What medicines do people with Parkinson's disease want?

Abstract

Parkinson's disease (PD) is a heterogeneous condition that presents variable clinical, neuropathological, and biomarker features. Disease progression can also vary significantly. It is essential to consider this heterogeneity when considering the medicines that people with Parkinson's (PwP) want. Potential PD medicines may be classed as disease modifying (DMT) or symptomatic (ST). The ultimate hope of PwP is that, sooner rather than later, the core of the PD pharmacopeia will provide personalised cocktails of drugs that not only deliver motor and non-motor symptom relief, but also slow, stop and then reverse disease progression. Generally, PwP are less interested in the scientific details, they are more focused on maintaining or improving quality of life. For those people at risk of PD, diagnosis in the pre-motor stage may herald the introduction of new medicines that arrest the progress of the disease before symptoms are manifest. One way to understand the medicines that PwP want is to ask which symptoms are the most bothersome, and target them accordingly. In practice, medicines that present optimal efficacy and convenience, at an affordable price, will be more likely to be accepted. Interactions between researchers and PwP should be encouraged in order to deepen the understanding of each other's needs and motivations. Finally, it is important to remember that PwP are individuals with emotions and concerns. As such, moderation in the communication of prognosis and of the potential of new medicines is essential, so that PwP can maintain hope rather than being misled by hype.

Plain language summary

Parkinson's disease (PD) is a highly variable condition for which no effective disease-modifying interventions exist. Disease variability is seen from person to person, from day to day, and even at different times of the same day. Currently, symptoms can be managed using medicines, surgical interventions, or lifestyle interventions. Major efforts are under way to discover new medicines, so it is important to ask the question, ‘what medicines do people with Parkinson's (PwP) want?’. A way to respond to this question is to assess which symptoms are the most troublesome, then to translate this information to help develop drugs that target them. Together with drugs to slow, stop and reverse the progression of PD, options will be available from a portfolio of drugs that enable PwP to maintain their quality of life for longer. New drugs should also provide efficacy and convenience and not present any barriers to their administration. Interactions between researchers and PwP should be encouraged in order to deepen the understanding of each other's needs and motivation. We also need open and direct communication about the real potential of new drugs, so that we can distinguish the hope from the hype.

Introduction

Parkinson's disease (PD) is a highly heterogeneous condition that presents variable clinical, neuropathological, and biomarker features. Consistently, disease progression can also vary significantly, for reasons we do not fully understand. Therefore, when considering the medicines that people with Parkinson's (PwP) would like to have, it is essential to consider this heterogeneity.

In an ideal world, people with Parkinson's (PwP) would receive an early diagnosis not only of PD, but also which sub-type, and then receive the appropriate medication to stop the progression of the disease and restore lost function, without interference with their quality of life in any respect. Unfortunately, such an ideal world does not yet exist. Meanwhile, basic and clinical researchers, alongside PwP and support groups, continue the intensive search for interventions that will slow, stop or reverse the progression of PD.

The start and finish points of this journey are the same – the PwP, also known as the patient, the subject, or the participant. That person lives with the condition day in and day out, and is the ultimate recipient of the output of all this research – as such, this person can be termed as ‘an expert from experience’. Therefore, this expertise can be applied to defining the needs of PwP, particularly, which aspects of their life they want to change with pharmaceutical interventions. In short, what medicines do they want?

The dream: to slow, to stop, to restore? or simply to relieve?

Most PwP would embrace a cure for PD; but what does a ‘cure’ actually mean? New therapies for PD are often characterised as disease-modifying therapies (DMT), that is to slow or stop progression, or to restore lost function; or to relieve symptoms (symptomatic therapy, ST). A cure would undoubtedly be a DMT, but the chances of restoring function to a pre-PD era is unlikely in the foreseeable future, given the amount of time it takes for PD to develop and the anatomical complexity of the dopaminergic and other systems. This is underlined by the fact that dopamine cell replacement is still in the early stages of development, and that it is unclear whether complete replacement of the lost cells will ever be possible.

On the other hand, it seems more realistic to aim for therapies that will slow or preferably stop the progression of PD, particularly in the early or even pre-motor stages. Indeed, the clinical pipeline is relatively healthy with regard to DMTs, particularly in phase 1 and phase 2, albeit less so in phase 3. ¹ However, it is important for PwP to appreciate that DMTs may not provide symptomatic relief, as they are aimed at stabilising symptoms over time.

