Welcome to the AD/PD™ 2022 Interactive Program

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Displaying One Session

Session Type
SYMPOSIUM
Date
Sat, 19.03.2022
Session Time
02:45 PM - 04:45 PM
Room
ONSITE: 112

THERAPEUTIC STRATEGIES FOR SYNUCLEINOPATHIES

Session Type
SYMPOSIUM
Date
Sat, 19.03.2022
Session Time
02:45 PM - 04:45 PM
Room
ONSITE: 112
Lecture Time
02:45 PM - 03:00 PM

Abstract

Abstract Body

Expression levels of αsyn have been intimately linked to Lewy body disease pathogenesis with the transmission of αsyn pathology from cell-to-cell via synaptically-interconnected brain regions presumably contributing to the progression of disease. Downregulating alpha-synuclein expression has the potential to decrease pathology transmission, seeding, and aggregation, and significantly slow or even halt the progression of symptoms in patients with Lewy body diseases. Consistent with this hypothesis, regions that are typically spared in dementia with Lewy bodies, such as the visual cortex and cerebellum, have consistently lower levels of alpha-synuclein expression compared to regions that are more vulnerable to developing Lewy pathology.

Downregulation of alpha-synuclein is an attractive disease-modifying strategy because it holds the promise of delayed progression and neuroprotective benefits. In support of an alpha-synuclein downregulation strategy, multiple preclinical studies have demonstrated the effectiveness of antisense oligonucleotides targeting SNCA in reducing alpha-synuclein expression and mitigating related cellular dysfunction.

Here we will discuss alternative strategies to target alpha-synuclein expression levels including the use of small molecules and gene-editing technologies. Both offer an alternative strategy to modulate disease progression from those currently in clinical trials and will inform the efficacy of alpha-synuclein lowering strategies.

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TREATMENT OF PARKINSON’S DISEASE: WHAT ABOUT THE NEXT FUTURE

Session Type
SYMPOSIUM
Date
Sat, 19.03.2022
Session Time
02:45 PM - 04:45 PM
Room
ONSITE: 112
Lecture Time
03:00 PM - 03:15 PM

Abstract

Abstract Body

Research for the treatment of Parkinson’s disease is moving in two directions: one to delay or alt disease progression and another to provide better symptomatic treatment. Alpha-synuclein (α-Syn) is a major component of pathology that characterizes several neurodegenerative disorders including PD, dementia with Lewy bodies, and MSA. In synucleinopathies, the synuclein protein can misfold and aggregate to form soluble aggregates and insoluble fibrils that contribute to neuronal death. This disease-causing synuclein can be propagated and transmitted from neuron to neuron, resulting in an infection-like spread of neuronal death. Two studies with passive immunotherapies has been concluded. The PASADENA study tested prasinezumab and despite the primary end-point was not met positive signals were seen. A phase IIB study with this drug just started. The PARK study with BIIB054 did not met primary and secondary en-points. The ORCHESTRA study with UCB0059, an oral Asyn antibody is also recruiting. Attention is now paid to genetic forms of parkinsonism. Two molecules are in clinical trials for GBA mutation, ambroxol and venglustat and one for patients with LRKK2 mutation, DNL151. But research is also active for symptomatic treatment. Two rescue therapy were just approved an inhaling formulation of levodopa and a sublingual apomorphine. Moreover to achive a more contnuos delivery of drug two subcutaneous preparation of levodopa are in clinical trials and olso an otal micropump able to deliver levodopa continuously. A new dopamine agonist, tavapadon and two drugs for dyskinesia are in clinical trial too.

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DELAYED START ANALYSIS OF ROCHE PD MOBILE APPLICATION V2 IN PASADENA SHOWS PERSISTENT POSITIVE EFFECTS OF PRASINEZUMAB ON BRADYKINESIA PROGRESSION

Session Type
SYMPOSIUM
Date
Sat, 19.03.2022
Session Time
02:45 PM - 04:45 PM
Room
ONSITE: 112
Lecture Time
03:15 PM - 03:30 PM

Abstract

Aims

To determine whether the positive effects of prasinezumab on motor progression measured by the exploratory Roche PD Mobile Application v2 (PASADENA study Part 1; 0-52 weeks; NCT03100149) persisted in PASADENA Part 2 (52-104 weeks) when all patients received prasinezumab.

Methods

316 individuals with early PD were randomized to prasinezumab (low or high dose) for 104 weeks (early-start group), or placebo for 52 weeks then prasinezumab (low or high dose) for 52 weeks (delayed-start group). Roche PD Mobile Application v2 administered daily “active tests” and “passively monitored” motor behavior in daily life (phone, smartwatch). Seventeen pre-specified sensor features were aggregated over every two-week period until start of dopaminergic therapy. Linear mixed effect models or mixed models for repeated measures were fitted to each feature’s change from baseline to week 104. Exploratory significance was defined as α<0.2 and false discovery rate (FDR) correction applied at 15%.

