutaneous APO PEN injection is licenced in Poland but currently not reimbursed. It is envisaged that its wider use in early-stage APD might delay the transition of patients to more costly DAT treatments, and also reduce waiting lists for treatment in addition to improving self-confidence and quality of life of patients. APO is the only dopamine agonist with equivalent efficacy to levodopa and has a proven history of safety and tolerability in clinical use for more than 30 years. The PEN injection formulation has been shown in a range of clinical trials, and from extensive experience in clinical practice, to provide rapid and reliable resolution of motor OFF periods, returning patients to the ON state usually within 10–12 minutes which is not achievable by oral therapies or even sublingual apomorphine [31]. PEN formulation is also effective when there may be a ‘no ON’ state after oral levodopa use.
Unpredictable (and predictable) OFF periods for young PD patients remain among the greatest clinical challenges and have been rated as the most troublesome symptoms in a survey of advanced PD patients [32]. If reimbursed, an APO PEN injection would be a valuable addition to the range of options in APD treatment in Poland and fill gaps in the control of motor function alongside the patient’s usual medication.
As of July 2024, Poland’s STP for PD has been updated to include equal access to subcutaneous APO infusion, LCIG infusion and subcutaneous foslevodopa/foscarbidopa infusion. APO infusion has a well-established history of clinical use worldwide and its long-term efficacy and tolerability is supported by randomised controlled clinical trial (RCT) evidence and long-term open label study data [20, 31]. The European Academy of Neurology/Movement Disorder Society guidelines on the treatment of PD with invasive therapies recommend APO infusion for people with APD in whom fluctuations are not satisfactorily controlled with medication [28]. The UK’s National Institute for Health and Care Excellence (NICE) guidelines suggest it should be started before patients are considered for foslevodopa/foscarbidopa and prior to invasive DATs such as DBS or LCIG, while an APO PEN injection can be used even earlier for managing troublesome predictable OFF periods [33].
Non-motor issues can drive management of advanced therapies and also device-aided therapies. The evidence is available from the EuroInf 2 study data and has been discussed by Leta et al. [6]. In addition to motor efficacy in PD, beneficial effects of APO infusion on PD non-motor symptoms (NMS) have been widely reported. EuroInf 2 was a prospective, multicentre, international, observational study that compared clinical outcomes with APO infusion, LCIG infusion and DBS in clinical practice [34]. All three therapies provided good control of motor symptoms and improved quality of life but had different NMS effect profiles. APO infusion was found to provide particular improvement in Non-Motor Symptom Scale (NMSS) domains of mood/cognition, perceptual problems/hallucinations, attention/memory, and miscellaneous. It has also been known for some time that nocturnal use of continuous APO infusion has beneficial effects on sleep disorders in PD and can provide reduction of nocturnal awakenings, nocturnal OFF periods, pain, dystonia and nocturia [35]. More recently, the APOMORPHEE study was the first RCT to assess the safety, tolerability and efficacy of a night-time only APO infusion regimen, demonstrating fewer sleep disturbances in APD patients with moderate-to-severe insomnia [36]. Sleep issues are a common occurrence in PD, and this accumulating evidence suggests that APO infusion may be an effective option to help resolve them. However, despite the proven efficacy of APO infusion on motor PD symptoms and the reported benefits on common NMS such as sleep disorders, the newer pump systems are not reimbursed in Poland, thereby limiting patient choice and potentially dissuading patients from choosing this treatment option.
Another new development for APO infusion is the APO-go® POD system (Britannia Pharmaceuticals Ltd., Reading, UK) which extends the benefits of the currently pre-filled syringe. This has been designed to support patient autonomy as there is no liquid transfer required and set-up time is reduced. It would therefore represent a valuable addition to the Polish STP.
LECIG infusion is currently not included in Poland’s STP for PD. LECIG is a combination of levodopa, carbidopa and entacapone in a single intestinal gel formulation, and requires the same surgical procedure as LCIG infusion [37]. Due to the presence of entacapone in the formulation, equivalent levodopa exposure can be achieved with a reduction in total daily levodopa dose ofc.35% [22, 38], and the treatment regimen can be somewhat simplified without the need for oral entacapone. The safety profile of LECIG is in line with data from published clinical studies of standard LCIG and oral entacapone [22]. However, a large, international observational study, ELEGANCE (NCT05043103), is now underway that aims to gather outcomes data for LECIG in clinical practice and this will add to the evidence base. LECIG is delivered using the Crono® LECIG pump which is smaller and lighter that the LCIG pump and has received favourable reports from patients [17].
In view of the growing evidence of the benefits of LECIG in the countries where it has been launched from both a clinical and practical perspective, our opinion is that LECIG should be added to the STP in Poland. If these suggested additions to the STP are implemented, we recommend that the treatment pathway for APD should be followed, as shown in the algorithm in Figure 2.
One of the key factors for successful implementation of device-aided infusion therapies, such as APO and LECIG, in other European countries has been the comprehensive education of PD Nurse Specialists (PDNS) about the products and their use, which allows them to feel empowered and confident when managing these treatment options. Currently, Poland has no official specialised training for PDNS, so this is a key strategic issue that needs to be addressed in relation to all DATs used for APD to maximise the success of each treatment.
Discussion
Effective control of PD motor and non-motor PD symptoms and the best possible quality of life should be paramount in the management of PD, particularly in APD.
Considering the evidence from published clinical trials for the efficacy of DATs such as subcutaneous APO PEN injection, subcutaneous APO infusion, and more recently LECIG infusion, our collective expert opinion is that APD patients in Poland would greatly benefit from reimbursement access to these proven treatment options, including the newer, smaller lightweight pump systems that are generally preferred by patients, and which may be important in encouraging treatment adherence.
