Welcome to the AD/PD™ 2024 Interactive Program
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DEVELOPMENT OF AX-5006, A SMALL MOLECULE INHIBITOR OF CSGA AGGREGATION AS A POTENTIAL DISEASE-MODIFYING TREATMENT FOR PARKINSON’S DISEASE
Abstract
Aims
Gastrointestinal dysfunction can often manifest years before the appearance of motor symptoms in Parkinson’s disease. The gut microbiome contributes to pathology in Parkinson’s disease mouse models via production of the bacterial amyloid protein CsgA, which can induce α-synuclein aggregation in the gut. CsgA can accelerate α-synuclein aggregation in the brain and increase motor symptoms; thus, blockage of this initiating step represents a potential therapeutic intervention. The goal of this program is to develop AX-5006, a small molecule inhibitor of CsgA aggregation, for the treatment of Parkinson’s disease.
Methods
AX-5006 was identified as an inhibitor of microbial CsgA aggregation through medicinal chemistry efforts. It is designed to act in the gut and have minimal systemic distribution. The pharmacokinetic profile of AX-5006 was established in mice, rats, and dogs. The efficacy of AX-5006 was evaluated in germ-free α-synuclein over-expressing (ASO) mice that were mono-colonized with CsgA producing bacteria.
Results
AX-5006 demonstrates a predominantly gut-acting pharmacokinetic profile, with high fecal drug levels and low plasma levels observed in vivo following oral dosing. In the mono-colonized ASO mouse model, target engagement, measured by reduction in csgA mRNA expression, was demonstrated in the cecum following 18 weeks of treatment with AX-5006. Additionally, AX-5006 treatment reduced α-synuclein aggregation in the brains of mice, improved motor function, and delayed disease progression over time.
Conclusions
AX-5006 is a small molecule inhibitor of bacterial CsgA aggregation in the gut. Efficacy data in the ASO mouse model as well as its pharmacokinetic profile support AX-5006 as a novel development candidate. IND-enabling nonclinical studies are underway, and a clinical study is anticipated to begin in 2024.
"INDUCING CHAPERONE-MEDIATED AUTOPHAGY AS A MEANS TO COUNTERACT ALPHA-SYNUCLEIN PATHOLOGY IN NON-HUMAN PRIMATES"
Abstract
Aims
Lysosomal impairment is strongly implicated in Parkinson’s disease (PD). Chaperone-Mediated Autophagy (CMA) is a major lysosomal pathway responsible for alpha-synuclein (aSyn) clearance but, at the same time, can be a direct target of aSyn-related neurotoxic effects. Herein, we investigated the therapeutic potential of boosting the CMA pathway by targeting its rate-limiting step, the LAMP2A receptor, in primates, representing the most advanced non-human model of synucleinopathy.
Methods
We performed bilateral injections of the AAV2/9-LAMP2A vector (or a control Stuffer vector) in the substantia nigra of 14 male rhesus macaque monkeys. Additionally, we administered unilateral intrastriatal injections of low-dose aSyn-containing Lewy body (LB) extracts from PD or non-PD brains. After a 15-month observation period, extensive histochemical and biochemical analyses were performed to assess PD-related pathological markers. We characterized the pattern of dopaminergic loss in the striatum and the substantia nigra, the regional distribution of aSyn immunoreactivity in several brain structures, as well as its pathological status (i.e., S129 phosphorylation) and the occurrence of lysosomal dysfunction.
Results
Our data so far indicate that viral-mediated LAMP2A overexpression protects dopaminergic neurons from cell loss induced by PD brain extract injection. Significantly, total aSyn and pathological pSer129 aSyn protein levels were significantly decreased in the LAMP2A-injected animals as compared to the Stuffer-injected ones. Interestingly, LAMP2A-injected, compared to Stuffer-injected animals, exhibited enhanced performance in pre-frontal cortex-dependent cognitive function tests, suggesting a beneficial cognitive effect. Lastly, LAMP2A overexpression decreased extracellular aSyn levels in the monkey biological fluids.