We believe that PwP are willing to accept medicines that make their daily life better for longer. They are less interested in molecular mechanisms and scientific detail and primarily look for the impact a drug will have on their quality of life (QoL). It would be preferable if an individual medicine could relieve a number of symptoms rather than just one, but options that could effectively banish the most bothersome symptoms on a daily basis are also welcome.

No two PwP are the same

There is a constellation of symptoms that can appear in PD. It is often referred to as a ‘snowflake’ disease in that every case is unique. For example, 20–30% of PwP exhibit no signs of tremor. For others, non-motor symptoms such as sleep disturbance or constipation cause the greatest distress to daily life. Studies also indicate that not only do the number and severity of symptoms increase, but also the relative importance of symptoms changes as the condition progresses. ² Therefore, it is increasingly important to exploit the understanding of the underlying biology in order to develop disease classification systems that can distinguish different forms of PD. Such efforts are ongoing. ³

From a lifestyle perspective, medicines that enable PwP to keep their regular routine with family, work and friends, for as well and as long as possible, are important. Regarding symptom heterogeneity, other factors also play an important role. These include, among others, gender differences, time since diagnosis, professional situation, or the personal importance given to different symptoms as the disease progresses. A PwP diagnosed under the age of 40 may have different requirements to another who receives the bad news when at the average age of diagnosis, which is around 72. ⁴ For example, the impact of daytime sleepiness will be different for somebody who is still in full time employment compared to someone who is retired. We should also consider other health challenges, such as other co-morbidities or the menopause.

Much work has been done to classify PwP into sub-types, in order to better tailor treatments to groups of symptoms. This work includes attempts to relate genotype (our genetic makeup), to phenotype, (observable symptoms and traits). Ultimately, whichever biological or clinical sub-type a PwP is in, the primary interest is for ‘medicines that work for me’.

Which symptoms do PwP want to relieve the most?

This question of which medicines PwP want may be best approached by asking the reverse question – which symptoms of the 40 + which could manifest do PwP wish to relieve? Then, experts can work out which potential therapies may best be able to deliver that relief.

Several research groups have surveyed PwP on the symptoms they find the most troublesome. The Parkinson's Disease Patient Report of Problems (PD-PROP) is a module contained in the Fox Insight quarterly survey of people with and without PD and has been used as the primary source of data to analyse the symptoms that are most bothersome to PwP. ⁵ Using a combination of human curation and machine learning, almost 170,000 verbatim responses were analysed. A higher proportion of women reported problems across the board. Gender differences were largest in the psychological, pain, motor fluctuations and dyskinesia domains. Compared with respondents below the age of 60, a higher proportion of those above age 60 reported gait, balance, and autonomic problems, cognitive problems (a priority for men only) and fatigue (a priority for women only).

The most frequently reported symptoms were tremor (46%), gait (39%), and pain/discomfort (33%). The reported symptoms were then split into motor and non-motor domains. The top three most bothersome motor symptoms were tremor (46%), gait (39%) and impaired dexterity/micrographia (31%). The top non-motor symptoms were pain (33%), fatigue (29%) and negative emotions (22%).

An online survey comprising 27 questions was completed by 492 PwP. ⁶ The most commonly reported motor symptoms were slowness of movement (82%), tremor (62%), balance (60%), rigidity (57%) and dyskinesia (39%). The top non-motor symptoms were lack of energy (61%), difficulty sleeping (55%), daytime sleepiness (52%), tiredness/exhaustion (54%) and loss of smell/taste (51%). ⁵ The same survey also assessed which symptoms PwP would wish to monitor in order to understand the progress of their PD, with 75% believing that monitoring their most bothersome symptoms would help them to understand their own PD. In addition, 64% felt that self-monitoring would improve their wellbeing and ability to cope, with 59% thinking that it would improve communication with their healthcare support team. These data support the proposition that adding monitoring to pharmaceutical therapy will not only help PwP in the ways described but also put them in a position to assess the impact of that medicine on their most troublesome symptoms. ⁶

A further study examined which symptoms, when uncontrolled, have the largest negative impact on quality of life (QoL). ⁷ Even though motor symptoms were some of the most prevalent in the cohort, uncontrolled non-motor symptoms had the largest negative impact on QoL. PwP at Hoehn and Yahr stage two or three found their QoL most affected by uncontrolled depression, confusion and need for speech therapy. PwP with advanced disease were most affected by uncontrolled anxiety, hallucinations and wheelchair dependence.

