Could targeting lysosomal dysfunction be the key to treating Parkinson’s disease?

by Dana Miller on November 12, 2020


There is an increasing interest in the clinical development of therapies targeting genetically defined PD, despite this only representing a small proportion of the overall PD population. Why does this provide such an attractive target for pharmaceutical intervention?

Parkinson’s disease occurs when patients are unable to produce enough of the neurotransmitter dopamine, which occurs due to the death of some of their neurons. The exact mechanism behind this cell death remains unclear.

α-synuclein and PD

α-synuclein, a presynaptic neuronal protein, is commonly linked to the pathology of PD as it forms part of potentially toxic aggregates in neurons of PD patients. Targeting α-syn has been the focus of PD disease modifying treatment developments to date, commonly using monoclonal antibodies.

In recent interim analyses of Roche’s PASADENA Ph2 study, its α-syn mAb prasinezumab failed to reach its primary endpoint of slowing disease progression, however showed promising signs of efficacy on multiple secondary and exploratory measures. It remains to be seen if an interim analysis for Biogen’s competitor cinpanemab, which is expected to be released by the end of 2020, follows a similar fate.

Lysosomal dysfunction as a treatment target

It has been proposed that by treating a genetically validated disease mechanism, the probability of success of a clinical trial increases by two-fold. The most common mutations associated with PD are in the GBA and LRRK2 genes, leading to lysosomal dysfunction. Considering the increased probability of success, therapeutics that target lysosomal dysfunction are a growing focus in the PD field.

Sanofi’s venglustat, a GCS inhibitor aimed at GBA-PD, is currently in Ph2 development, with a pivotal trial expected to conclude in 2025, allowing potential filing in that same year. Interestingly, Sanofi announced that the FDA recommended that its Ph3 development plan includes a 20% proportion of patients with sporadic disease. This suggests a confidence from the regulators and company that venglustat has the potential to provide a benefit for a broader PD population.

This is consistent with Denali Therapeutics’ claims for its Ph1 LRRK2 inhibitors, which it plans to investigate in two parallel Ph2 trials in LRRK2 and sporadic PD patients. In August, Biogen and Denali announced that they had signed an agreement to co-develop and co-commercialise Denali’s LRRK2 inhibitors, showing a significant confidence in the likelihood of success for this program.

Subsequently, in early October further big pharma interest in the genetic PD space was revealed, with Bial’s acquisition of worldwide rights to Lysosomal Therapeutics Ph1 GBA-PD therapy LTI-291.

Despite the significant recent investments made by big pharma in the genetic PD space, and the associated confidence and positive messaging on the possibility to expand potential use to a sporadic population, neuroscience KOLs appear less convinced. During recent conference presentations, the consensus was that if therapies can provide a benefit to those without a genetically defined diagnosis it is unlikely to be as significant. As such, these KOLs believe that clinical development of these genetically targeted therapies should initially be restricted to genetic PD patients. Only time will tell if big pharma’s confidence translates into successful disease modifying treatments for a broad PD population.

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