Conclusions
Our results suggest that enhancing CMA through LAMP2A overexpression or other means, potentially pharmacological, could offer new avenues to slow down the degenerative synucleinopathy process underlying PD.
REDUCED PREVALENCE OF PARKINSON'S DISEASE IN PATIENTS PRESCRIBED CALCINEURIN INHIBITORS
Abstract
Aims
Preclinical evidence suggests calcineurin inhibitors (CNIs) combat alpha-synuclein-induced neuronal dysfunction and motor impairments. However, whether CNIs prevent or treat Parkinson’s disease (PD) in humans remains unknown. We aim to determine if prescription of CNIs is associated with a reduced prevalence of PD in a diverse patient population and to gain insight into the mechanism(s) and site of action for CNIs in this context.
Methods
We analyzed electronic health records (EHRs) from patients prescribed the brain-penetrant CNI tacrolimus (TAC), the peripherally-restricted CNI cyclosporine (CySp), or the non-CNI sirolimus (SIR). EHRs from a random, heterogeneous population from the same network served as a general population-like control. After propensity-score matching, we compared prevalence, odds, and hazards of PD diagnoses between cohorts.
Results
Patients prescribed CNIs have reduced prevalence, odds, and hazards of a PD diagnosis compared to the general population-like control, while patients prescribed SIR do not. Notably, patients prescribed TAC have a reduced prevalence of PD relative to patients prescribed SIR or CySp.
Conclusions
Our findings suggest that CNIs, especially those acting within the brain, are effective at preventing PD. The reduced prevalence of PD in patients prescribed TAC, compared to patients prescribed SIR, suggests that mechanisms of calcineurin inhibition—other than general immunosuppression, which is common to both drugs—are driving the reduction. Therefore, CNIs may provide a promising therapeutic approach for PD.
VACSYN STUDY: AN INNOVATIVE BIOMARKER-BASED PHASE 2 CLINICAL TRAIL TO EVALUATE ACI-7104.056, A NOVEL ACTIVE IMMUNOTHERAPY FOR PARKINSON'S DISEASE
Abstract
Aims
The central pathological hallmark of Parkinson’s disease (PD) is characterized by the loss of dopaminergic neurons within the substantia nigra pars compacta. This neuronal cell loss is triggered by the accumulation of aggregated alpha-synuclein (aSyn) and subsequent spreading of the Lewy pathology from neuron to neuron. ACI-7104.056 is a novel active immunotherapy designed to trigger an antibody response against pathological aggregated forms of aSyn and to halt their propagation, thus enabling the treatment of PD. ACI-7014.056 is currently being tested in a phase 2 clinical trial (VacSYn; NCT06015841).
Methods
We established an innovative clinical study design that is intended to: (i) assess the safety and immunogenicity of ACI-7104.056 (assessment of the kinetics and magnitude of vaccine-elicited serum IgG levels specific for aSyn), and (ii) evaluate pharmacodynamic (oligomeric aSyn levels in the CSF) and clinical effects (the MDS-UPDRS Part III) using dedicated measures. This approach is intended to facilitate timely, adaptive and robust data-driven decisions to identify the most immunogenic dose and scheduling regiment and to capture early clinical signals of efficacy, based on predefined interim analyses, that trigger subsequent clinical stages in an accelerated and de-risked manner.
Results
Preliminary safety and tolerability data from first randomized subjects of the VacSYn phase 2 study in early-stage PD will be presented and put into context.
Conclusions
With a focus on identifying treatment effects early through comprehensive biomarker and immunogenicity analyses and leveraging interim analyses of biomarker responses for informed decision-making, the VacSYn Phase 2 clinical study aims to assess the therapeutic potential of ACI-7104.056, priming the way for targeted interventions in PD management.
