landipirdine (SYN120) / Acorda - LARVOL DELTA

ASSESSMENT OF PRODROMAL STRIATAL DOPAMINERGIC CHANGES BY CONFOCAL AND TWO-PHOTON MICROSCOPY AND IN VIVO IMAGING IN ALPHA-SYNUCLEIN TRANSGENIC MICE (ADPD 2024) - "The progressive accumulation of alpha-synuclein at nigrostriatal terminals produces a very early loss of VMAT2 that anticipates dopamine release deficits. Moreover, the initial phase of pathological alpha-synuclein-induced dopaminergic dysfunction is characterized by dopamine turnover perturbation with increased [18F]-FP-CIT and accumulation of dysfunctional DAT that can initiate nigrostriatal deafferentation, reflected by a reduction in the synaptic contacts established with cholinergic neurons and alpha-synuclein seeding and spreading."

Preclinical • CNS Disorders • Movement Disorders • Parkinson's Disease • CHAT

Cognitive Impairment in Parkinson's Disease: An Updated Overview Focusing on Emerging Pharmaceutical Treatment Approaches. (PubMed, Medicina (Kaunas)) - "Accumulating preclinical and clinical evidence shows that several agents may provide beneficial effects on patients with PD and cognitive impairment, including ceftriaxone, ambroxol, intranasal insulin, nilotinib, atomoxetine, mevidalen, blarcamesine, prasinezumab, SYN120, ENT-01, NYX-458, GRF6021, fosgonimeton, INT-777, Neuropeptide S, silibinin, osmotin, cordycepin, huperzine A, fibroblast growth factor 21, Poloxamer 188, ginsenoside Rb1, thioredoxin-1, tangeretin, istradefylline and Eugenia uniflora. In this updated overview, we aim to cover the clinical aspects of the spectrum of PD-related cognitive impairment and discuss recent evidence on emerging treatment approaches that are under investigation at a preclinical and clinical level. Finally, we aim to provide additional insights and propose new ideas for investigation that may be feasible and effective for the spectrum of PD-related cognitive impairment."

Journal • Review • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • Inflammation • Movement Disorders • Parkinson's Disease • FGF21

Safety, tolerability, and preliminary efficacy of SYN120, a dual 5-HT6/5-HT2A antagonist, for the treatment of Parkinson disease dementia: A randomized, controlled, proof-of-concept trial. (PubMed, Parkinsonism Relat Disord) - P2 | "SYN120 was adequately tolerated, mild worsening of motor symptoms was noted and it did not improve cognition in PDD patients. Its potential benefits for cognitive activities of daily living and apathy warrant further study."

Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • Movement Disorders • Parkinson's Disease • Psychiatry • Sleep Disorder

Progress in Investigational Agents Targeting Serotonin-6 Receptors for the Treatment of Brain Disorders. (PubMed, Biomolecules) - "Several 5-HT receptor antagonists (idalopirdine, intepirdine and latrepirdine) showed efficacy in alleviating cognitive deficits associated with AD in the proof-of-concept clinical studies; however, the outcomes of the subsequent phase 3 studies were largely disappointing...Masupirdine, a selective 5-HT receptor antagonist, reduced agitation/aggression-like behaviors in animal models, and a post hoc analysis of a phase 2 trial suggested potential beneficial effects on agitation/aggression and psychosis in AD. This agent will be assessed in additional trials, and the outcome of the trials will inform the use of 5-HT receptor antagonists in the treatment of agitation in dementia of the Alzheimer's type."

