Abstract Body

Abstract Body

Decreasing alpha-synuclein expression is a recognized target for Parkinson’s disease (PD) therapeutics however it remains to be determined if targeting alpha-synuclein expression will translate into symptomatic improvements and will modify disease progression. Until there is a therapeutic that can be tested in patients for its ability to modify alpha-synuclein levels, it remains to be determined if decreasing alpha-synuclein levels will be beneficial to PD patients and will alter the course of the disease. Current efforts to modulate alpha-synuclein levels are focused on immunotherapy and antisense oligonucleotides with recent announcements of promising results from Phase I and II trials of active and passive immunization targeting alpha-synuclein.

Here we will discuss ongoing strategies to target alpha-synuclein expression levels including the development of small molecules that target alpha-synuclein expression at the transcriptional level. Small molecules targeting alpha-synuclein expression offer an alternative strategy to modulate disease progression from those currently in clinical trials and will be informative regarding the efficacy of alpha-synuclein lowering strategies.

Aims

Cerebral dopamine neurotrophic factor (CDNF) is an unconventional neurotrophic factor that in preclinical models of Parkinson’s disease (PD) protects dopamine neurons via a unique multi-modal mechanism of action. In this first-in-man study, we assessed the safety and tolerability and explored the efficacy of intermittent bilateral intraputamenal monthly infusions of CDNF protein in subjects with moderately advanced PD.

Methods

A randomized, placebo-controlled, double-blind phase I-II trial in 17 patients with moderate PD, comprising placebo or incremental CDNF dosing for six-month followed by an active treatment six-month extension study. A drug delivery system (Renishaw) was implanted into putamina in all patients. Primary endpoint was safety and tolerability. Secondary and exploratory endpoints included UPDRS, dopamine transporter (DAT) PET, actigraphy and CSF biomarkers.

Results

At screening, the patients had on average disease duration of 10.6±2.6 years, H&Y 2.4±0.4 and >5 h daily off-time. Two patients discontinued in the first 6-month period due to serious adverse events (SAE) related to infusion procedures with the implanted device. Study drug-related AEs were mild to moderate. The primary endpoint was met. At the 12-month timepoint, the least square means change in UPDRS III (off) from baseline in all patients receiving CDNF was -2.2 points (p>0.05, repeated-measures ANCOVA). Increased DAT availability in the putamen was observed at 6 and 12-month timepoints in some patients that received CDNF.

Conclusions

Intraputamenal CDNF infusions were safe and well tolerated despite the AEs and SAEs related to the route of administration. Signs of potential clinical and biological response to the treatment were observed in some patients.

Aims

This study aimed to evaluate the efficacy and safety of prasinezumab, a monoclonal antibody which targets extracellular α-synuclein, following 52 weeks of treatment in early PD.

Methods

A 52-week randomised, double-blind, placebo-controlled study (PASADENA Part 1) was performed to assess efficacy and safety of prasinezumab (low or high dose) in early PD (N=316, diagnosis ≤2 years; Hoehn & Yahr Stages I–II). The primary endpoint was the change in Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Total score (Parts I + II + III) from baseline to Week 52. Secondary and exploratory endpoints included: changes in MDS-UPDRS Part III, MDS-UPDRS Part III subscores, other clinical and digital endpoints and imaging biomarkers.

Results

At Week 52, MDS-UPDRS Total score was –1.30 (–14%; 80% CI: –3.18, 0.58) for pooled doses versus placebo; –2.02 for low dose (–21.5%; 80% CI: –4.21, 0.18) and –0.62 for high dose (–6.6%; 80% CI: –2.82, 1.58). MDS-UPDRS Part III was –1.88 (–35.0%; 80% CI: –3.31, –0.45) for pooled treatment groups versus placebo; –2.44 for low dose (–45.4%; 80% CI: –4.09, –0.78) and –1.33 for high dose (–24.7%; 80% CI: –2.99, 0.34). MDS-UPDRS Part III site rating, MDS-UPDRS Part III bradykinesia subscore, digital motor endpoints, and time to worsening of motor symptoms supported the MDS-UPDRS Part III positive motor signals. There were no life-threatening adverse events or immunogenicity concerns.

Conclusions

Prasinezumab had a favourable safety profile and is the first potentially disease-modifying, anti-α-synuclein antibody to show efficacy signals on clinical progression of core motor features of PD. Further studies are warranted.

Aims

Objectives: Digital health technologies (DHTTs) enable remote and frequent monitoring of motor symptoms in Parkinson’s disease (PD), and may more readily detect effects of disease modifying therapies compared to infrequently administered clinical scales. We report the effects of prasinezumab, an anti-alpha synuclein monoclonal antibody, on motor disease progression measured with the Roche PD Mobile Application v2 in the phase 2 PASADENA study (NCT03100149).

