Arimoclomol: a potential therapy under development for ALS

  title={Arimoclomol: a potential therapy under development for ALS},
  author={Veena Lanka and Scott Wieland and Jack R. Barber and Merit E Cudkowicz},
  journal={Expert Opinion on Investigational Drugs},
  pages={1907 - 1918}
Arimoclomol, an amplifier of heat shock protein expression involved in cellular stress response, has emerged as a potential therapeutic candidate in amyotrophic lateral sclerosis (ALS) in recent years. Treatment with arimoclomol was reported to improve survival and muscle function in a mouse model of motor neuron disease. Several single- and multiple-dose safety studies have been completed in healthy control subjects. A 3-month Phase IIa study in people with ALS demonstrated safety at dosages… 

Amplifying the heat shock response ameliorates pathology in mouse and human models of ALS and FTD.

It is demonstrated that mice expressing mutant valosin containing protein (VCP) develop an ALS/FTD-like phenotype in the spinal cord and brain, and treatment with arimoclomol, a pharmacological amplifier of the cytoprotective heat shock response ameliorates this phenotype.

Arimoclomol as a potential therapy for neuronopathic Gaucher Disease

These studies provide proof-of-concept for the development of the Heat shock protein amplifier, arimoclomol, as a potential therapy for neuronopathic Gaucher disease as arimclomol enhances folding, maturation, activity and correct localization of GCase in neuronopathic and non-neuronopathic Gauchers disease models.

Targeting protein homeostasis in sporadic inclusion body myositis

Using rat myoblast cultures, it is found that up-regulation of the heat shock response with arimoclomol reduced key pathological markers of sIBM in vitro and in mutant valosin-containing protein mice, which develop an inclusion body myopathy, treatment with arimsol ameliorated disease pathology and improved muscle function.

Therapeutic progress in amyotrophic lateral sclerosis-beginning to learning.

Novel therapeutic approaches for inclusion body myositis

  • T. Lloyd
  • Biology, Medicine
    Current opinion in rheumatology
  • 2010
New discoveries of biomarkers in sIBM and new insights into the pathogenesis of familial IBM are opening novel therapeutic pathways for these disorders, and drugs that stimulate autophagy, already in development for cancer and neurodegenerative diseases, are candidates for clinical trials.

Heat shock protein–based therapy as a potential candidate for treating the sphingolipidoses

It is demonstrated that recombinant human heat shock protein 70 (HSP70) improves the binding of several sphingolipid-degrading enzymes to their essential cofactor bis(monoacyl)glycerophosphate in vitro.

Amyotrophic Lateral Sclerosis: Current Therapeutic Perspectives

This chapter focuses on studies of various small pharmacological compounds targeting the proposed pathogenic mechanisms of ALS and discusses their impact on disease progression, and summarizes the progress in the non-pharmacological therapy trials in ALS.

Amyotrophic lateral sclerosis: drug therapy from the bench to the bedside.

The proposed pathophysiology of ALS is reviewed including glutamate excitotoxicity, oxidative stress, mitochondrial dysfunction, autoimmune mechanisms, protein aggregation, SOD1 accumulation, and neuronal death.

Opportunities for histone deacetylase inhibition in amyotrophic lateral sclerosis

It is concluded that selective inhibitors with high tolerability and safety and sufficient blood–brain barrier permeability will be needed to interfere with both epigenetic and non‐epigenetic targets of these enzymes.



Late stage treatment with arimoclomol delays disease progression and prevents protein aggregation in the SOD1G93A mouse model of ALS

Interestingly, this up‐regulation in Hsp70 was accompanied by a decrease in the number of ubiquitin‐positive aggregates in the spinal cord of treated SODG93A mice, suggesting that arimoclomol directly effects protein aggregation and degradation.

Treatment with arimoclomol, a coinducer of heat shock proteins, delays disease progression in ALS mice

Treatment with arimoclomol, a coinducer of heat shock proteins (HSPs), significantly delays disease progression in mice expressing a SOD1 mutant in which glycine is substituted with alanine at position 93 (SOD1G93A).

Arimoclomol at dosages up to 300 mg/day is well tolerated and safe in amyotrophic lateral sclerosis

Serum pharmacokinetic profiles support dosing of three times per day and arimoclomol was shown to be safe, and it crosses the blood–brain barrier.

Heat Shock Proteins as Therapeutic Targets in Amyotrophic Lateral Sclerosis

Evidence for the involvement of the various Hsp families in disease pathology and their therapeutic potential is reviewed based on the molecular characteristics of the Hsp sub-families.

Phase II/III randomized trial of TCH346 in patients with ALS

The trial revealed no evidence of a beneficial effect of TCH346 on disease progression in patients with ALS and there were no significant differences between placebo and active treatment groups in the mean rate of decline of the ALSFRS-R or in the secondary outcome measures.

A clinical trial of dextromethorphan in amyotrophic lateral sclerosis

Treatment with a relatively low dose of dextromethorphan did not result in an improvement in 12‐month survival in ALS.

An open-randomized clinical trial of selegiline in amyotrophic lateral sclerosis

The data do not show any significant effect of selegiline in modifying the progression of ALS, and mean MRC and Norris disability scores and forced vital capacity were fairly similar in the two groups at all times.

Efficacy and safety of xaliproden in amyotrophic lateral sclerosis: results of two phase III trials

  • V. MeiningerG. Bensimon W. Robberecht
  • Medicine
    Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases
  • 2004
Although this effect did not reach statistical significance, xaliproden had a small effect on clinically noteworthy aspects of disease progression in ALS, and dose‐dependent side effects were largely associated with the serotonergic properties of the drug.

[Assessment of the efficacy of treatment with pimozide in patients with amyotrophic lateral sclerosis. Introductory notes].

The aim of the study was to assess the effect of pimozide voltage-dependent calcium channel blocker on the progression of ALS patients as compared to the potentially neuroprotective drugs, selegiline

A controlled trial of recombinant methionyl human BDNF in ALS

Although the primary end point analysis failed to demonstrate a statistically significant survival effect of BDNF in ALS, post hoc analyses showed that those ALS patients with early respiratory impairment and those developing altered bowel function showed statistically significant benefit.