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AD/PD 2024: early diagnosis key for disease-modifying therapies in Parkinson’s

Parkinson’s disease prevention through a combination of early diagnosis and the development of disease-modifying therapies has been a key theme presented by AC Immune at the industry symposium for the AD/PD 2024 International Conference on Alzheimer’s and Parkinson’s Diseases.

Parkinson’s is a chronic neurodegenerative disorder that affects movement control, causing tremor at rest, rigidity, slowness of voluntary movement, and postural instability. It is characterised by progressive degeneration of the neurons of the substantia nigra pars compacta, which reduces the levels of dopamine available for neurotransmission in the corpus striatum. The current treatments for Parkinson’s focus on the management of dopamine levels in the brain and are limited to providing symptomatic relief of motor symptoms. The need for disease-modifying therapies is one of highest unmet needs that was consistently highlighted by key opinion leaders (KOLs) previously interviewed by GlobalData. KOLs agreed that if a disease-modifying therapy that can halt disease progression is approved for Parkinson’s, it would bring a major shift in the way these patients are treated.

Aggregates of α-synuclein protein in the form of Lewy bodies have been identified as the pathological hallmark of the disease, playing an important role in disease pathogenesis and neurodegeneration. The α-synuclein hypothesis has led to the treatment strategies being pursued by several pharmaceutical companies developing a first-in-class disease-modifying therapy. According to GlobalData’s Drug Database, there are 13 pipeline assets in clinical development globally (Phase I to Phase III) for Parkinson’s that target α -synuclein. 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.

Prothena Biosciences/Roche’s anti-α-synuclein monoclonal antibody (mAb) prasinezumab is currently being studied in a Phase II study, while five other mAbs from Sanofi, BioArctic, Lundbeck, AstraZeneca, and UCB are in Phase I development. Non-mAb disease-modifying therapies include AC Immune’s ACI-7104056, which is in Phase II, and Vaxxinity’s UB-312 which is in a Phase I trial, both active immunotherapies that involve a vaccine to stimulate the patient’s immune system to produce antibodies against α-synuclein. In addition, there are four small molecules and an antisense oligonucleotide that inhibit α-synuclein in development.

The industry symposium included a presentation on the status of the Phase II placebo-controlled, double-blind, randomised two-part study of ACI-7104 vaccination in patients with early Parkinson’s (VacSYn; NCT06015841). Thus far, AC Immune has enrolled 26 patients (Hoehn and Yahr scale I-II) across Spain, Germany, and the UK for part one of the study, which evaluates the safety, pharmacokinetics, and pharmacodynamics of the asset.  There have been no deaths or other serious treatment-emergent adverse events (TEAEs), and no TEAEs leading to discontinuation. The most common TEAEs reported were injection site reactions such as redness and itching that were mild or moderate in severity. This is in line with the findings of the Phase I study, where ACI-7104 was safe and well tolerated with no safety concerns noted in patients with Parkinson’s who were followed for more than 3.5 years (EudraCT numbers 2011–002650–31, 2013–001774–20, 2014–002489–54, and 2015–004854–16). AC Immune intends to enroll 32 patients for part one of the study and up to 150 patients for the second part of the clinical trial as a proof-of-concept study.

A key challenge in the development of disease-modifying therapies for Parkinson’s is the lack of valid biomarkers that can measure changes in disease progression in the early stages of the disorder. During the industry symposium, it was noted that the current clinical diagnosis criteria of Parkinson’s have major shortcomings with suboptimal accuracy and an insensitivity to early disease, as the prodromal stages of the disease are challenging to capture. For example, KOLs stated that advanced imaging in the form of a Dopamine Transporter Scan (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.

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The development of predictive biomarkers of Parkinson’s progression would have multiple implications in developing disease-modifying therapies in this area. 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 catalyse scientific advancements in the understanding of Parkinson’s pathophysiology. AC Immune presented data on the potential of its α-synuclein positron emission tomography (PET) program, ACI-15916, capable of detecting α-synuclein in vitro when investigating target occupancy on PD brain homogenates and tissue sections. The completion of IND-enabling studies is anticipated in 2024, prior to human studies.

The development of disease-modifying therapies in Parkinson’s proves to be a risky strategy for pharmaceutical companies given their high rate of failure in clinical trials, for example, the discontinuation of Biogen’s cinpanemab, an α-synuclein mAb, following the failure of its Phase II proof-of-concept trial (SPARK; NCT03318523). Currently, there are no pathological or imaging-based biomarkers to measure a patient’s progression other than clinical examination and the monitoring of symptoms. However, 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 disease-modifying therapy candidate for Parkinson’s. A breakthrough therapy in this risky area of disease-modifying therapies coupled with a valid biomarker would result in significant commercial success.