Safety and efficacy of pridopidine in patients with Huntington's disease (PRIDE-HD): a phase 2, randomised, placebo-controlled, multicentre, dose-ranging study

Reilmann, Ralf; McGarry, Andrew; Grachev, Igor D.; Savola, Juha‐Matti; Borowsky, Beth; Eyal, Eli; Gross, Nicholas J.; Langbehn, Douglas R.; Schubert, Robin; Wickenberg, Anna Teige; Papapetropoulos, Spyros; Hayden, Michael R.; Kieburtz, Karl; Landwehrmeyer, G. Bernhard; Agarwal, Pinky; Anderson, Karen E.; Aziz, N. Ahmad; Azulay, J.P.; Bachoud-Lévi, A C; Barker, Roger A.; Bebak, Agnieszka; Beuth, Markus; Biglan, Kevin; Blin, Stephanie; Bohlen, Stefan; Bonelli, Raphael M.; Caldwell, Sue; Calvas, Fabienne; Carlos, Jonielyn; Castagliuolo, Simona; Chong, Terrence; Chua, Phyllis; Coleman, Allison; Corey–Bloom, Jody; Cousins, Rebecca; Craufurd, David; Davison, Jill; Decorte, Eric; Michele, Giuseppe De; Dornhege, Laura; Feigin, Andrew; Gallehawk, Stephanie; Gauteul, Pascale; Gonzales, Carey; Griffith, Jane; Густов, А В; Guttman, Mark; Heim, Beatrix; Heller, Hope; Hjermind, Lena E.; Иллариошкин, С.Н.; Ivanko, Larry; Jaynes, Jessica; Jenckes, Mollie W.; Kaminski, Barbara J.; Kampstra, Anne; Konkel, Agnieszka; Kopishinskaya, S V; Krystkowiak, Pierre; Komati, Suresh K; Kwako, Alexander; Lakoning, Stefan; Latipova, Guzal; Leavitt, Blair R.; Loy, Clement T.; MacFarlane, Cheryl; Madsen, Louise Hvilshøj; Marder, Karen; Mason, Sarah; Mendis, N. M. P.; Mendis, Tilak; Németh, Andrea H.; Nevitt, Louise; Norris, Virginia; OʼNeill, Christine; Olivier, Audrey; Orth, Michael; Owens, Ashley; Panegyres, Peter K.; Perlman, Susan; Preston, J. Samuel; Priller, Josef; Puch, Alicja; Quarrell, Oliver; Ragosta, Domenica; Rialland, Amandine; Rickards, Hugh; Romoli, Anna Maria; Ross, Christopher A.; Rosser, Anne Elizabeth; Rudzińska, Monika; Russo, Cinzina V; Saft, Carsten; Segro, Victoria; Seppi, Klaus; Shannon, Barbara; Shprecher, David; Simonin, C.; Skitt, Zara; Sławek, Jarosław; Soliveri, Paola; Sorbi, Sandro; Squitieri, Ferdinando; Suski, Valarie; Stępniak, Iwona; Park, Sungmee; Temirbaeva, Sofia; Testa, Claudia; Torvin-Moller, Anette; Uhl, Stefanie; Vangsted-Hansen, Christina; Verny, Christophe; Wall, Paola; Walker, Francis O.; Wasserman, Paula; Witkowski, Grzegorz; Wright, Jan; Zalyalova, Z. A.; Zielonka, Daniel

doi:10.1016/s1474-4422(18)30391-0

Cited by 85 publications

(86 citation statements)

References 39 publications

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“…In addition to the above, the published report of the PRIDE-HD trial (NCT02006472) is worthy of mention. The paper reports that "the study did not meet its primary of secondary endpoints at 26 weeks" [4], confirming the results of previous trials [5][6][7] and suggests that pridopidine is unlikely have an effect on the motor symptoms of HD as assessed with the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score (TMS).…”