The different symptom relief priorities in PwP that had been diagnosed for less than six years (the early group) and for more than six years (the late group) have also been investigated. ⁸ The early cohort complained most about slowness, tremor, stiffness, pain, and loss of smell and/or taste. The late group were most concerned about motor fluctuations (wearing off and dyskinesia), mood changes, drooling, sleep problems and tremor.

The relative importance of symptoms changes as PD progresses. ² Non-motor symptoms are prominent in early PD; and motor impact from walking, balance and falls; problems with speech; freezing and dyskinesia, all become increasingly important as the condition advances. Interestingly, tremor, stiffness and psychological issues become less important with time.

When it comes to priorities, PwP were more likely to report motor symptoms as the main priority, especially tremor, movement or walking issues. Non-motor symptoms were felt to be secondary or tertiary issues. Similar to other studies, the highest number of mentions in those PwP who were relatively recently diagnosed was for tremor.

Symptoms that become increasingly important as PD progresses include (i) motor problems like walking, balance and falls, and freezing; (ii) motor fluctuations (wearing off and dyskinesia); and (iii) speech difficulties. Balance problems and falls increase with time, becoming the most important issue for those PwP with diagnoses beyond 11 years. Non-motor symptoms can be present from early-stage PD and persist throughout the progression of the disease, with the exception of psychological health which, perhaps surprisingly, was reported less as time progressed. Stiffness and psychological health also decline in importance as the condition progresses. ²

Identifying people at risk of PD

There is a lot of interest and research under way to define the early pre-symptomatic stage of PD when the disease has started but clinical signs are not yet apparent, known as the prodromal stage. While PD remains a clinical diagnosis, people in the prodromal stage cannot yet be described as PwP; instead, they are People at Risk of Parkinson's (PaRoP).

At this point, unless someone has undergone genetic testing for risk variants that may prompt testing for early biological changes, the individual remains unaware. One prominent exception to this is people with REM sleep behaviour disorder (RBD), around 80% of whom will go on to develop clinical signs of PD. Given that PD may be better classed as a syndrome, people with RBD may be described as early stage PwP. In terms of the medicines that they want, it would seem to be straightforward to assume that therapies that eliminate the often distressing nightmares common in RBD and that enable a good night's sleep would be highly desirable. Other symptoms that are also potential early warning signs for eventual PD are hyposmia, gastrointestinal issues, autonomic problems, anxiety and depression.

Probably the most attractive medicine for RBD/PwP and PaRoP would be a therapy that arrested the progression of PD, ensuring that those people do not go on to develop clinical PD. We do not yet know whether therapies that slow or stop disease progression in PwP with clinically manifest symptoms would do the same for PaRoP, but would be the first options to choose to answer the question.

Do we care how the medicines are delivered?

There are various routes to enable medicines to be delivered to the recipient. Some are more convenient than others, with palatable liquids or easy to swallow tablets at the simple end of the spectrum. The more complicated administration routes include the need to attend a healthcare facility for an infusion, as with some of the recently marketed antibody treatments for Alzheimer's disease. In the case of lecanamab, for example, this is required every two weeks.

Balancing efficacy and convenience with medicines can sometimes be a fine judgment, but it is not in the interests of the PwP to accept borderline efficacy together with extreme inconvenience. The objective should be to have convincing efficacy and high convenience at the same time. So, if we must visit the hospital every two weeks, it had better be worth it.

Safety is the overriding parameter with medicines, whether for PD or any other indication. As PwP, we must accept that any medicine will have some side effects or potential problems. Again, this is a balance and drug developers carry the onus of ensuring that the full and appropriate information is available for the healthcare professional and the PwP to make an informed decision.

Therapies for advanced disease

The largest burden of disease affects PwP in the most advanced stages of PD, at levels four and five in the Hoehn and Yahr scale. These PwP have severe disability and are often wheelchair bound or bedridden. The most appropriate therapies are often infusions that deliver constant and continuous levels of medicine.