Results

In Part 2, patients performed all assigned active tests on average 5/7 days per week, and collected an average of 7.3h smartwatch and 4h smartphone passive monitoring data daily. 6/17 sensor features showed persistent effects favoring prasinezumab (Figure 1). Three sensor features demonstrated persistent positive effects of prasinezumab surviving FDR correction: speeded tapping variability (β=-0.0017, p=0.03), U-turn test (β=0.0006, p=0.02), and daily gesture power (Week 104 mean difference= 0.21, p=0.02) (Figure 2).

dbm figure 1.png

dbm figure 2.png

Conclusions

The early-start prasinezumab group showed a persistent reduction in bradykinesia progression compared with the delayed-start group as measured by the Roche PD Mobile Application v2.

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RESULTS OF A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY TO EVALUATE THE EFFICACY AND SAFETY OF AKST4290 IN PARKINSON’S DISEASE

Session Type
SYMPOSIUM
Date
Sat, 19.03.2022
Session Time
02:45 PM - 04:45 PM
Room
ONSITE: 112
Lecture Time
03:30 PM - 03:45 PM

Abstract

Aims

Development of novel therapeutic strategies in Parkinson’s disease (PD) is needed to treat the unmet needs of patients. Eotaxin and C-C motif chemokine receptor 3 (CCR3) are associated with neuroinflammatory processes. AKST4290, a small molecule CCR3 antagonist, demonstrated beneficial effects on motor function, microgliosis, and immune cell infiltration in preclinical models of PD. A clinical trial was conducted to evaluate the safety and therapeutic potential of AKST4290 in PD.

Methods

Patients were randomized 1:1 to AKST4290 (400 mg twice daily) or placebo for 12 weeks. The primary endpoint was the change from baseline in motor function during the off-medication state at 12 weeks as measured by the Movement Disorder Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Part 3. Secondary endpoints included assessment of safety/tolerability and changes in clinical function, motor function, and activities of daily living during the on-medication state, as well as cognitive, psychological, and motor assessments using validated tools.

Results

A total of 110 patients were randomized to AKST4290 or placebo, and 93 completed the study. Safety and tolerability were favorable, with adverse events similar across groups. Subjects on both AKST4290 and placebo improved at a similar magnitude for the MDS-UPDRS Part 3. AKST4290 demonstrated improvement over placebo in the MDS-UPDRS Part 2, Parkinson’s Disease Questionnaire-39 (PDQ-39), and Clinical Impression of Severity Index-PD (CISI-PD).

Conclusions

Improvements with AKST4290 treatment were evident in select important assessments of relevance to PD patients. The results of this study support continued investigation of AKST4290 in neuroinflammation in PD.

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A 104-WEEK DELAYED-START ANALYSIS OF PASADENA (PHASE II STUDY EVALUATING THE SAFETY AND EFFICACY OF PRASINEZUMAB IN EARLY PARKINSON'S DISEASE)

Session Type
SYMPOSIUM
Date
Sat, 19.03.2022
Session Time
02:45 PM - 04:45 PM
Room
ONSITE: 112
Lecture Time
03:45 PM - 04:00 PM

Abstract

Aims

To describe the effect of prasinezumab on motor progression in early Parkinson’s disease (ePD) using a delayed-start analysis of Part 2 (Week 104) of the Phase II PASADENA study (NCT03100149). PASADENA Part 1 did not meet the primary endpoint (Movement Disorders Society–Unified Parkinson’s disease Rating Scale [MDS-UPDRS] sum of Parts I+II+III); however, prasinezumab-treated patients showed less motor progression compared with placebo.

Methods

Individuals with ePD (diagnosis ≤2 years at screening; Hoehn & Yahr Stages I–II) were randomised to receive intravenous prasinezumab every 4 weeks (low or high dose) for 104 weeks (early-start group), or placebo for 52 weeks followed by prasinezumab (low or high dose) for 52 weeks (delayed-start group).

Results

Worsening from baseline in MDS-UPDRS Part III scores was less in the early-start group (n=204) versus the delayed-start group (n=105) at Week 52 (5.02 [SE: 0.673] points vs. 6.25 [0.911] points, respectively) and at Week 104 (9.18 [0.994] vs. 11.12 [1.376] points, respectively) (Figure 1), with the largest group difference in the bradykinesia subscore (Figure 2). Fewer patients in the early-start group (79.1%) reached a ≥5-point increase in MDS-UPDRS Part III versus the delayed-start group (89.5%) (hazard ratio: 0.77 [80% CI 0.66–0.91]) (Figure 3). Digital motor scores were consistent with these results.

pasadena part 2 figure 1.pngpasadena part 2 figure 2.pngpasadena part 2 figure 3.png

Conclusions

After 2 years, prasinezumab-treated individuals showed less motor progression on MDS-UPDRS Part III in the early-start versus the delayed-start group. The ongoing Phase IIb PADOVA (NCT04777331) study will further assess efficacy and safety of prasinezumab in people with ePD on stable symptomatic treatment.

