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Upcoming treatments for amyotrophic lateral sclerosis

While some progress has been made in the treatment of ALS, combination therapies with drugs that target other pathways, alongside stem cell technology, are sorely needed

Drug research

Amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative disease of the upper and lower motor neurons characterised by rapidly progressive muscle atrophy and spasticity. Sufferers of ALS lose the ability to control and initiate voluntary movements which, in addition to eventual immobility, manifests most obviously as difficulty speaking, swallowing and finally breathing.

The median survival time from onset until death is only 39 months, with just 4 per cent of sufferers surviving more than 10 years. Respiratory failure or pneumonia are the most common causes of death.

ALS is referred to as motor neurone disease or Lou Gehrig's Disease and is best known as the disease afflicting physicist Stephen Hawking who, despite all odds, has survived more than 50 years since his diagnosis.

It affects approximately five in 100,000 individuals. In 95 per cent of ALS cases there is no known cause. A hereditary factor is known for the remaining 5 per cent of cases, with a defect on chromosome 21 coding for superoxide dismutase (SOD1) being the most common identified causative mechanism in these cases.

It is still not clear how this SOD1 mutation leads to ALS, although resultant protein aggregations and free-radical accumulation appear to be involved. Symptoms typically  manifest between the ages of 40 – 60 and men are affecteds lightly more often than women. The disease is invariably fatal.

Pharmacological care
Treatment of ALS primarily focuses on alleviation of specific symptoms and improving patient quality of life. Physical and occupational therapy can delay strength loss and limit pain but do not affect the progression of the disease itself.

Typical pharmacological care includes medications to treat pain, spasticity, depression and the other common aspects of palliative care. The holy grail of ALS treatment however is to achieve true slowing (or even reversal) of the degenerative processes involved in disease progression.

Riluzole (Rilutek; Sanofi) is a small molecule glutamate antagonist which has been approved in almost 50 countries for the treatment of ALS and is the only currently marketed compound used to treat this disease. Although the registrational studies did not meet the FDA's usual statistical standards, they did show a definite survival benefit when compared with placebo.

In a preliminary study by Bensimon et al involving 155 patients with amyotrophic lateral sclerosis, riluzole 100 mg/day was associated with an overall survival after 12 months of 74 per cent.

This compared with 58 per cent in patients who had received placebo. Patients with bulbar onset disease demonstrated the most obvious improvement in survival and there was a significant slowing in the deterioration of muscle strength in riluzole recipients versus placebo recipients.

The results of a two-year multinational trial in patients with amyotrophic lateral sclerosis confirmed the preliminary analyses indicating that riluzole has a beneficial effect on prolonging survival. The trial involved 959 patients with amyotrophic lateral sclerosis who were randomised to receive treatment with placebo or riluzole 50, 100 or 200 mg/day. After 18 months, these doses reduced the risk of death or tracheostomy by 24 per cent, 35 per cent and 39 per cent, respectively.

Due to the unknown aetiology of ALS, the development of drugs to slow disease progression is difficult and is usually the product of development for other neurodegenerative diseases and conditions. An example of this is Edaravone (Radicut), a free radical scavenger developed by Mitsubishi Tanabe Pharma. The agent blocks the action of the lipoperoxide 15-HPETE, which normally increases with age and may be associated with neurodegeneration.

Edaravone IV injection launched in Japan as a neuroprotective agent for acute-stage cerebral infarction, where phase III trials for the treatment of ALS are also underway and the compound has been granted orphan drug status. Mitsubishi Tanabe Pharma has completed a phase III trial of edaravone in patients with ALS in Japan with the primary objective of confirming the efficacy of edaravone (60mg, once-daily IV infusion) based on changes in Revised ALS Functional Rating Scale (ALSFRS-R) scores after 24 weeks administration, and to examine drug safety.

Researchers reported a significant improvement in ALSFRS-R scores during the six-month treatment period compared with the six months before administration of edaravone. Treatment also resulted in a marked reduction in cerebrospinal fluid levels of 3-nitrotyrosine, a marker of oxidative stress, suggesting that antioxidant therapy may achieve some success in slowing disease progression.

In December 2011, Mitsubishi Tanabe Pharma initiated a randomised, double-blind, placebo-controlled phase III trial to investigate the efficacy and safety of edaravone in patients with ALS (NCT01492686). The primary outcome measure is the change in ALSFRS-R scores after 24 weeks of once-daily edaravone 60mg, given by IV drip. Enrolment of 128 patients is underway in Japan.

Synthetic Biologics is developing another free radical scavenger, a proprietary formulation of orally available zinc monocysteine, for the treatment of both ALS Alzheimer's disease. Investigators at the PNA Center for Neurological Research have conducted a phase I/II, three-month open-label study of oral high-dose zinc to determine the safety of the product when given in combination with low doses of copper sulphate in patients with ALS.

Preparations are also underway to assess the safety and efficacy of the company's zinc tablet in a double-blind, placebo-controlled, phase II/III clinical trial in ALS patients.This trial will enrol approximately 65 patients who will continue on riluzole as the standard of care treatment.

AAD 2004 is another such drug being developed by GNT Pharma and AmKor Pharma for the treatment of ALS. The drug provides neuroprotection via both antioxidative and anti-inflammatory effects, as well as the inhibition and reduction of beta-amyloid (Aß) peptide levels and Aß plaque formation and is undergoing a phase I study in the EU in healthy volunteers.

In mutant SOD1 mice, death of motor neurons occurs by apoptosis and is mediated by sequential activation of caspase-1 and -3. Preclinical studies indicated that disrupting the apoptotic pathways appeared to slow disease progression.

