Bringing Advanced Therapy Medicinal Products (ATMPs) for Parkinson’s Disease to the Clinic: The Investigator’s Perspective

INTRODUCTION

Advanced therapy medicinal products (ATMPs) include tissue engineered products as well as cell and gene treatments, and there is much excitement around treating Parkinson’s disease (PD) with such therapies. These treatments need to be seen as distinct from advanced therapies for PD, such as deep brain stimulation or infusional dopamine therapies. Furthermore, it is critically important at the outset of this short review to distinguish between those therapies that have been developed over many years from sound scientific principles from those that have little or no scientific basis. One particular area of concern, in this regard, is the burgeoning field of stem cell tourism with clinics offering unproven stem cell therapies for money and for which physicians have a duty of care to warn patients about them when approached or asked [1–3].

In PD, the majority of ATMPs that are in, or soon to enter, the clinic are designed around replacing or restoring dopaminergic innervation in the striatum [4]. These approaches can simplistically be thought of in terms of:

cell replacement therapies using stem cell de-rived dopaminergic neurons that are then grafted to the striatum;

The rationale for the first two therapies is to directly replace the striatal dopamine loss of PD while, for growth factors, it is to rescue or slow down the loss of the failing dopaminergic nigrostriatal pathway. In all cases, the therapies are not designed to be curative as none are targeting the fundamental problems that lead to, and drive, PD. Rather, what they are seeking to do is to provide better symptomatic control of the dopaminergic responsive elements of the patients’ disease. These elements, which include rigidity, bradykinesia as well as the tremor and cognitive deficits in some PD patients, are not inconsequential to the quality of life and symptomatic control of their condition, as is evident by the power of oral dopamine drugs to dramatically help these aspects of PD [7, 8]. Thus, ultimately the best that these therapies can hope to achieve is to obviate the need for any oral or enteral dopaminergic therapies and the complications that these treatments bring with them [9]. As such ATMP therapies could dramatically alter the natural history of treated PD and in this sense, they could be seen to be disease modifying, as discussed by Kieburtz et al. (2021) [10].

THE CLINICAL HOPE AND CHALLENGES

If we start from this position of understanding, then we need to ask: “What is the clinician/investigator hoping to achieve (and not achieve) with such therapies?” This can be summarized as follows:

better, more stable control of many of the core motor elements of PD for many years;

In order for this to become a reality, several key questions need to be answered for these ATMPs which includes whether they can:

work as well as those dopaminergic and related therapies that are currently available in the clinic now and do so over many years (see, e.g., [11]) and/or provide additional benefits not offered by conventional dopaminergic drug therapies;

If all this can be realized, then we will have useful new “dopaminergic” treatments for PD which ultimately could be combined with true disease modifying therapies targeting the underlying disease process and the non-dopaminergic aspects of this condition.

THE REALITY OF CLINICAL TRANSLATION AND ITS CHALLENGES

The regulatory landscape for ATMPs is continuously evolving and brings with it many complexities, which vary to some extent depending on which regulatory agency one is operating under, e.g., U.S. Food and Drug Administration (FDA) versus European Medicines Agency (EMA) or Pharmaceuticals and Medical Devices Agency (PMDA). In this section, we aim to highlight some of the challenges faced when translating any ATMP to a first in human clinical trial for PD and which any investigator will have to engage with at an early stage of ATMP development and translation.

In order to set up and conduct a clinical trial of an ATMP, there are many processes which need to be followed, each dependent on the country-specific regulatory guidelines. There is not a ‘one fits all’ approach to the set-up, approval, and conduct of such trials. In a survey of European-based ATMP developers, it was found that challenges were faced in the following areas: regulatory, technical, scientific, financial, clinical, human resource management, and others (including intellectual property and public perception) [16].

In Table 1, we outline in further detail some of these key challenges.

CONCLUSION

The taking of an ATMP for patients with PD through to clinical trials is complex and from an investigator’s perspective there are two main questions: why are you doing it, and do you understand what is needed to conduct a clinical trial with that product? Thus, it is critical that the rationale for the therapy is clearly understood along with what competitive advantage it could ultimately bring to PD patients. There is no point pursuing such therapies if the improvement is not equivalent to or better than that which can already be achieved with existing therapies. At the present time, the therapies being considered in this space are ones looking to better deliver dopamine to the striatum and the reasons as to why this approach is of merit have been briefly laid out. However, as we have also summarized, the investigator in addition has the responsibility of deciding how they will move that therapy to a trial. This is not straightforward and requires considerable time and input from a large number of specialists as well as a significant budget. As such pursuing such ATMPs is a major undertaking and those investigators seeking to do this should understand the complexity and responsibilities that this brings with it not only for their own work but the field more generally.