Clinical trials of DMTs may exclude PwP at an advanced stage of PD, often for valid scientific and logistical reasons. This begs the question of how to include PwP at an advanced stage. Perhaps at this point it is best to simply state that there is no reason why they should not be prescribed a DMT to stop the progression of their condition, no matter which stage their disease has reached.

Involvement of PwP in research

The best way to understand what medicines PwP want is to involve them in the research process. This means creating opportunities for different stakeholders to meet and discuss their needs, their views and their doubts. For this, it is important to change the research culture, which often is disconnected from the real-life situation, and promote interactions between junior researchers and patients, so they understand the needs of PwP, and focus on questions that really matter. We understand the need for basic science, and there are many historical examples of how initial discoveries ended up impacting the way we live. However, in a field like PD, it is important to foster opportunities for both basic and clinical researchers to interact, and to also interact with PwP. This goes much beyond the simple interest in publishing journal articles, which is an important part of research, but should not be the end of the road. It should also involve learning to communicate the complexities of research to people who may not dominate the jargon, but definitely dominate the problem, and are often interested in understanding the origins of their condition.

The direct contribution that PwP can make is, understandably, more difficult for a project focused on fundamental research, compared to the design of a late-stage clinical trial. However, the psychological impact that interacting with PwP can have on researchers should not be underestimated. It can increase motivation and sense of purpose and put their work into a broader context.

Therefore, the first objective is for researchers to connect with PwP. This can be done using national and local contact points. For example, many patient-focused organisations exist such as the Parkinson's Foundation (USA), Parkinson's France, Parkinson's UK, Cure Parkinson's and Shake it Up Australia. Some organisations focus on younger PwP, such as Young Parkies Portugal. These national organisations often have local branches, easing the logistics of collaboration. Others have sub-groups that focus on research, such as the Parkinson's UK Research Support Network. Attending conferences that attract both researchers and PwP, such as the World Parkinson's Congress, or even the Synuclein Meetings, provides another route for each to understand more about the other's agenda and challenges.

Once contacts are established, the partnership can build, for example, with attendance at lab meetings, presentations on living with PD, and attendance at joint social events. In our view, such interactions should not involve financial incentives; rather, they should be seen as an alliance with mutual benefits. However, we understand that there may be circumstances where financial support is important, for example if a company establishes a formal patient advisory board, or if transportation costs need to be covered to enable the participation of PwP or researchers in joint meetings.

Ultimately, we are confident that stronger and more frequent interactions will enable researchers to understand more about what medicines PwP want and need.

Hope not hype

News about breakthroughs in PD research and drug development breaks quite frequently. We consider that most of it is done responsibly, albeit with optimism that may be overly positive but understandable. However, claims are occasionally made that are not supported by the data or the stage of development. This was exemplified by the case of nilotinib in 2016. ⁹ This caused a wave of what was subsequently shown to be misplaced optimism as well as off-label prescribing of a drug originally developed as a chemotherapeutic in cancer. Our role here is not to blame anyone in particular, but to call for moderation, both from the side of researchers as well as journalists who may be tempted to stretch the impact or importance of new findings.

PwP are generally old enough, and wise enough, to take in the truth of a new observation or a potentially new medicine, and the whole PD scientific and patient community should play the roles of concerned challengers of data in the best traditions of science. It is also the role of the neurologist to guide PwP to the best sources of information.

Conclusion

In conclusion, the search for the right medicine for each PwP or PwP group reflects the heterogeneous nature of Parkinson's disease, enhancing its management complexity and highlighting the need for personalised approaches.

The natural focus of the research community is on the development of DMT that will slow or alter disease progression. Involving PwP in the research process and knowing their day-to-day challenges, is also crucial to shape the development of medicines that will allow relief of the most bothersome symptoms. This will allow PwP to live better for longer. This collaborative environment will also foster PwP knowledge, and balance hope with realism.

Knowing that the discovery of a complete cure is unlikely in the near future, PwP are hoping for personalised therapies that will, simultaneously, improve their quality of life in each stage of the disease. While this ambition is not fulfilled, PwP want medicines that not only address the most prevalent symptoms, but also balance convenience, efficacy, safety and cost.