Such observations have led Biogen Idec and Knopp Biosciences to develop dexpramipexole, an optical enantiomer of pramipexole, for the oral treatment of ALS. The small molecule, synthetic benzothiazole compound is a selective dopamine receptor agonist that is in phase III development in the US, Europe, Canada, and Australia and is the only molecule currently in phase III development for this disease.

Dexpramipexole also displays significant antioxidant activity, providing a two-pronged attack on the progression of ALS. Knopp completed a phase IIa trial of dexpramipexole oral tablets in patients with ALS in November 2009, which achieved its primary endpoint for safety and tolerability.

Dexpramipexole showed favourable dose-related effects in preserving motor function and extending survival and these encouraging results were presented at the 20th International Symposium on ALS/MND in December 2009.

The FDA has granted fast-track designation of dexpramipexole in the US. A phase III randomised placebo-controlled clinical trial, known as EMPOWER, is being conducted in patients with amyotrophic lateral sclerosis (ALS) (NCT01281189). The aim of the study is to determine the safety and efficacy of dexpramipexole 150mg twice-daily for up to 18 months. The trial has completed enrolment of 804 patients in the US, Australia, Belgium, Canada, France, Germany, Ireland, Netherlands, Spain, Sweden, and the UK. Preliminary results are expected in late 2012.

Heat shock proteins serve as intracellular chaperones with anti-apoptotic properties but become depleted during mutant SOD1-mediated toxicity. Arimoclomol is a hydroxylamine derivative that was originally developed by Biorex, but is now being developed by Orphazyme ApS, for the treatment of ALS. This oral drug is thought to repair or induce destruction of misfolded proteins by amplifying molecular chaperone proteins and upregulating the cellular stress response.

The University of Miami and the ALS Association are conducting a phase II/III adaptive trial to evaluate arimoclomol (100mg, thrice-daily) in a subset of patients with familial ALS bearing SOD1 gene mutations in the US. Previous studies have reported positive findings and the drug has been designated fast-track status in the US and orphan drug status in the EU.

Cell replacement therapies
The use of cell replacement therapies is another growing field in the treatment of ALS as the potential of stem cells is increasingly realised. This technology is still in the early phases of development but some promising findings have been made to date. BrainStorm Cell Therapeutics is developing a glial neurotrophic factor (GDNF)-producing adult bone marrow-derived stem cell therapy for the treatment of neurodegenerative disorders, primarily ALS and Parkinson's disease, but also for spinal cord injury and sciatica.

The strategy is based on NurOwn technology in-licensed from researchers at Tel Aviv University. Adult stem cells are collected from the patient's own bone marrow and used to create healthy neuron-like cells to replace and/or support degenerating neurons. These cells are believed to provide neuroprotection of neurons and could treat underlying disease pathology, rather than simply alleviating symptoms and the feasibility of this approach has been proven in animal models.

In August 2012, BrainStorm completed recruitment of approximately 24 patients in a phase I/II trial of the GDNF-producing adult stem cell therapy in patients with ALS at the Hadassah Medical Center in Israel. The phase I part of the study was designed to establish the safety of the stem cell therapy in a small number of patients with early ALS, while phase II also included patients with progressive ALS.

Positive safety data from the first four patients were reported in January 2012. Further interim safety results from 12 patients were released in July 2012, demonstrating that the primary endpoint of the study had been reached and GNDF-producing adult stem cell therapy was well tolerated. Some tendencies towards clinical efficacy were also seen.

Neuralstem is developing neural stem cells from the human brain and spinal cord for the treatment of a range of neurological disorders including ALS. A phase I trial of the spinal cord stem cell product, known as NSI 566RSC, is nearing completion in patients with ALS in the US.
Neuralstem's spinal cord stem cell product is delivered directly into the grey matter of the spinal cord using the company's proprietary Spinal Cord Delivery Platform and Floating Cannula.

Once in the spinal cord, the cells are able to integrate with and protect the spinal cord neurons. Neuralstem treated the last patient in a phase I trial of its neural stem cell product for ALS in August 2012. The trial will conclude when this patient has been followed up for 18 months. Positive interim data from 12 patients has been reported, including a publication in the peer-reviewed journal Stem Cells in April 2012.

TCA Cellular Therapy is developing autologous stem cell therapies for the treatment of neurological disorders including ALS and spinal cord injury. Treatments are being designed based on a patient's own stem cells, which are extracted from their bone marrow, processed in TCA's laboratory and then infused into patients via lumbar puncture. TCA Cellular Therapy commenced a phase I trial of its autologous stem cell product in March 2010. The non-randomised, single centre, safety and efficacy trial has completed enrolment of an estimated six patients with ALS in the US.

Additional mechanisms of action are also being explored in the preclinical and very early clinical stages for the treatment of ALS including nerve growth factors, macrophage modulators, immunomodulators and antisense oligonucleotides. However the applicability of preclinical studies in mutant SOD1 rodent models to human trials is limited by differences in pharmacokinetics, routes of delivery, timing of therapeutic intervention, and relevance of the animal model of ALS to human patients. Therefore it will be of paramount importance to focus future treatments on pathogenic features seen solely in human ALS.

The importance of multidisciplinary management of ALS is supported by a recent report documenting improved prognosis in patients who received symptomatic care in addition to disease-modifying treatment with riluzole.

The Author
Pipeline was written by William Stow of Adis International (Springer Healthcare), using data derived from Adis R&D Insight and Clinical Trials Insight. For more information on Adis services, contact Daniela Ranzani on +39 02 423 4562 or email

27th November 2012

From: Research



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