Unravelling the mysteries of motor neurone disease

Motor Neurone Disease (MND) is a debilitating neurodegenerative disease that affects the brain and spinal cord, leading to the death of the motor neurons that control muscle movement. The disease was first described in 1869 by Jean-Martin Charcot, the so-called ‘Father of Neurology’, who named it “la sclérose latérale amyotrophique” (amyotrophic lateral sclerosis).

MND causes messages from the nervous system to gradually stop reaching the muscles, leading them to weaken, stiffen and eventually waste. The progressive disease affects a patient’s ability to walk, talk, use their arms and hands, eat and even breathe.

Early research

In the 1940s and 1950s, researchers began to investigate the role of genetics in the disease. In 1955, the first case of familial or ‘inherited’ MND was reported, suggesting that the disease had a genetic contribution. Over the following few decades, more cases of familial MND were identified, leading to the discovery of several different genes associated with the disease.

One of the most significant breakthroughs in MND research came in the 1990s, with the discovery of a mutation in the gene coding for Superoxide dismutase 1 (SOD1). SOD1 is an enzyme whose mutant form is commonly associated with MND and appears to be responsible for approximately 20% of familial MND cases.

In the early 2000s, researchers made another important discovery when they identified mutations in the TARDBP gene, which is responsible for encoding a protein called TDP-43 that is found in the abnormal protein aggregates that are characteristic of MND. Mutations in this gene have been found in around 5% of familial cases.

More recently, mutations in the C9orf72 gene were identified as the most common genetic cause of MND, accounting for around 40% of familial cases. The C9orf72 gene encodes a protein that is present in different tissues. It is particularly abundant in neurons located in the cerebral cortex, the outer layers of the brain, as well as in specialized motor neurons found in the brain and spinal cord, which are responsible for controlling movement.

Although these three mutations account for the majority of inherited motor neurone disease cases, there are other genes that can contribute to the development of the disease.

It is currently thought that a number of genetic, environmental and lifestyle risk factors need to combine before most forms of MND develop. In combination, these risk factors may ‘tip the balance’ towards someone developing the disease.

Some key factors include: inherited genetic mutations; environmental factors such as exposure to certain chemicals, infections or trauma; oxidative stress; and glutamate excitotoxicity.

Current research and treatment

Whilst there is currently no cure for MND, researchers have continued in recent years to make important strides in the development of treatments which aim to manage symptoms, improve quality of life and prolong survival.

There is currently only one drug licensed in the UK to treat MND. The drug Riluzole (6-(trifluoromethoxy)-2-benzothiazolamine) works by suppressing the release of glutamate, a neurotransmitter that can damage motor neurons when present in high concentrations, and has been shown to extend survival by several months. Riluzole is described in U.S. Pat. No. 4,370,338 and its use in the treatment of motor nerve diseases is described in European Patent 558,861.

After the expiration of the original patent, other pharmaceutical companies were able to produce generic versions of Riluzole. A generic drug contains the same chemical substance as a drug that was originally protected by a patent and is permitted for sale after the patents on the original drugs expire.

While the original patent has expired, other patents related to Riluzole and its use in MND treatment are still in force. These additional patents cover aspects such as new formulations, improved delivery methods, or combination therapies.

New treatment

In recent news, last month another new drug Tofersen (developed by Biogen) was approved for medical use in the United States. In a study published in the New England Journal of Medicine, Tofersen was shown to slow disease progression in patients diagnosed with a specific form of MND known as SOD1-ALS. The drug is an antisense nucleotide that works by inactivating the mRNA coding for the SOD1 enzyme.

Tofersen was submitted and approved under the accelerated approval pathway, which was built to facilitate drug development for serious or life-threatening conditions. The move follows the recommendation from an FDA advisory committee in March.

Notably, the panel voted against full approval. This is because during the phase 3 Valor study, no benefit was observed over 28 days on the revised amyotrophic lateral sclerosis functional rating scale (ALSFRS-R) in either subgroup studied: those with fast-progressing disease – the primary analysis population – or slowly-progressing ALS.

Nonetheless, nine experts agreed that Tofersen’s ability to reduce plasma biomarkers of nerve injury and neurodegeneration provides enough basis for a conditional approval.

The European Medicines Agency (EMA) are currently reviewing the data around Tofersen to determine whether it is deemed fit for approval in the European Union. Once a decision is made by the EMA, the UK Medicines and Healthcare products Regulatory Agency (MHRA) may rely on this to inform their decision on regulatory approval of the treatment in the UK.

The process of bringing a drug to market involves extensive research and development, preclinical and clinical trials , regulatory approvals, and manufacturing. Additionally, there is a high failure rate, with many potential drugs not making it through the various stages of development. It typically takes 10 to 15 years and potentially billions of dollars to complete this process, with the high costs often attributed to the need for rigorous testing and safety measures, as well as the significant investment required for research and clinical trials.

Patenting is therefore absolutely essential for protecting the investment made in drug development and ensuring a return on that investment.

Barker Brettell has a dedicated medical sector group that can assist and advise you on how to achieve the best protection for your invention. To continue the conversation, please contact the author or your usual Barker Brettell patent attorney.