BIIB122 for Parkinson's Disease
Palo Alto (17 mi)Age: 18+
Sex: Any
Travel: May be covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: Denali Therapeutics Inc.
Prior Safety Data
Trial Summary
What is the purpose of this trial?This Phase 2a, multicenter, randomized, 12-week double-blind, placebo-controlled, parallel-group study, followed by an OLE, is designed to evaluate the safety, tolerability, and pharmacodynamic effects of BIIB122 in participants with LRRK2-PD. LRRK2-PD is defined as Parkinson's Disease (PD) in individuals who are heterozygous or homozygous carriers of a pathogenic LRRK2 variant that increases LRRK2 kinase activity.
What safety data is available for BIIB122/DNL151 in treating Parkinson's Disease?The provided research does not contain specific safety data for BIIB122 or DNL151 in treating Parkinson's Disease. The studies focus on deep brain stimulation and other treatments, but not on BIIB122/DNL151.2361214
What data supports the idea that BIIB122 for Parkinson's Disease is an effective drug?The available research does not provide specific data on the effectiveness of BIIB122 for Parkinson's Disease. Instead, it discusses other treatments like deep brain stimulation and levodopa-carbidopa therapies, which have shown improvements in symptoms such as tremors, rigidity, and motor fluctuations. Without direct data on BIIB122, we cannot compare its effectiveness to these treatments.15111315
Is the drug BIIB122 (DNL151) a promising treatment for Parkinson's Disease?Yes, BIIB122 (DNL151) is a promising drug for Parkinson's Disease because it targets the FBXO7 protein, which is important for maintaining healthy brain cells. This could help protect the brain cells that are lost in Parkinson's Disease, potentially slowing down or improving symptoms.478910
Do I need to stop my current medications for this trial?The trial protocol does not specify whether you need to stop taking your current medications. Please consult with the trial coordinators for more details.
Eligibility Criteria
This trial is for people aged 30-80 with Parkinson's Disease who carry a specific genetic change (LRRK2 variant) that increases LRRK2 activity. They must meet the clinical criteria for PD diagnosis and have verified genetic test results showing they have this mutation.Inclusion Criteria
I am between 30 and 80 years old with a specific genetic mutation.
I am 30 years or older with a specific genetic mutation.
My genetic test shows I have a LRRK2 mutation.
I have been diagnosed with Parkinson's disease according to specific criteria.
Treatment Details
The study tests BIIB122, a potential new treatment for Parkinson's Disease, against a placebo. Participants are randomly assigned to receive either BIIB122 or a fake pill without active ingredients, in order to compare effects over 12 weeks.
2Treatment groups
Experimental Treatment
Placebo Group
Group I: BIIB122 225 mgExperimental Treatment1 Intervention
Oral 225 mg dose, once daily (QD)
Group II: BIIB122 Matching PlaceboPlacebo Group1 Intervention
Oral BIIB122 matching placebo, once daily (QD)
Find a clinic near you
Research locations nearbySelect from list below to view details:
Inland Northwest ResearchSpokane, WA
Parkinson's Disease and Movement Disorders CenterBoca Raton, FL
Evergreen Health LaboratoryKirkland, WA
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Who is running the clinical trial?
Denali Therapeutics Inc.Lead Sponsor
BiogenIndustry Sponsor
References
Thalamic, subthalamic nucleus and internal pallidum stimulation in Parkinson's disease. [2019]The limits of drug therapy in severe forms of Parkinson's disease have lead to a renewal of functional neurosurgery of the basal ganglia and the thalamus. Deep brain stimulation (DBS) of these structures was developed with the aims of reducing the morbidity of surgery and of offering an adaptative treatment. DBS was first applied to the thalamus in patients with severe tremor. Tremor of the hemibody is greatly reduced by stimulation of the contralateral electrode in 85% of the cases. There is little change in other symptoms. However, motor fluctuations and dyskinesias are a more frequent problem than severe tremor; in attempt to treat these symptoms, DBS has recently been applied to the subthalamic nucleus (STN) and the internal pallidum (GPi). STN stimulation greatly decreases off motor symptoms and motor fluctuations, which allows a reduction of drug dosage and consequently of dyskinesias. GPi stimulation decreases dyskinesias in most patients, but the effect on off motor symptoms is more variable from one series to another, from very good to nil. The severe morbidity of DBS applied to these 3 targets is low. Comparative studies of the cost and the efficacy of DBS and lesions applied to these different targets are now required.
