MDS 2021 | Why do PD trials keep failing? Seven solutions for neuroprotection
Etienne Hirsch, PhD, Institut du Cerveau-ICM, Inserm, Sorbonne Université, Paris, France, outlines seven solutions for neuroprotection in Parkinson’s disease (PD), which he presented in the C. David Marsden presidential lecture at the Movement Disorder Society congress 2021. Despite a plethora of attempted strategies and much preclinical success,, no neuroprotective agent has demonstrated efficacy in clinical trials. Prof. Hirsch shares seven reasons why these trials may have been unsuccessful and how we can change our approach for successful development of neuroprotective drugs. These include selecting defined patient subgroups in which the targeted mechanism is involved in the pathological process, intervening earlier in the disease course, improving drug delivery to the appropriate brain regions, combining treatments that target different disease mechanisms, and considering variation in disease mechanisms throughout the disease course. This interview took place during the 2021 International Congress of Parkinson’s Disease and Movement Disorders.
Transcript (edited for clarity)
Neuroprotection in Parkinson’s disease is really the holy grail. We really are facing a major issue. Several clinical trials have been performed, targeting multiple mechanisms of degeneration in Parkinson’s disease, but none of them were really successful. So, what I will be doing is to try to do a post-mortem study of these clinical trials and try to explain why they are not successful...
Neuroprotection in Parkinson’s disease is really the holy grail. We really are facing a major issue. Several clinical trials have been performed, targeting multiple mechanisms of degeneration in Parkinson’s disease, but none of them were really successful. So, what I will be doing is to try to do a post-mortem study of these clinical trials and try to explain why they are not successful. And I will cover seven reasons.
The first reason is that multiple etiology account for Parkinson’s disease. For instance, there are some forms which are inherited forms, some are more environmental, and for instance, in my group, we have studied a very peculiar parkinsonian syndrome in the French Caribbean, which is due to consumption of traditional medicine, including a toxic compound. And therefore, we suggest to perform clinical trial in more defined small population of patients with known etiology.
The second reason is that the treatment is administered too late. There is a presymptomatic phase, and we suggest that clinical trials for neuroprotection should be started during this presymptomatic phase. And we have patients at risk which are carriers of mutations, but which do not express the clinical manifestation of the disease. And this might be an interesting population to test these clinical trials. The third reason is that the drugs are not delivered properly to the brain and to the very specific regions in which degeneration occur in the brain. So, we propose to deliver the molecule in the right place.
The fourth reason is that most of the clinical trial focus on the dopaminergic neurons, but we know that non-dopaminergic neurons, they generate also in Parkinson’s Disease. And my group has shown that a very small nucleus in the brain stem, it is called the pedunculopontine nucleus, is involved in gait and balance disorders in PD. So we should also take into account the non-dopaminergic lesion. The fourth reason is that the mechanics involved in cell death might vary during the development of the disease. So, in other words, at the beginning and end stage of the disease, we might have different mechanism. And for instance, at end stage of the disease, we are facing a very strong neuroinflammatory process, which in fact might be involved in the self-perpetuation of the pathological process. And this is a very interesting target that should be analyzed.
Finally, the different ways by which the neuron degenerate in Parkinson’s disease might be additive and therefore we might need to use a cocktail of molecules. For instance, molecules targeting the protein processing, and anti-inflammatory drugs. And the brain environment is also changing in Parkinson’s disease with changes in blood-brain-barrier, which might in fact also have to be taken into account. So, we have multiple ways of improving the clinical trials, and we hope that this might lead to successful story for the benefit of the patients.
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