In relation to APO infusion, the newer POD system would promote greater ease of use in fluctuating PD where APO offers the least invasive option, along with newly available foslevodopa/foscarbidopa therapy. In the rescue medication setting, time to ON after a subcutaneous APO injection is superior to oral therapies, and therefore of substantial potential benefit to patients who are active and working. LECIG also appears to be beneficial in APD in several regards. From a practical standpoint, the smaller pump is of great advantage and preferred by patients as reported in the original Swedish study undertaken by Öthman et al. [17]. Peripheral neuropathy has been described with intrajejunal levodopa infusion therapies and has been linked to malabsorption as well as possible hyperhomocysteinaemia [39,40]. While axonal neuropathy has been observed, there are also reports of concomitant co-pathologies as well as occasional cases of demyelinating polyneuropathy, although real-life data from a one-year follow up study of LECIG in PD showed no evidence of polyneuropathy thus far [41, 42]. The risk of polyneuropathy may in fact be lower with the use of LECIG due to the presence of the catechol-O-methyltransferase (COMT) inhibitor entacapone in the formulation.
There are theoretical advantages of combining a COMT inhibitor such as entacapone with levodopa, as it reduces levels of the metabolites 3-O-methyldopa (3-OMD) and homocysteine and therefore hyperhomocysteine-related rates of polyneuropathy may be lower. 3-OMD competes with levodopa at the blood brain barrier and so a reduction of the 3-OMD level is an additional advantage.
We acknowledge the inherent limitations in the development of these recommendations, as they are based on opinions and insights from a limited number of experts. However, the majority of participants have direct experience of the management of APD at a high level within Poland and have a detailed knowledge of its associated challenges. We are also aware that the experience at these specific centres may not necessarily be generalisable to all centres in the country, but it does raise important issues for further discussion in order to improve overall APD patient outcomes.
Conclusions
In the Polish clinical landscape of DATs for the management of APD, it is apparent that there are currently specific and important gaps in the availability of some effective therapeutic options. These include the use and availability of the most up-to-date versions of APO formulations i.e. an APO PEN injection that can be used for rescue therapy or an APO infusion using a modern POD system.
In addition, there is currently no availability of LECIG infusion, the levodopa–entacapone–carbidopa combination that can be administered with a substantially smaller pump than the currently available LCIG formulation. LECIG also provides pharmacological benefits in that a lower levodopa dose can be administered, reducing the accumulation of potentially harmful metabolites. The availability of these formulations in the therapeutic arena in Poland will improve patient care and enhance patient choice and quality of life in APD.
Article information
Acknowledgements: Editorial assistance in the development of the manuscript was provided by Dr Karen Wolstencroft, funded by Britannia Pharmaceuticals Ltd.
Authors’ contributions: All authors participated in the Polish Expert Consensus Meeting, contributed to the development and review of the manuscript, and agreed to submission of the final version.
Funding: The Polish Expert Consensus Meeting was funded by Britannia Pharmaceuticals Ltd.; the company did not have input into the development of the manuscript, its content, or the decision to submit the final version.
Availability of data and materials: Further inquiries regarding the Expert Consensus Meeting and content of the article should be directed to the corresponding author.
Ethical approval and consent to participate: As no patients were directly involved in this project, ethical approval and/or consent to participate were not required.
Conflicts of interest: KP-D has received honoraria for participating in sponsored academic symposia and Advisory Boards organised by Britannia Pharmaceuticals Ltd., Stada, AbbVie, and Woerwag Pharma and has received academic support from GKC and Altoida.
JS has undertaken lectures and/or participated in Advisory Boards organised by AbbVie, Ever Pharma, Stada and Polpharma.
MR-B has received honoraria for lectures and participation in Advisory Boards organised by AbbVie, Stada and Vipharm.
SB has undertaken lectures and/or participated in Advisory Boards for: AbbVie, Ever Pharma, Stada, Polpharma and Orion Pharma.
DK has received honoraria for lectures and participated in Advisory Boards organised by AbbVie, Ever Pharma, Teva, GE HealthCare and Adamed.
AB has received honoraria for lectures and consultation fees from Merz, GE, Abbvie, Sandoz, Krka and Vipharm.
KRC is Editor in chief of JPM (Movement Disorders section), Nature Parkinson’s Journal (Founder Editor). He has participated in recent Advisory Boards organised by AbbVie, UCB, GKC, Bial, Cynapsus, Lobsor, Stada, Zambon, Profile Pharma, Synovion, Roche, Therevance, Scion, Britannia Pharmaceuticals Ltd., Acadia, and 4D Pharma; Advisory Board over two years ago: Medtronic; he has received honoraria for recent lectures from AbbVie, Britannia Pharmaceuticals Ltd., UCB, Zambon, Novartis, Boehringer Ingelheim, Bial, Kyowa Kirin, SK Pharma, Scion, GKC, MDS, and EAN; recent grant (Investigator Initiated): Bial; grants (Investigator Initiated) over two years ago: Britannia Pharmaceuticals Ltd., AbbVie, UCB, and GKC; recent academic grants: EU Horizon 2020, Parkinson’s UK, NIHR, Parkinson’s Foundation, and the Wellcome Trust; academic grants over two years ago: Kirby Laing Foundation, MRC, and MDS (MDS NMS Project); royalties or licences (ongoing): Oxford (book), Cambridge publishers (book), MAPI institute (KPPS, PDSS 2); payment for expert testimony: GMC, NICE, and NIHR.
JSł is a Co-Editor in Chief of the Polish Journal of Neurology and Neurosurgery and has undertaken lectures and participated in Advisory Boards organised by AbbVie, Ever Pharma, Novartis, Roche, Woerwag Pharma, Stada, Exeltis, AskBio, Biogen and Polpharma.
