The journey of a drug – what it takes to be approved

Each year, the MND Association dedicates the month of June to raising MND awareness. This year, we focus on the eyes – in most people with MND the only part of their body they can still move and the only way left for them to communicate. Alongside the Association-wide campaign, the Research Development team selected six most-enquired about topics, which we will address through six dedicated blogs.

So far, there is no cure for MND. In the past 22 years, we have only seen approval of two drugs that were either shown to prolong the life of MND patients by several months (riluzole in 1995 in the US) or to slow down symptom progression (edaravone in 2015 in Japan). It is only reasonable that you might wonder ‘what is taking so long?’ or ‘why are there not more drugs available?’.

It is very competitive in the world of medicinal drugs. From thousands of chemical compounds that are gradually eliminated as they go through different stages of drug development, only one makes it near the finish line. This line represents approval for marketing authorisation and there is no guarantee that this ‘top compound’ will actually make it to the end. So let’s have a closer look at the individual stages that a potential drug has to go through in order to be crowned the champion. Continue reading

‘Hothouse’ meeting on drug discovery

Sadie’s recent post on the emerging partnership between Peakdale Molecular and the Sheffield Institute for Translational Neuroscience prompted me to say a little about last month’s Drug Discovery Workshop, held in Washington DC and organised our friends at the ALS Association.

I was fortunate to be invited along to this workshop, which brought together over 100 representatives from industry, academia, drug regulators and government and charitable funding agencies, to share their findings and discuss the future directions and opportunities for MND drug discovery. ‘Hothouse’ meetings like these are vital in giving those working in academic labs an important insight into the complexities of turning new knowledge of disease processes into ‘druggable’ compounds.

Those from industry get to see the new theories that are coming out of the academic labs, while the funders can start to identify where targeted early-stage support may help to encourage industry to follow up with the larger-scale investment needed to take ideas from bench to bedside At a time when some of the biggest drug companies are pulling back from working in neurodegeneration, the mood at the meeting might have been muted, but delegates were positively upbeat. One cause for optimism is that some companies, such as Biogen Idec, have seized the opportunity to fill the gap and increase their investment in this area.

Moreover, universities around the world have benefitted from an influx of new staff with extensive expertise in drug discovery, strengthening one of their historical areas of weaknesses. Universities are generally very good at unpicking the complex biological processes that occur in health and disease, but very poor at turning this knowledge into treatments. Another reason for the optimistic mood at the meeting was the clutch of new gene discoveries that occurred last year, in particular the identification of the chromosome 9 form of MND  which promises to open up many of new secrets of the disease. Researchers have collectively now found about two-thirds of all the causes of familial MND. As we identify more causes, generate better models and home in on the common cellular changes that drive the disease, the opportunities for drug development are going to increase.

Meetings such as this help focus attention on the major challenges – but also the exciting opportunities – that lie ahead.

Come fly with me

The Fly

The Fly. Courtesy of MND Association funded researcher Dr Frank Hirth, based at King's College London

Although millions of years of evolution separate humans from insects, a tiny fruit fly called Drosophila melanogaster has been one of the most extensively studied organisms for more than a century, leading to many advances in research. But why are flies so useful? And can we really learn anything from them?

Why fly?

It is easy to see that this fly has advantages in the laboratory. They are very small and easy to keep, but still large enough to study in detail with relatively simple microscopes. They breed easily from 10 days old, producing many genetically identical offspring from each mating. This makes it easy to study several generations over a matter of weeks.

Simple yet sophisticated

Although considered a simple species, the fly is actually quite sophisticated, with structures that are equivalent to organs such as the heart, kidneys and gut.  The brain and nervous system are considered particularly complex, making the fly valuable for the study of neurodegenerative diseases.

Genetically the fruit fly is also much simpler than a human – it has approximately half the number of genes that we do. But it’s not the number of genes you have that counts; it’s what you do with them!

Luckily, about three-quarters of the genes implicated in human disease have a related gene in the fly, with a high level of similarity between the two. Many methods and techniques have been developed, so researchers can switch the fly’s genes on and off at various points in its life-cycle, or in different parts of the body, and then observe the consequences.

MND fly research

Between 2004 and 2009, only about four scientific papers per year described studies using these fruit flies for MND research. In conjunction with the recent upsurge in genetic discoveries related to MND, there has been a rapid increase to twelve publications in 2010, and a further seven already in 2011.

The MND Association is a leader in funding and promoting cutting edge research and we are currently funding two PhD studentships making extensive use of the fruit fly. You can find out more about these projects on our website:

Understanding disease mechanisms of MND in the fruit fly

How does faulty TDP-43 affect MND in fruit flies?

Learning to fly toward drug discovery

There is considerable interest in using the fly to test potential drugs for MND, as there has been some success in this approach in other conditions.  Like the zebrafish model many more substances can be tested than would be possible with a mouse model, and the results may tell scientists more than a cell-based screen. However, this is not yet a routine approach to drug discovery – historically fruit flies have not been used in this way by pharmaceutical companies. It remains to be seen whether any promising compounds identified using fly models will actually progress to being drugs for the treatment of human diseases.    

For such an approach to be useful for MND, there needs to be a reliable and relevant fly model. Recently published work has been focussed on exploring the role of proteins known to be involved in MND such as TDP-43 and FUS. When they publish their work, researchers often hint that their models will be useful in the development of new treatments, even if this was not their main aim.

The use of the fly to discover new medicines may still be some way off, but we can be sure that the tiny fruit fly is already contributing to research in a very big way.