In the run up to Christmas we are publishing summaries of the progress made this year towards treatments for muscular dystrophies and related neuromuscular conditions. This week we focus on the conditions that affect the motor neurons – spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS, also known as motor neurone disease or Lou Gehrig’s disease).

Spinal muscular atrophy
In recent years many SMA clinical trials have started and there are now multiple pharmaceutical companies in the race to develop treatments. There are now close to 20 potential treatments in the SMA drug pipeline – the latest news from the clinical trials is detailed below.

Olesoxime for SMA
A European phase 2 trial of olesoxime — a cholesterol-like compound that may protect nerve cells from damage — has produced promising results. The trial conducted by Trophos, a French pharmaceutical company, involved 165 people with SMA types 2 and 3 aged between three and 25 years. It showed that loss of motor function was prevented in those taking olesoxime for two years while those taking the placebo had the typical progressive loss of motor function. Participants taking the olesoxime also had fewer of the medical complications that are normally associated with SMA such as lower respiratory tract infections. The safety of olesoxime was also confirmed and Trophos plans to file for regulatory approval in both the US and Europe as soon as possible.

ISIS Pharmaceutical’s clinical trials
In the US, Isis Pharmaceuticals is currently testing a potential drug called ISIS-SMNRx in two clinical trials and results part-way through the phase 2 trials have recently been announced. ISIS-SMNRx is a therapy based on antisense oligonucleotides (AONs) — small pieces of genetic material that can specifically manipulate the way that the genetic code is read. The aim of using AONs for SMA is to encourage the cells to produce more of the SMN protein that is missing in people with SMA. It acts on SMN2 gene which is similar to the SMN1 gene that is missing in people with SMA. The SMN2 gene produces several different versions of the SMN protein; and unfortunately only small amounts of the full size and functional version. The AONs encourage the SMN2 gene to produce more of the full size SMN protein which is crucial for the survival of the motor neurons.

The first of the ongoing trials aims to test two different doses of ISIS-SMNRx in infants with SMA type 1 and the second aims to test four different doses in children with the less severe types 2 and 3 SMA. ISIS-SMNRx is injected into the fluid around the spinal cord (intrathecal injection). In both studies the results are encouraging with the children faring better than the typical course of the disease. Importantly, ISIS-SMNRx has been well tolerated.

The ISIS-SMNRx trials involve only a small number of participants and assessments have only been made over a short time period, so further clinical trials will be needed to further assess the safety and effectiveness. However, the results so far are encouraging enough for a phase 3 trial in infants to have already begun which will be conducted at 31 locations around the world including Melbourne and Sydney.

A phase 3 trial involving children aged 2 to 12 with types 2 and 3 SMA also started recruiting in November in the USA .

More information can be found in the ISIS press release.

Gene therapy clinical trial starts
In June 2014 a phase 1 clinical trial of gene therapy for SMA was started by US company Avexis Inc. in collaboration with researchers at Nationwide Children’s Hospital in Ohio. The therapy involves using a virus to introduce a healthy synthetic copy of the SMN1 gene into the motor neurons.

The trial will involve about nine babies with SMA type 1 younger than nine months of age. The infants will have a one-off injection of the gene therapy drug into their blood stream. Three of them have already received a low dose, and another six will soon receive a five-fold higher dose. The main objective of this trial is to assess safety, so side effects will be carefully monitored. Some preliminary data will also be collected on the effectiveness of the gene therapy but larger, longer term studies will be needed to thoroughly assess if the drug works. More information about this gene therapy trial.

A second trial for type 1 SMA-affected babies, in which the drug will be infused into the fluid around the spinal cord (called “intrathecal” delivery), is being planned for the first half of 2015; and a trial of for type 2 SMA patients is being considered for 2015.

Clinical trial of oral SMA drug started
On the 19th of November PTC Therapeutics (in partnership with Roche and the SMA Foundation) announced that it had started recruiting for its trial of a drug called RG7800. The drug, like the ISIS Pharmaceuticals drug described above, acts on the SMN2 gene to increase the amount of full length SMN protein produced. RG7800 is a small molecule drug which is taken by mouth. Most of the drugs currently on the market are small molecules so, unlike the innovative AON drugs being developed by ISIS, its development may be more straightforward.