Section: Introductionsupporting

confidence: 72%

Huntington’s Disease Clinical Trials Corner: January 2019

Rodrigues

Quinn

Wild

2019

JHD

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Section: Introductionsupporting

confidence: 72%

Huntington’s Disease Clinical Trials Corner: January 2019

Rodrigues

Quinn

Wild

2019

JHD

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“…Pridopidine is a modulator of the dopamine 2 receptor [130] and activates the sigma-1 receptor [131]. In the most recent trials of pridopidine, no improvement in motor symptoms (unified Huntington's Disease rating scale -total motor score (UHDRS-TMS)) was observed with placebo [132][133][134]. High level of pridopidine is found in brain-derived neurotrophic factor (BDNF) and diminishes mHTT aggregate size and improved motor performance in R6/2 mice [135,136].…”

Section: Pridopidinementioning

confidence: 99%

Therapeutic Advances for Huntington’s Disease

et al. 2020

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Huntington’s disease (HD) is a progressive neurological disease that is inherited in an autosomal fashion. The cause of disease pathology is an expansion of cytosine-adenine-guanine (CAG) repeats within the huntingtin gene (HTT) on chromosome 4 (4p16.3), which codes the huntingtin protein (mHTT). The common symptoms of HD include motor and cognitive impairment of psychiatric functions. Patients exhibit a representative phenotype of involuntary movement (chorea) of limbs, impaired cognition, and severe psychiatric disturbances (mood swings, depression, and personality changes). A variety of symptomatic treatments (which target glutamate and dopamine pathways, caspases, inhibition of aggregation, mitochondrial dysfunction, transcriptional dysregulation, and fetal neural transplants, etc.) are available and some are in the pipeline. Advancement in novel therapeutic approaches include targeting the mutant huntingtin (mHTT) protein and the HTT gene. New gene editing techniques will reduce the CAG repeats. More appropriate and readily tractable treatment goals, coupled with advances in analytical tools will help to assess the clinical outcomes of HD treatments. This will not only improve the quality of life and life span of HD patients, but it will also provide a beneficial role in other inherited and neurological disorders. In this review, we aim to discuss current therapeutic research approaches and their possible uses for HD.

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“…Indeed, recent evidence indicates that at behaviourally relevant doses pridopidine does bind to S1R but not to the D2 receptor (Sahlholm et al, ). Furthermore, the most recent clinical trial of pridopidine (PRIDE‐HD), which did not reach its primary or secondary endpoints, found improvements on its exploratory endpoints of total functional score and Q‐Motor score only in the group receiving the lowest dosage (45 mg) (Reilmann et al, ). This suggests that the most effective doses of pridopidine may be those that stimulate only S1R, and are not high enough to stimulate the D2 receptor.…”

Section: Dopaminementioning

confidence: 99%

Alterations in synaptic function and plasticity in Huntington disease

Smith-Dijak

Sepers

Raymond

2019

Journal of Neurochemistry

104

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Huntington disease (HD) is an inherited neurodegenerative disorder caused by an expansion of the CAG repeat region in the first exon of the huntingtin gene. Neurodegeneration, which begins in the striatum and then spreads to other brain areas, is preceded by dysfunction in multiple aspects of neurotransmission across a variety of brain areas. This review will provide an overview of the neurochemical mediators and modulators of synaptic transmission that are disrupted in HD. This includes classical neurotransmitters like glutamate and gamma‐aminobutyric acid, modulators such as dopamine, adenosine and endocannabinoids, and molecules like brain‐derived neurotrophic factor which affect neurotransmission in a more indirect manner. Alterations in the functioning of these signaling pathways can occur across multiple brain regions such as striatum, cortex and hippocampus, and affect transmission and plasticity at the synapses within these regions, which may ultimately change behaviour and contribute to the pathophysiology of HD. The current state of knowledge in this area has already yielded useful information about the causes of synaptic dysfunction and selective cell death. A full understanding of the mechanisms and consequences of disruptions in synaptic function and plasticity will lend insight into the development of the symptoms of HD, and potential drug targets for ameliorating them.

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Safety and efficacy of pridopidine in patients with Huntington's disease (PRIDE-HD): a phase 2, randomised, placebo-controlled, multicentre, dose-ranging study

Cited by 85 publications

References 39 publications

Huntington’s Disease Clinical Trials Corner: January 2019

Huntington’s Disease Clinical Trials Corner: January 2019

Therapeutic Advances for Huntington’s Disease

Alterations in synaptic function and plasticity in Huntington disease

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