Vorapaxar and Amyotrophic Lateral Sclerosis: Coincidence or Adverse Association?

Serebruany, Victor L.; Fortmann, Seth D.; Hanley, Daniel F.; Kim, Moo Hyun

doi:10.1097/mjt.0000000000000395

Cited by 5 publications

(4 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Finally, the total number of ALS cases in PAR1 inhibitor phase III studies was four versus two, comparing Vorapaxar with the placebo group. However, the expected number of ALS cases, considering the number of patients, the mean age of the cohorts, and the incidence of ALS, itself should be 2.8, which is almost in line with the observed data [ 79 ].…”

Section: Neurodegenerative Diseasessupporting

confidence: 82%

Neuro-Coagulopathy: Blood Coagulation Factors in Central Nervous System Diseases

Luca

Virtuoso

Maggio

et al. 2017

IJMS

View full text Add to dashboard Cite

Blood coagulation factors and other proteins, with modulatory effects or modulated by the coagulation cascade have been reported to affect the pathophysiology of the central nervous system (CNS). The protease-activated receptors (PARs) pathway can be considered the central hub of this regulatory network, mainly through thrombin or activated protein C (aPC). These proteins, in fact, showed peculiar properties, being able to interfere with synaptic homeostasis other than coagulation itself. These specific functions modulate neuronal networks, acting both on resident (neurons, astrocytes, and microglia) as well as circulating immune system cells and the extracellular matrix. The pleiotropy of these effects is produced through different receptors, expressed in various cell types, in a dose- and time-dependent pattern. We reviewed how these pathways may be involved in neurodegenerative diseases (amyotrophic lateral sclerosis, Alzheimer’s and Parkinson’s diseases), multiple sclerosis, ischemic stroke and post-ischemic epilepsy, CNS cancer, addiction, and mental health. These data open up a new path for the potential therapeutic use of the agonist/antagonist of these proteins in the management of several central nervous system diseases.

show abstract

Section: Neurodegenerative Diseasessupporting

confidence: 82%

Neuro-Coagulopathy: Blood Coagulation Factors in Central Nervous System Diseases

Luca

Virtuoso

Maggio

et al. 2017

IJMS

View full text Add to dashboard Cite

show abstract

“…APC and 3K3A-APC have been shown to be beneficial in animal models of amyotrophic lateral sclerosis [102] and neurogenesis [97], respectively. Evidence of beneficial PAR1-mediated cytoprotection in CNS may be suggested from extremely rare side effects of vorapaxar such as diplopia [103] and amyotrophic lateral sclerosis [104], if these prove to be bona fide adverse effects of PAR1 inhibition. PAR1-mediated protective signaling by rAPC and signaling-selective APC variants are protective in preclinical models of ischemia reperfusion injury evaluating reperfusion injury in heart, brain, liver, and kidney [22].…”

Section: Indications For Par1 Modulationmentioning

confidence: 99%

Targeting PAR1: Now What?

Flaumenhaft

Ceunynck

2017

Trends in Pharmacological Sciences

View full text Add to dashboard Cite

Protease-activated receptors (PARs) are a ubiquitously expressed class of GPCRs that enable cells to respond to proteases in the extracellular environment in a nuanced and dynamic manner. PAR1 is the archetypal family member and has been the object of large-scale drug development programs since the 1990s. Vorapaxar and drotrecogin-alfa are approved PAR1-targeted therapeutics, but safety concerns have limited clinical use of vorapaxar and questions regarding the efficacy of drotrecogin-alfa led to its withdrawal from the market. New understanding of mechanisms of PAR1 function, discovery of improved strategies for modifying PAR1 function, and identification of novel indications for PAR1 modulators have provided new opportunities for therapies targeting PAR1. This review will critically evaluate prospects for the next generation of PAR1-targeted therapeutics.

show abstract

“…Surprisingly, there was an increased number of ALS diagnoses in the treatment arms compared to the placebo arms of the TRACER [ 78 ] and TRA2P [ 136 ] phase 3 trials; however, the low number of events (2 vs. 4 diagnoses in ~35,000 patient-years of exposure in each pooled arm of the two studies) is unlikely to have reached statistical significance. This was not mentioned in the publications of the results but was discussed in the FDA’s analysis of the vorapaxar NDA data [ 137 , 138 ]. Data beyond those obtained in the maximum 3 year trial would obviously be desirable.…”

Section: Discussionmentioning

confidence: 99%

The Evolving Concept of Neuro-Thromboinflammation for Neurodegenerative Disorders and Neurotrauma: A Rationale for PAR1-Targeting Therapies

Festoff

Dockendorff²

2021

Biomolecules

View full text Add to dashboard Cite

Interest in the role of coagulation and fibrinolysis in the nervous system was active in several laboratories dating back before cloning of the functional thrombin receptor in 1991. As one of those, our attention was initially on thrombin and plasminogen activators in synapse formation and elimination in the neuromuscular system, with orientation towards diseases such as amyotrophic lateral sclerosis (ALS) and how clotting and fibrinolytic pathways fit into its pathogenesis. This perspective is on neuro-thromboinflammation, emphasizing this emerging concept from studies and reports over more than three decades. It underscores how it may lead to novel therapeutic approaches to treat the ravages of neurotrauma and neurodegenerative diseases, with a focus on PAR1, ALS, and parmodulins.

show abstract

Vorapaxar and Amyotrophic Lateral Sclerosis: Coincidence or Adverse Association?

Abstract: Potential adverse association of vorapaxar with ALS risks may be related to off-target neuronal PAR receptor(s) blockade beyond platelet inhibition.

Cited by 5 publications

References 38 publications

Neuro-Coagulopathy: Blood Coagulation Factors in Central Nervous System Diseases

Neuro-Coagulopathy: Blood Coagulation Factors in Central Nervous System Diseases

Targeting PAR1: Now What?

The Evolving Concept of Neuro-Thromboinflammation for Neurodegenerative Disorders and Neurotrauma: A Rationale for PAR1-Targeting Therapies

Contact Info

Product

Resources

About