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SAFETY, TOLERABILITY, PHARMACOKINETICS AND PHARMACODYNAMICS OF THE OLIGOMER MODULATOR ANLE138B IN PARKINSON´S DISEASE: A RANDOMISED, DOUBLE-BLIND, PLACEBO-CONTROLLED PHASE 1B TRIAL

Session Type
SYMPOSIUM
Date
Sat, 19.03.2022
Session Time
02:45 PM - 04:45 PM
Room
ONSITE: 112
Lecture Time
04:00 PM - 04:15 PM

Abstract

Aims

Synucleinopathies such as Parkinson ́s disease (PD) and Multiple System Atrophy are characterized by deposition of misfolded and aggregated α-synuclein. Small aggregates (oligomers) of α-synuclein have been shown to be the most relevant neurotoxic species and are targeted by anle138b, an orally bioavailable small molecule compound which shows strong disease-modifying effects in animal models of synucleinopathies. Here we present fist-in-patient data of anle138b in patients with PD.

Methods

Anle138b was studied in a single-centre, double-blind, randomised, placebo-controlled multiple ascending dose (MAD) study in patients with mild to moderate PD. Participants were randomly assigned to placebo or anle138b (dose range 150 mg to 300 mg per day), respectively. The primary endpoints were safety and tolerability, the secondary endpoint was pharmacokinetics. In addition, exploratory endpoints related to pharmacodynamics were assessed and the effect of food on the pharmacokinetics of anle138b was examined. Treatment was administered orally in hard gelatine capsules containing anle138b or excipient only. Clinicaltrials.gov-identifier: NCT04685265. EudraCT-number: 2020-004869-38.

Results

22 participants were enrolled in cohorts A-C. Of these, all completed the study per protocol. There were no major protocol violations. Anle138b demonstrated excellent safety and tolerability at all dose levels. No abnormal trend was seen in any system organ class. Pharmacokinetics of anle138b in PD patients was largely identical to the pharmacokinetics previously observed in healthy volunteers (Clinicaltrials.gov-identifier: NCT04208152).

Conclusions

In patients with PD, anle138b was safe and well tolerated in doses resulting in exposures above the putatively effective plasma levels. These findings warrant long-term efficacy trials in patients with synucleinopathies.

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PRE-RECORDED: GENE THERAPY APPROACHES TARGETING SNCA EXPRESSION FOR PRECISION MEDICINE IN PARKINSON’S DISEASE AND RELATED DISORDERS

Session Type
SYMPOSIUM
Date
Sat, 19.03.2022
Session Time
02:45 PM - 04:45 PM
Room
ONSITE: 112
Lecture Time
04:15 PM - 04:30 PM

Abstract

Abstract Body

Aims: Elevated SNCA levels are causative in Parkinson’s Disease (PD) pathogenesis. Patients with SNCA triplication and duplication suffer from familial early onset PD, suggesting a therapeutics window of <30%. We aim to translate mechanistic knowledge of SNCA dysregulation towards the development of epigenome therapy targeting SNCA expression.

Methods: We developed all-in-one lentiviral vector carrying the CRISPR/deactivated(d)Cas9 and selected gRNAs targeted at SNCA-intron1 fused with effector molecules specifically, the catalytic domain of DNMT3A or the transcription repressors KRAB/MeCP2.

Results: We previously transduced the gRNA-dCas9-repressor system into human iPSC-derived ‘aged’ dopaminergic neurons from a PD-patient with the SNCA triplication and showed fine-tuned downregulation of SNCA-mRNA and protein levels that led to the rescue of disease-related pathalogical phenotypes including, mitochondrial dysfunction, neuronal-cell death, DNA damage and nuclear deficits. We now pursued with in vivo validation studies. Stereotaxic injection of the gRNA/dCas9-effector system into the mouse sub-nigra lowered Snca-mRNA and protein expression levels, whereas the effect of the KRAB-MeCP2 construct was greater than that of the DNMT3A. The effect on gene expression was specific to Snca gene and no changes were observed in other brain structures including the striatum and cerebellum. Safety measures demonstrated no abnormalities in daily monitored well-being criterions and no weight loss.

Conclusions: We developed a novel technology to intervene with the transcription program of SNCA, based on precise epigenome editing, and validated effective and specific fine-tuned reduction in SNCA expression sufficient for reversing PD-associated perturbations. This study provides a proof-of-concept for advancing the development towards precision medicine for PD.

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DISCUSSION

Session Type
SYMPOSIUM
Date
Sat, 19.03.2022
Session Time
02:45 PM - 04:45 PM
Room
ONSITE: 112
Lecture Time
04:30 PM - 04:45 PM