A STUDY TO EVALUATE THE EFFICACY AND SAFETY OF INTRAVENOUS PRASINEZUMAB IN PARTICIPANTS WITH EARLY PARKINSON'S DISEASE (PADOVA): RATIONALE, DESIGN, AND BASELINE DATA
Abstract
Aims
Prasinezumab, a humanized monoclonal antibody targeting aggregated alpha-synuclein, previously showed a signal of reduced 1-year progression on MDS-UPDRS part III compared to placebo in early-stage PD (PASADENA, NCT03100149). The PADOVA study will evaluate the efficacy and safety of prasinezumab for delaying motor progression in individuals with early PD on stable symptomatic therapy.
Methods
This is a randomized, double blind, placebo-controlled multicenter study. Individuals with early PD receive monthly intravenous doses of prasinezumab 1,500 mg or placebo for at least 76 weeks, followed by a 2-year extension with all participants on active treatment. Key inclusion criteria are: age 50-85 years; Diagnosis of idiopathic PD based on MDS criteria; Hoehn & Yahr (H&Y) Stage I or II; time from diagnosis 3 months to 3 years; DAT-SPECT imaging consistent with PD; and on a stable dose of monoamine oxidase B inhibitor (MAO-Bi) or levodopa. The primary endpoint is time to confirmed motor progression defined as 5 points on MDS-UPDRS part III
Results
Baseline demographic and clinical characteristics are presented. The PADOVA study enrolled 586 individuals: 74.4% were on stable doses of L-DOPA (n=436) and 25.6 % on MAO-Bi (n=150). The PADOVA study population was slightly more advanced than PASADENA in terms of disease duration (18.6 vs 10.1 mo.), H&Y stage (stage II 83.9 vs 75.3 %) and MDS-UPDRS part III (24.5 vs 21.5 points). A comparison between the MAO-Bi- and levodopa-treated sub-cohorts as well as to PASADENA (treatment naïve and on MAO-Bi) will be provided.
Conclusions
The study has successfully completed enrollment. The PADOVA study population is suitable for investigating the potential of prasinezumab to slow disease progression in individuals with early PD on stable symptomatic therapy. Trial Registration: NCT04777331.
GLP1 RECEPTOR AGONISM RESCUES SYNUCLEINOPATHY IN HUMANS THROUGH MODULATION OF NEURONAL INSULIN SIGNALLING AND GLIAL ACTIVATION
Abstract
Aims
Insulin resistance drives key pathophysiological processes in Parkinson’s through unclear, but potentially targetable, mechanisms. We utilised a patient-derived iPSC platform to delineate neuronal and glial mechanisms of insulin resistance and glucagon-like 1 peptide (GLP-1) receptor agonism in synucleinopathy.
Methods
We utilised a patient-derived iPSC platform to delineate neuronal and glial mechanisms of insulin resistance and glucagon-like 1 peptide (GLP-1) receptor agonism in synucleinopathy. We corroborated our findings in patient samples from a Phase 2 trial of a GLP-1R agonist in Parkinson’s (NCT01971242)
Results
Parkinson’s patients, and human cell models of synucleinopathy, exhibit neuronal insulin resistance and dysfunctional insulin signalling. Downstream of the insulin receptor, insulin resistance is associated with a reduction in the neuroprotective Akt pathways, and increased expression of the MAPK and MAPK-associated p38 and JNK stress pathways. In both patients and cell models, this imbalance is associated with cellular stress, impaired proteostasis, accumulation of α-synuclein, and neuronal loss. Treatment with the exenatide led to reversal of neuronal insulin resistance in both patient CSF and in human PD neurons. In our cell model, restoration of insulin signalling, suppression of the MAPK pathways and reversal of ERK 1/2 signalling, leads to reversal of oxidative stress, lysosomal pathology and improves neuronal viability. This is associated with reduced α-synuclein aggregation, which is also observed in patients treated with exenatide. The effect of exenatide in glia is also mediated by the GLP1R, reducing the inflammatory state induced by protein aggregates, release of cytokines and neuronal injury.