Randomized placebo-controlled study of the nicotinic agonist SIB-1508Y in Parkinson disease. [2012]This randomized, placebo-controlled, 5-week Phase II trial evaluated the safety and tolerability of SIB-1508Y, a selective alpha4beta2 nicotinic acetylcholine receptor agonist, in 77 individuals with early Parkinson disease. Lightheadedness was a common dosage-related adverse effect at higher dosages, leading to frequent dosage reduction, drug discontinuation, and eventual trial redesign. A maximally tolerated dosage of 10 mg daily was identified. No antiparkinsonian or cognitive-enhancing effects were demonstrated in this trial.
Multicenter study on deep brain stimulation in Parkinson's disease: an independent assessment of reported adverse events at 4 years. [2008]Ongoing adverse events (AEs) at 4-years postsurgery in 69 patients with advanced Parkinson's disease (PD) who received deep brain stimulation (DBS) of the subthalamic nucleus (STN) (n = 49) or the internal globus pallidus (GPi) (n = 20), in the framework of a subset of eight centers of a multicenter study, were analyzed by an independent ad hoc committee. At baseline, the patients' age, sex, disease duration, and clinical condition were virtually identical, as was the duration of follow-up. There were 64 AEs reported in 53% of STN DBS patients and eight AEs reported in 35% of GPi DBS patients. Most of the AEs were not deemed severe and were reported to be present "both with and without stimulation." The majority of the AEs affected patients' cognitive, psychiatric and behavioral status, as well as speech, gait, and balance, and most of these AEs occurred in STN DBS patients. When comparing patients who exhibited AEs with those who did not, it was found that in the STN DBS group, the patients with AEs had a longer disease duration, as well as more gait disorders and psychiatric disturbances at baseline.
Loss of nuclear activity of the FBXO7 protein in patients with parkinsonian-pyramidal syndrome (PARK15). [2021]Mutations in the F-box only protein 7 gene (FBXO7) cause PARK15, an autosomal recessive neurodegenerative disease presenting with severe levodopa-responsive parkinsonism and pyramidal disturbances. Understanding the PARK15 pathogenesis might thus provide clues on the mechanisms of maintenance of brain dopaminergic neurons, the same which are lost in Parkinson's disease. The protein(s) encoded by FBXO7 remain very poorly characterized. Here, we show that two protein isoforms are expressed from the FBXO7 gene in normal human cells. The isoform 1 is more abundant, particularly in primary skin fibroblasts. Both isoforms are undetectable in cell lines from the PARK15 patient of an Italian family; the isoform 1 is undetectable and the isoform 2 is severely decreased in the patients from a Dutch PARK15 family. In human cell lines and mouse primary neurons, the endogenous or over-expressed, wild type FBXO7 isoform 1 displays mostly a diffuse nuclear localization. An intact N-terminus is needed for the nuclear FBXO7 localization, as N-terminal modification by PARK15-linked missense mutation, or N-terminus tag leads to cytoplasmic mislocalization. Furthermore, the N-terminus of wild type FBXO7 (but not of mutant FBXO7) is able to confer nuclear localization to profilin (a cytoplasmic protein). Our data also suggest that overexpressed mutant FBXO7 proteins (T22M, R378G and R498X) have decreased stability compared to their wild type counterpart. In human brain, FBXO7 immunoreactivity was highest in the nuclei of neurons throughout the cerebral cortex, intermediate in the globus pallidum and the substantia nigra, and lowest in the hippocampus and cerebellum. In conclusion, the common cellular abnormality found in the PARK15 patients from the Dutch and Italian families is the depletion of the FBXO7 isoform 1, which normally localizes in the cell nucleus. The activity of FBXO7 in the nucleus appears therefore crucial for the maintenance of brain neurons and the pathogenesis of PARK15.