An earlier, phase 1 study of RG7800 in healthy volunteers showed that all doses studied were safe, well tolerated and demonstrated a beneficial effect on SMN2 gene processing.

The new study will involve approximately 48 adults and children with SMA types 1, 2 or 3 aged 2 to 55 years of age. Planned study sites are located in the Netherlands, Switzerland and the UK. Participants will be randomly assigned to receive RG7800 or a placebo for 12 weeks. The main aim of the trial is to assess the safety of the drug and find the best dose for further trials. However, the amount of SMN protein in the blood will be measured and some tests of muscle function will also be done.

More information about the RG7800 trial.

Amyotrophic lateral sclerosis
The research into treatments for ALS is much more complex than for SMA as there is not just one cause. Only about 5 to 10 percent of cases have a genetic cause and at least five different genes are known to cause ALS in these families. For the remaining 90-95 percent, there is still a lot of speculation about the cause. Environmental factors such as exposure to certain viruses or toxins may play a role in conjunction with genetic factors that make some people more susceptible to developing ALS. So researchers are working to further understand the causes of ALS, what goes wrong in the motor neurons of people with ALS and develop potential treatments. Below are some of this year’s research highlights.

Improving drug effectiveness
Despite promising early-stage research, the majority of drugs in development for ALS have failed. Now researchers have uncovered a possible explanation. In a recent study researchers showed that the brain’s machinery for pumping out toxins works in overdrive in people with ALS and that this machinery also pumps out drugs designed to treat ALS, thereby decreasing their effectiveness. The work showed that when these pumps are blocked, the drug riluzole (currently the only drug available for ALS) becomes more effective at slowing the progression of the disease in mouse models. It is hoped that this research may be able to improve the effectiveness of riluzole (which currently only increases life expectancy by three to six months) and other treatments being developed.

Stem cell trial to start
Israeli biotechnology company BrainStorm Cell Therapeutics has started recruiting for a clinical trial to test a type of stem cell therapy in ALS patients in the USA. The procedure involves cells that the company calls “NurOwn” cells which are derived from the patient’s own bone marrow. Certain cells are isolated from the bone marrow and coaxed to develop into neuron-supporting cells which are injected back into the patient’s spinal cord and muscles. These cells secrete substances that may be able to protect existing motor neurons and promote motor neuron growth.

More information about the NurOwn clinical trial.

It is important to remember that no stem cell therapies have been proven safe and effective for ALS or any other neuromuscular condition. Please read our warning on stem cell therapies.

New insights into ALS gene
Researchers from John Hopkins University in the USA have unravelled more details of how the most common ALS gene – C9orf72 – causes ALS. Changes to this gene account for up to 40 percent of familial ALS and 6 percent of sporadic ALS. In these people the C9orf72 gene has an extra piece of repetitive genetic code which causes it to fold into unusual looped structures. As a result reduced amounts of protein are made from this gene and also other important proteins are trapped in these looped structures. This causes stress in the nucleus of the cell. These insights will be critical in designing therapies to interrupt these processes.

More ALS news:
• Research in the laboratory has shown that a modified version of the yeast protein “HSP104” might be able to break up the clumps of improperly folded proteins that are present in the cells of people with ALS.
• Medicinova Inc. has started recruiting in the USA for a clinical trial of MN-166 (ibudilast) in people with ALS. This anti-inflammatory drug is mainly used in the treatment of asthma and stroke and is also in clinical trial for MS.
• A phase 2 clinical trial in North America and Europe showed that the muscle-stimulating drug Tirasemtiv did not improve motor function in people with amyotrophic lateral sclerosis (ALS) but it may slow respiratory decline.
• A small clinical trial has shown that people with ALS who were tube fed a high carbohydrate, high calorie diet appeared to fair better than those on other diets. A larger trial is now needed to confirm this.

Further information
• The MDA’s SMA factsheets contain more information about the condition and include a research summary
Clinical trials – your questions answered
• For any terms you are unfamiliar with please take a look at our glossary

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Updated 3 July 2018