Methods

Methods: 316 individuals recently diagnosed with PD were randomized to placebo, low and high dose groups. All received a smartphone/watch, performed daily active motor tests, and carried/wore devices throughout the day. 17 pre-specified sensor features were aggregated over fortnights. Linear mixed effect models with random slopes fit each feature’s change from baseline. Random mixed effects models modeled nonlinear data. Effects of interest were defined as p<0.2, and multiple comparison correction was applied at 15% false discovery rate.

Results

Results: 75% of patients had mean adherence >75.9% (median adherence=93.1%). 5/17 sensor features showed treatment effects favoring prasinezumab: speeded tapping variability of most, least affected sides; maximum speed of pronation/supination most affected side; passively-monitored spontaneous gesture power; maximal turn speed on U-turn test. 1 feature (spiral drawing accuracy/time) showed an effect favoring placebo. Two analyses survived FDR-correction, both favoring prasinezumab: speeded tapping least affected side, power of gestures in daily life (see Figure).

Conclusions

Conclusions: Daily quantification of motor severity via a DHTT in early-stage PD demonstrated a divergence of slopes in bradykinesia progression, consistent with a disease-modifying effect of prasinezumab.

Aims

To investigate time to a clinical meaningful change of 4 points on the Unified Parkinson’s Disease Rating Scale motor score (UPDRS-Motor)¹ and a clinical meaningful change of 2 points on the UPDRS-ADL.²

Methods

This is a secondary analysis of placebo arm data from the National Institute of Neurological Disorders and Stroke Exploratory Clinical Trials in Parkinson Disease Long-Term Study 1 (NET-PD LS-1) trial, conducted from 2007-2013.³ Trial eligibility criteria included a PD diagnosis within 5 years and dopaminergic therapy use (minimal 90 days, maximal 2 years, adjustments permitted during trial). UPDRS-Motor (ON-state) and UPDRS-ADL were assessed annually up to 72 months. Using Kaplan-Meier analysis, median time to event was calculated for: 1) UPDRS-Motor +4 points from baseline (motor event); 2) motor event co-occurring with UPDRS-ADL +2 points from baseline (combined motor/ADL event).

Results

This analysis included 248 levodopa treated individuals (mean age 66.4 years, 65.3% men). Median time to the motor event was 24 months and median time to the combined motor/ADL event was 36 months. Comparing those with a motor event versus no motor event during the first 24 months, 24-months UPDRS-ADL mean (SD) change from baseline was 3.5 (4.7) and 0.3 (3.5) respectively.

Conclusions

Among levodopa treated individuals with PD, median time to reaching a clinical meaningful change on UPDRS-Motor was 2 years, which coincided with a clinical meaningful decline of daily life functioning.

References

1 Horvath K et al. Parkinsonism Relat Disord. 2015;21(12):1421-6.

2 Martinez-Martin et al. Value Health. 2006;9(6):386-93.

3 Kieburtz, K et al. JAMA. 2015;313(6):584-93

Aims

Execute a national Norwegian multicenter phase IIa RCT clinical intervention study with Ambroxol in prodromal and mild DLB, and include persons living with prodromal (DLB-MCI) or mild DLB with MMSE >=15 to Ambroxol or placebo. We will stratify participants based on genotypes for APOE and GBA and the CSF biomarker amyloid-beta. We will build a national trial platform for drug trials in neurodegenerative disorders in Norway and aim to include more centers in Europe for next phase studies via the European DLB Consortium (E-DLB). We will execute a PPI program to raise awareness and reduce stigma for people living with DLB and their families.

Methods

Multicenter phase IIa RCT clinical intervention study with Ambroxol in prodromal and mild DLB. MMSE will be used as the primary outcome measure.

Results

The ANeED-study has received funding from the national Norwegian health authorities. Ethical approval and data protection approvals are granted. Ambroxol and placebo tablets a 60mg, 315mg and 420mg are produced, and formal approval from the Norwegian Medicine Agency is ongoing.

Conclusions

Phase III studies with Ambroxol in PD, PDD and DLB are currently being planned. APOE, GBA and GCase are central to the disease process in both PD, PDD and in DLB. Patients, carers and health providers now need to be offered participation in clinical studies also when diagnosed with one of the α-synucleinopathies. Preliminary data find Ambroxol to be potentially disease modifying in these disorders, and potential collaborators for a phase III study in DLB in Europe and the US are welcome.

Abstract Body