GPi and STN deep brain stimulation can suppress dyskinesia in Parkinson's disease. [2012]To compare subthalamic nucleus (STN) to globus pallidus internus (GPi) deep brain stimulation (DBS) for control of motor fluctuations and for potential dyskinesia-suppressing qualities.
Subthalamic deep brain stimulation with a new device in Parkinson's disease: an open-label trial. [2022]We aimed to evaluate the safety and efficacy of subthalamic nucleus deep brain stimulation (STN-DBS) with a new stimulator (Beijing PINS Medical Co., Ltd, PNS 1101) in Parkinson's disease (PD).
Ser129D mutant alpha-synuclein induces earlier motor dysfunction while S129A results in distinctive pathology in a rat model of Parkinson's disease. [2013]Alpha-synuclein phosphorylated at serine 129 (S129) is highly elevated in Parkinson's disease patients where it mainly accumulates in the Lewy bodies. Several groups have studied the role of phosphorylation at the S129 in α-synuclein in a rat model for Parkinson's disease using recombinant adeno-associated viral (rAAV) vectors. The results obtained are inconsistent and accordingly the role of S129 phosphorylation in α-synuclein toxicity remains unclear. This prompted us to re-examine the neuropathological and behavioral effects of the S129 modified α-synuclein species in vivo. For this purpose, we used two mutated forms of human α-synuclein in which the S129 was replaced either with an alanine (S129A), to block phosphorylation, or with an aspartate (S129D), to mimic phosphorylation, and compared them with the wild type α-synuclein. This approach was similar in design to previous studies, however our investigation of dopaminergic degeneration also included performing a detailed study of the α-synuclein induced pathology in the striatum and the analysis of motor deficits. Our results showed that overexpressing S129D or wild type α-synuclein resulted in an accelerated dopaminergic fiber loss as compared with S129A α-synuclein. Furthermore, the motor deficit seen in the group treated with the mutant S129D α-synuclein appeared earlier than the other two forms of α-synuclein. Conversely, S129A α-synuclein showed significantly larger pathological α-synuclein-positive inclusions, and slower dopaminergic fiber loss, when compared to the other two forms of α-synuclein, suggesting a neuroprotective effect of the mutation. When examined at long-term, all three α-synuclein forms resulted in pathological accumulations of α-synuclein in striatal fibers and dopaminergic cell death in the substantia nigra. Our data show that changes in the S129 residue of α-synuclein influence the rate of pathology and neurodegeneration, with an overall deleterious effect of exchanging S129 to a residue mimicking its phosphorylated state.
FBXO7 immunoreactivity in α-synuclein-containing inclusions in Parkinson disease and multiple system atrophy. [2013]Mutations in the gene encoding the F-box only protein 7 (FBXO7) cause PARK15, an autosomal recessive form of juvenile parkinsonism. Although the brain pathology in PARK15 patients remains unexplored, in vivo imaging displays severe loss of nigrostriatal dopaminergic terminals. Understanding the pathogenesis of PARK15 might therefore illuminate the mechanisms of the selective dopaminergic neuronal degeneration, which could also be important for understanding idiopathic Parkinson disease (PD). The expression of FBXO7 in the human brain remains poorly characterized, and its expression in idiopathic PD and different neurodegenerative diseases has not been investigated. Here, we studied FBXO7 protein expression in brain samples of normal controls (n = 9) and from patients with PD (n = 13), multiple system atrophy (MSA) (n = 5), Alzheimer disease (AD) (n = 5), and progressive supranuclear palsy (PSP) (n = 5) using immunohistochemistry with 2 anti-FBXO7 antibodies. We detected widespread brain FBXO7 immunoreactivity, with the highest levels in neurons of the cerebral cortex, putamen, and cerebellum. There were no major differences between normal and PD brains overall, but FBXO7 immunoreactivity was detected in large proportions of α-synuclein-positive inclusions (Lewy bodies, Lewy neurites, glial cytoplasmic inclusions), where it colocalized with α-synuclein in PD and MSA cases. By contrast, weak FBXO7 immunoreactivity was occasionally detected in tau-positive inclusions in AD and PSP. These findings suggest a role for FBXO7 in the pathogenesis of the synucleinopathies.