Journal • Review • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • Psychiatry • Schizophrenia

COMBINED TWO-PHOTON-BASED IMAGING OF STRIATAL DOPAMINERGIC FIBERS AND INTEGRATIVE ASSESSMENT OF SYNAPTIC MARKERS ALLOWS TO STAGE RETROGRADE DEGENERATION IN Α-SYNUCLEIN TRANSGENIC MICE (ADPD 2023) - "In this study , we used a well -established model of PD, mice overexpressing the truncated form of α -syn on the C57BL/6JOlaHsd background (SYN120 tg), exhibiting progressive deposition of α -syn fibrillary microaggregates in nigrostriatal terminals with dopamine release d eficits, to stage the retrograde degeneration of dopaminergic neurons... These data support that the progressive accumulation of α -syn at nigrostriatal terminals in the prodromal stages of PD produces a very early loss of VMAT2 that anticipates the synaptic dopamine r elease deficits. Moreover, they support that the initial phase of pathological α -syn-induced dopaminergic dysfunction is characterized by dopamine turnover perturbation with accumulation of dysfunctional DAT and that these pre -degenerative synaptic alterat ions can initiate nigrostriatal deafferentation."

Preclinical • CNS Disorders • Movement Disorders • Parkinson's Disease

Dopamine signaling modulates microglial NLRP3 inflammasome activation: implications for Parkinson's disease. (PubMed, J Neuroinflammation) - "Dopamine inhibits canonical, non-canonical, and α-syn-mediated activation of the NLRP3 inflammasome in primary human microglia, as does high extracellular K. We suggest that dopamine serves as an endogenous repressor of the K efflux-dependent microglial NLRP3 inflammasome activation that contributes to dopaminergic neurodegeneration in PD, and that this reciprocation may account for the specific vulnerability of these neurons to disease pathology."

Journal • CNS Disorders • Immunology • Inflammation • Movement Disorders • Parkinson's Disease • DRD2 • IL1B • NLRP3

Treatment of Parkinson's Disease with Cognitive Impairment: Current Approaches and Future Directions. (PubMed, Behav Sci (Basel)) - "The only recommended treatment for PDD currently is rivastigmine, a cholinesterase inhibitor. Donepezil and galantamine-other cholinesterase inhibitors-are possibly useful...Drug repurposing (atomoxetine, levodopa, insulin, atomoxetine for PD-MCI; ambroxol and ceftriaxone for PDD) and novel medications (SYN120, GRF6021, NYX-458 for PD-MCI; ANAVEX2-73, LY3154207, ENT-01, DAAOI-P for PDD) currently have insufficient evidence. There is growing research supporting exercise in the treatment of PD-MCI, but most non-pharmacological approaches have insufficient evidence for use in PD-MCI (cognitive rehabilitation, deep brain stimulation, transcranial direct current stimulation, transcranial ultrasound, vestibular nerve stimulation) and PDD (cognitive intervention, deep brain stimulation, transcranial alternating current stimulation, transcranial ultrasound, temporal blood brain barrier disruption). Research is needed for both disease-modifying and symptomatic treatments in PD..."

Journal • Review • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • Immunology • Movement Disorders • Parkinson's Disease

Alpha-synuclein/synapsin III pathological interplay boosts the motor response to methylphenidate. (PubMed, Neurobiol Dis) - "Here, we studied α-syn/Syn III co-deposition and longitudinal changes of α-syn, Syn III and DA transporter (DAT) striatal levels in nigrostriatal neurons of a PD model, the human C-terminally truncated (1-120) α-syn transgenic (SYN120 tg) mouse, in comparison with C57BL/6J wild type (wt) and C57BL/6JOlaHsd α-syn null littermates. Our observations indicate that the motor-stimulating effect of MPH can be positively fostered in the presence of α-syn/Syn III co-aggregation. This evidence holds significant implications for PD and ADHD therapeutic management."

Journal • ADHD (Impulsive Aggression) • Attention Deficit Hyperactivity Disorder • CNS Disorders • Developmental Disorders • Movement Disorders • Parkinson's Disease • Psychiatry • MRI

Serotonin Type 6 and 7 Receptors as a Novel Therapeutic Target for the Treatment of Schizophrenia. (PubMed, Neuropsychiatr Dis Treat) - "SGS-518, ABT-354, Lu AE58054, SB-742,457, S-518, AVN-211, AVN-322, SYN-114 and SYN-120 are serotonin 6 receptor antagonists and aripiprazole-controlled release serotonin 7 receptor agonists under clinical trial for schizophrenia. Thus, research on novel drugs that act on serotonin 6 and 7 receptors likely facilitates the intervention into schizophrenia patients seeking better quality of life in the future."

