GlobalData : Early diagnosis continues to pose challenges for Parkinson’s disease-modifying therapies, says GlobalData

Parkinson's disease (PD) prevention through a combination of early diagnosis and the development of disease-modifying therapies (DMTs) that can halt the progression of PD was a key theme presented by AC Immune at the industry symposium for AD/PD 2024 International Conference on Alzheimer's disease (AD) and PD. However, the lack of valid biomarkers that can measure changes in disease progression in the early stages of PD is a key challenge in the development of DMTs, says GlobalData, a leading data and analytics company.

Christie Wong, Pharma Analyst at GlobalData, comments: "Aggregates of α-synuclein protein in the form of Lewy bodies have been identified as the pathological hallmark of PD, playing an important role in disease pathogenesis and neurodegeneration. The α-synuclein hypothesis is a treatment strategy pursued by several pharmaceutical companies developing a first-in-class DMT."

According to GlobalData's Drug Database, there are 13 pipeline assets in clinical development globally (Phase III-Phase I) for PD that targets α -synuclein. There are four small molecules and an antisense oligonucleotide that inhibit α-synuclein in development.

Six of the pipeline assets are passive immunotherapies, which rely on the direct administration of antibodies to degrade extracellular α -synuclein aggregates and to prevent disease propagation. In contrast, two active immunotherapies that involve a vaccine to stimulate the patient's immune system to produce antibodies against α-synuclein are in clinical development including AC Immune's ACI-7104056 in Phase II development.

Thus far, AC Immune have enrolled 26 PD patients for part one of the study, which evaluates the safety, pharmacokinetics, and pharmacodynamics of the asset. Based on the data presented at AD/PD industry symposium, there has been no deaths or other serious treatment-emergent adverse events (TEAEs), and no TEAEs leading to discontinuation. In addition, ACI-7104 was safe and well tolerated with no safety concerns noted in patients with PD who were followed for more than 3.5 years in a Phase I study.

A key challenge in the development of DMTs for PD is the lack of valid biomarkers that can measure changes in disease progression in the early stages of the disorder. The current clinical diagnosis criteria of PD have major shortcomings with suboptimal accuracy and an insensitivity to early disease as the prodromal stages of PD is challenging to capture.

The key opinion leaders (KOLs) previously interviewed by GlobalData stated that an advanced imaging in the form of a DaTSCAN is used if there are diagnostic doubts, but it does not support early diagnosis and there is poor diagnostic specificity between other movement disorders such as multiple system atrophy and progressive supranuclear palsy.

Wong adds: "The development of predictive biomarkers of PD progression would have multiple implications in developing DMTs for PD. These implications include improvements in diagnosis allowing for earlier intervention, improved disease staging and stratification of patient populations, improved clinical trial design, and an ability to predict patient prognosis. In addition to clinical benefits, biomarkers would likely catalyze scientific advancements in the understanding of PD pathophysiology."

AC Immune presented data on the potential of its α-synuclein positron emission tomography (PET) program, ACI-15916. It was able to detect α -synuclein in PD brain homogenates and tissue sections. The completion of IND-enabling studies is anticipated in 2024, prior to human studies.

Wong concludes: "The development of DMTs in PD proves to be a risky strategy for pharmaceutical companies given the high rate of failure in clinical trials. But AC Immune's ACI-15916 has promising preclinical data and holds potential for the diagnosis of PD. Furthermore, should the ACI-7104 vaccine demonstrate improved motor and non-motor function alongside a good safety profile in the Phase II trial, ACI-7104 could be a promising DMT candidate for PD. A breakthrough therapy in this risky area of DMT coupled with a valid biomarker would result in significant commercial success."