A new Turkish family with homozygous FBXO7 truncating mutation and juvenile atypical parkinsonism. [2014]Juvenile parkinsonism can be caused by recessive mutations in several genes. Among these, homozygous or compound heterozygous mutations in the F-box only protein 7 gene (FBXO7) cause juvenile parkinsonism with variable degrees of pyramidal disturbances (PARK15). So far, only five families (from Iran, Italy, The Netherlands, Pakistan, and Turkey) have been reported with this form. Here, we describe a new Turkish family with homozygous FBXO7 mutation (c.1492C > T, p.Arg498*). Three out of nine siblings born from consanguineous parents suffered from juvenile-onset progressive parkinsonism. Mental retardation was also documented in two of them. Of note, pyramidal signs were absent. The response to dopaminergic medications was present, but limited by dyskinesias and psychiatric side effects. Further genetic analysis of this Turkish family and the Italian PARK15 family reported previously revealed that the c.1492C > T mutation is present on two different haplotypes in the Italian family, and one of these haplotypes is shared in homozygous state in the Turkish patients. These findings contribute to the ongoing delineation of the genetic and clinical spectrum of PARK15.
The loss of inhibitory C-terminal conformations in disease associated P123H β-synuclein. [2018]β-synuclein (βS) is a homologue of α-synuclein (αS), the major protein component of Lewy bodies in patients with Parkinson's disease. In contrast to αS, βS does not form fibrils, mitigates αS toxicity in vivo and inhibits αS fibril formation in vitro. Previously a missense mutation of βS, P123H, was identified in patients with Dementia with Lewy Body disease. The single P123H mutation at the C-terminus of βS is able to convert βS from a nontoxic to a toxic protein that is also able to accelerate formation of inclusions when it is in the presence of αS in vivo. To elucidate the molecular mechanisms of these processes, we compare the conformational properties of the monomer forms of αS, βS and P123H-βS, and the effects on fibril formation of coincubation of αS with βS, and with P123H-βS. NMR residual dipolar couplings and secondary structure propensities show that the P123H mutation of βS renders it more flexible C-terminal to the mutation site and more αS-like. In vitro Thioflavin T fluorescence experiments show that P123H-βS accelerates αS fibril formation upon coincubation, as opposed to wild type βS that acts as an inhibitor of αS aggregation. When P123H-βS becomes more αS-like it is unable to perform the protective function of βS, which suggests that the extended polyproline II motif of βS in the C-terminus is critical to its nontoxic nature and to inhibition of αS upon coincubation. These studies may provide a basis for understanding which regions to target for therapeutic intervention in Parkinson's disease.
The effect of levodopa-carbidopa intestinal gel infusion long-term therapy on motor complications in advanced Parkinson's disease: a multicenter Romanian experience. [2022]Chronic treatment with oral levodopa is associated with an increased frequency of motor complications in the late stages of Parkinson's disease (PD). Continuous administration of levodopa-carbidopa intestinal gel (LCIG-Duodopa(®), Abbott Laboratories), which has been available in Romania since 2009, represents an option for treating patients with advanced PD. Our primary objective was to report changes in motor complications after initiation of LCIG therapy. The secondary objectives were as follows: to determine the impact of LCIG therapy on the daily levodopa dose variation before/and after LCIG, to collect patient self-assessments of quality of life (QoL), and to study the overall tolerability and safety of LCIG administration. A retrospective analysis (2009-2013) of LCIG therapy and the experience in nine neurology centers in Romania was performed. The impact of LCIG therapy was evaluated by analyzing changes in motor fluctuations, dyskinesia and the patients' QoL after initiating therapy. The safety of LCIG therapy was estimated by noting agent-related adverse events (AEs) and medical device-related AEs. In the 113 patients included, we observed a significant improvement in PD symptoms after initiation of LCIG therapy. The "on" period increased, with a mean value of 6.14 h, and the dyskinesia period was reduced, with a mean value of 29.4 %. The quantified non-motor symptoms subsided. The patients exhibited significant improvements in QoL scores. There were few AEs and few cases of LCIG therapy discontinuation. LCIG is an important and available therapeutic option for managing patients with advanced PD.