Journal • Review • CNS Disorders • Psychiatry • Schizophrenia

Acorda provides financial and pipeline update for fourth quarter and year end 2017 (Businesswire) - "SYN120 Phase 2 Data in Parkinson’s disease: Data from the Phase 2 proof-of-concept study for SYN120 showed that several of the outcome measures trended in favor of drug versus placebo; neither the primary nor key secondary endpoints achieved statistical significance. The Company continues to review the data, which will be presented at an upcoming medical meeting."

P2 data • CNS Disorders • Parkinson's Disease

Acorda to acquire Biotie Therapies (Businesswire) - "...Acorda will also obtain global rights to SYN120...for Parkinson’s-related dementia, in Phase 2 development with support from the Michael J. Fox Foundation....Dr. Cohen added, 'Tozadenant is a compelling opportunity with potential market exclusivity to 2030. The Phase 2 data were highly statistically significant and clinically meaningful. We are targeting an NDA filing by the end of 2018.' Subject to customary closing conditions, the tender offer is expected to be completed in the first or second quarter of 2016, and the acquisition is expected to be completed in the third quarter of 2016."

Anticipated launch • Anticipated NDA • M&A • Alzheimer's Disease • Parkinson's Disease

SYN120 a Dual 5-HT6/5-HT2A Antagonist Proof of Concept Study to Evaluate Its Safety, Tolerability and Efficacy in Parkinson's Disease Dementia (SYNAPSE) (clinicaltrials.gov) - P2; N=80; Active, not recruiting; Sponsor: Biotie Therapies Inc.; Recruiting ➔ Active, not recruiting

Enrollment closed • Alzheimer's Disease • Biosimilar • CNS Disorders • Gene Therapies • Parkinson's Disease

Biotie Therapies selects Bracket's CDR System for phase 2 trial of treatment of Parkinson's disease (Digital Journal) - "Bracket is pleased to announce that Biotie Therapies...has selected the CDR System for use as the primary endpoint for their phase 2 trial of SYN120, an orally administered, dual 5HT6/5HT2a antagonist. Biotie is collaborating with the Michael J. Fox Foundation and the Parkinson Study Group to advance SYN120 into an 80 patient Phase 2 trial later this year."

Anticipated licensing / partnership • Parkinson's Disease

SYN120 fails to show efficacy against Parkinson dementia in phase 2a synapse trial (Cleveland Clinic) - P2a, N=82, SYNAPSE (NCT02258152); Sponsor: Biotie Therapies Inc; "'Despite the promising ‘pedigree’ that this drug had from years of experience in animal models and patients, it did not deliver in a rigorous clinical trial,' says neurologist Hubert Fernandez...'Addressing dementia remains one of the most important unmet needs in Parkinson disease and continues to be the area with the deepest knowledge gaps,' Dr. Fernandez observes."

Media quote • P2a data

SYN120 (a dual 5-HT6/5-HT2A antagonist) study to evaluate safety, tolerability, and efficacy in Parkinson’s disease dementia (SYNAPSE): Phase 2a study results (AAN 2019) - "SYN120 did not improve cognition in patients with PDD, but it may have improved cognition-based daily function. SYN120 was generally well tolerated, however, a worsening in motor symptoms was observed."

Clinical • P2a data

IN VIVO SYNAPSIN III GENE SILENCING RESCUES PARKINSON’S DISEASE TRANSGENIC MICE FROM ALPHA-SYNUCLEIN AGGREGATION AND STRIATAL SYNAPTIC DEFICITS (ADPD 2019) - "...We recently found that Synapsin III (Syn III) is accumulated in association with alpha-synuclein in the brain of PD patients and of mice transgenic for human C-terminally truncated alpha-synuclein (SYN120 Tg)...These findings indicate that Syn III silencing is able to reduce alpha-synuclein aggregation and the related motor deficits in a mouse model of PD. This evidence supports that Syn III is crucially involved in PD pathophysiology and may constitute a novel therapeutic target for PD."

Preclinical