Conclusions
Taken together, our iPSC and patient biomarker platform defines the mechanisms of GLP1R action in neurons and astrocytes, highlighting the utility of GLP-1R agonism as a disease modifying strategy in synucleinopathies.
A RANDOMIZED, PLACEBO-CONTROLLED, DOUBLE-BLIND, MAD STUDY TO EVALUATE SAFETY, TOLERABILITY, PHARMACOKINETICS AND PHARMACODYNAMICS OF NX210C PEPTIDE IN HEALTHY ELDERLY VOLUNTEERS
Abstract
Aims
NX210c is an oligopeptide that reduces blood-brain barrier (BBB) permeability via increased recruitment of Claudin-5, supports neuroprotection and promotes synaptic transmission in several preclinical models. These are all features shared by several neurological disorders, including Parkinson’s disease (PD), Amyotrophic Lateral Sclerosis and Multiple Sclerosis. After a single ascending dose phase 1a clinical study that showed a good safety profile and preliminary signals of effect, a phase 1b study was performed to evaluate two doses of NX210c (5-10 mg/kg) in healthy elderly volunteers (HEVs) to assess safety and tolerability as primary objectives. Blood pharmacokinetics was the secondary objective. Exploratory objectives assessed pharmacodynamic parameters including blood and cerebrospinal fluid biomarkers.
Methods
This was a randomized, double-blind, placebo-controlled, multiple ascending dose study in HEVs performed at a single phase 1 unit in the Netherlands. Two cohorts of 15 HEVs were planned to be randomized successively (4:1 ratio), with two sentinels per cohort. HEVs received treatment 3x/week for 4 weeks with a follow-up visit 2 weeks after last dosing.
Results
Preliminary results showed overall 73 treatment emergent adverse events (TEAEs) in 20 out of 29 subjects, all mild in severity (one moderate due to procedural complication), and no serious adverse events. NX210c half-life was ~18 min (no accumulation). Plasma Claudin-5 was significantly modified at 5 mg/kg (trend for 10 mg/kg). Detailed pharmacodynamic results from both cohorts will be presented further.
Conclusions
NX210c demonstrated a good safety profile following multiple doses in HEVs (both dose levels) and early signals of effect on biomarkers, especially on BBB repair. To further evaluate NX210c in a neurodegenerative patient population, a PD cohort is planned for 2024.
THE 201 TRIAL IN UNTREATED PARKINSON'S DISEASE
Abstract
Aims
To evalute the safety, tolerability and clinical benefit of risvodetinib (IkT-148009) in untreated Parkinson's disease.
Methods
Risvodetinib is given once daily at 50, 100 or 200 mg, three doses believed to be therapeutically effective based on extensive studies of therapeutic benefit in animal studies of human disease. 120 patients will be randomized 1:1:1:1 across the three doses or placebo for 12 weeks and then roll into a 12 month extension study with the placebo group moving onto the top therapeutic dose. Safety and tolerability will be measured by evaluation of frequency and severity of trreatment-emergent adverse events, measures of cardiovascular safety, standard laboratory analyses and monitoring for changes in vision. A hierarchy of 15 secondary endpoints will evaluate the potential benefit of risvodetinib on measures of motor and non-motor function iin the Central and Enteric Nervous Systems. Biomarker analysis using CSF/plasma assessmenet by seed-amplification assay and skin biopsy complement functional assessments.
Results
As of this writing the trial is ongoing with 29 participants in consenting, screening or enrolled. 75 potential participants have been identified using a proprietary pre-qualification portal that allows pre-qualified participants to communicate directly with trial sites. By the time this presentation will be made public, it is anticpated that the trial will be fully enrolled and blinded or unblinded data evaluating treatment benefit and safety/tolerability of risvodetinib (IkT-148009) over 12 weeks of once daily dosing will be discussed.
Conclusions
Data from a 12 week double-blinded, placebo controlled trial will be presented providing a first look into whether a treatment validated in models of heritbale and sporadic PD can impact disease in human Parkinson's.