Critical reappraisal of DBS targeting for movement disorders. [2017]Deep brain stimulation (DBS) is used as a surgical treatment of movement disorders such as Parkinson's disease, dystonia and essential tremor. Fundamental understanding of DBS effects on the pathological neural circuitry remains insufficient. In 2002 DBS of the subthalamic nucleus (STN) and the globus pallidus internus (GPi) was approved for use in patients with PD. Next year, DBS of Gpi and STN for dystonia received a Humanitarian Device exemption from the FDA. The commonly targets for DBS are subthalamic nucleus (STN) or globus pallidus internus (GPi) for Parkinson's disease, Gpi for dystonia and ventro-intermediate (VIM) nucleus of the thalamus for essential tremor. However, VIM DBS cannot sufficiently improve akinesia and rigidity. Pedunculopontine nucleus (PPN) is currently investigated as potential target to improve gait and posture. It is determined that DBS sometimes influences not only motor functions but also the cognitive and affective functions of patients. In this article we review the present state of DBS for movement disorders, appropriate indications, practical effects and stimulation-induced adverse events established in previous studies. We discuss target selection and the effect of DBS on motor and non-motor symptoms of Parkinson's disease, dystonia and essential tremor.
Improvement of Advanced Parkinson's Disease Manifestations with Deep Brain Stimulation of the Subthalamic Nucleus: A Single Institution Experience. [2020]We present our experience at the University of Illinois at Chicago (UIC) in deep brain stimulation (DBS) of the subthalamic nucleus (STN), describing our surgical technique, and reporting our clinical results, and morbidities. Twenty patients with advanced Parkinson's disease (PD) who underwent bilateral STN-DBS were studied. Patients were assessed preoperatively and followed up for one year using the Unified Parkinson's Disease Rating Scale (UPDRS) in "on" and "off" medication and "on" and "off" stimulation conditions. At one-year follow-up, we calculated significant improvement in all the motor aspects of PD (UPDRS III) and in activities of daily living (UPDRS II) in the "off" medication state. The "off" medication UPDRS improved by 49.3%, tremors improved by 81.6%, rigidity improved by 50.0%, and bradykinesia improved by 39.3%. The "off" medication UPDRS II scores improved by 73.8%. The Levodopa equivalent daily dose was reduced by 54.1%. The UPDRS IVa score (dyskinesia) was reduced by 65.1%. The UPDRS IVb score (motor fluctuation) was reduced by 48.6%. Deep brain stimulation of the STN improves the cardinal motor manifestations of the idiopathic PD. It also improves activities of daily living, and reduces medication-induced complications.
Bilateral subthalamic deep brain stimulation is an effective and safe treatment option for the older patients with Parkinson's disease. [2019]We aimed to provide evidence that subthalamic nucleus (STN) deep brain stimulation (DBS) is an effective and safe treatment option for older patients with Parkinson's disease (PD).
ND0612 (levodopa/carbidopa for subcutaneous infusion) in patients with Parkinson's disease and motor response fluctuations: A randomized, placebo-controlled phase 2 study. [2022]ND0612 is a continuous, subcutaneous levodopa/carbidopa delivery system under development for patients with Parkinson's disease (PD) and motor fluctuations.